Search

Heat stress, as an environmental stressor, can lead to temperature dysregulation and neuroinflammation, causing depression and anxiety by disrupting brain physiology and functional connectivity. This study looked at how co-enzyme Q10 (Q10) and vitamin E (Vit E), alone and together, affected heat stress-caused anxiety and depression symptoms and inflammation in male mice. Five groups were utilized in the study: control, heat stress (NS), Q10, Vit E, and the combination group (Q10+Vit E). The mice were subjected for 15 min/day to a temperature of 43°C for 14 consecutive days, followed by daily treatments for two weeks with either normal saline, Q10 (500 mg/kg), Vit E (250 mg/kg), or their combination. The forced swimming test (FST) and tail suspension test (TST) were employed to evaluate despair behavior, whereas the elevated plus maze (EPM) and open field test (OFT) were used to assess anxious behaviors. Subsequently, the animals were sacrificed, and serum corticosterone levels, protein expression of inflammasome-related proteins, and hsp70 gene expression were evaluated in the prefrontal cortex (PFC). The study revealed that treatment with Vit E and Q10, alone or together, provided anxiolytic and antidepressant effects in the heat-stress-subjected animals. Also, giving Vit E and Q10 alone or together greatly lowered serum corticosterone levels. In the PFC, they also lowered the levels of hsp70 mRNA and NF-κB, caspase 1, NLRP3, and IL-1β proteins. It is speculated that treatment with Q10 and Vit E can attenuate heat stress-associated anxious and depressive responses by inhibiting the inflammatory pathways and modulating the hypothalamus-pituitary-adrenal axis., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for depression neurobiology. As the latest member of the RFamide peptide family in mammals, pyroglutamylated RFamide peptide (QRFP) is closely implicated in neuroendocrine maintenance by activating G-protein-coupled receptor 103 (GPR103). We hypothesized that QRFP and GPR103 might contribute to chronic stress-induced depression by promoting corticotropin-releasing hormone (CRH) release from neurons in the paraventricular nucleus (PVN), and various methods were employed in this study, with male C57BL/6J mice adopted as the experimental subjects. Chronic stress induced not only depression-like behaviors but also significant enhancement in QRFP and GPR103 in the PVN. Genetic overexpression of QRFP/GPR103 and stereotactic infusion of QRFP-26/QRFP-43 peptide in the PVN all mimicked chronic stress that induced various depression-like phenotypes in naïve mice, and this was mediated by promoting CRH biosynthesis and HPA activity. In contrast, genetic knockdown of QRFP/GPR103 in the PVN produced notable antidepressant-like effects in mice exposed to chronic stress. Furthermore, genetic knockout of QRFP also protected against chronic stress in mice. In addition, both the C-terminal biological region of QRFP and the downstream PKA/PKC-CREB signaling coupled to GPR103 stimulation underlie the role of QRFP and GPR103 in depression. Collectively, QRFP and GPR103 in PVN neurons could be viable targets for novel antidepressants., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest for this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The mycotoxin deoxynivalenol (DON) is highly prevalent in cereals as an immune stressor. The hypothalamic-pituitary-adrenal (HPA) axis is activated during periods of stress, and the organism is accompanied by inflammation. Necroptosis is a newly identified type of cell death. However, the relationship between necroptosis and HPA axis activation induced by DON is rarely reported. Our study aimed to explore the role played by necroptosis in HPA activation in a stress of piglet model produced by DON. Our results indicated that both feeding with a contaminated-DON diet (4 ppm) and DON injection at 0.8 mg/kg BW increased the concentration of plasma corticotropin-releasing hormone (CRH) and adrenocorticotrophic hormone (ACTH) and the mRNA expression of adrenal steroidogenic acute regulatory protein (StAR). Furthermore, the mRNA expression of pro-inflammatory cytokines and factors related to necroptosis in the hypothalamus, pituitary gland, and adrenal gland were increased. As an inhibitor of necroptosis, necrostatin-1 (Nec-1) inhibited necroptosis through decreasing mRNA expression of necroptosis signal factors in the HPA axis. Nec-1 also reduced the mRNA levels of pro-inflammatory cytokines in the HPA axis. Meanwhile, the activation of the HPA axis was inhibited by Nec-1 as shown by the decrease of plasma CRH and ACTH concentrations and the mRNA expressions of hypothalamus CRH and pituitary POMC. These findings indicated that as a result of necroptosis, the HPA axis was activated by DON. In light of these findings, necroptosis could be considered as an intervention target that alleviates HPA axis activation and stress responses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Pregnant people are widely exposed to numerous synthetic chemicals with known endocrine-disrupting properties (e.g., phthalates, phenols, per- and poly-fluoroalkyl substances (PFAS)). To date, most epidemiological research on how endocrine-disrupting chemicals (EDCs) disrupt hormone pathways has focused on estrogens, androgens, and thyroid hormones. Far less research has examined the impact of EDCs on the hypothalamic-pituitary-adrenal (HPA) axis, despite its central role in the physiologic stress response and metabolic function., Objective: To systematically review the epidemiological literature on prenatal synthetic EDC exposures in relation to HPA axis hormones (e.g., corticotropin-releasing hormone, adrenocorticotropic hormone, cortisol, cortisone) in pregnant people and their offspring., Methods: A literature search of PubMed, Scopus, and Embase was conducted. Primary research studies were selected for inclusion by two independent reviewers and risk of bias was assessed using the Office of Health Assessment and Translation guidelines established by the National Toxicology Program with customization for the specific research topic. Data were extracted from each study and included in a qualitative synthesis., Results: 22 published studies met the inclusion criteria. Phthalates were the most prevalent EDC studied, followed by PFAS, phenols, and parabens, with fewer studies considering other synthetic chemicals. Offspring glucocorticoids were the most commonly considered outcome, followed by maternal glucocorticoids and placental corticotropin-releasing hormone. There was considerable heterogeneity in methods across studies, particularly in HPA axis outcome measures and matrices, making cross-study comparisons challenging. Numerous studies suggested disruption of HPA axis hormones and sex differences in association, but results varied considerably across studies and EDC classes., Conclusions: The limited literature to date suggests the HPA axis may be vulnerable to disruption by synthetic EDCs. Carefully designed studies that prioritize biospecimen collection specific to HPA axis hormones are needed along with greater standardization of biospecimen collection and analysis protocols to facilitate cross-study comparisons and interpretation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Antioxidants that can scavenge reactive oxygen in the brain and inhibit hyperactivity of the HPA axis are desirable., Aims: We investigated the cerebral translocation of the antioxidant 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA) and the effects of DHMBA administration on the hypothalamus-pituitary-adrenal (HPA) axis in stress-loaded rats., Methods: Experiment 1: Plasma and brain DHMBA concentrations were measured over time after oral DHMBA administration to male B6 mice. Experiment 2: Female Wistar Imamichi rats were used. The normal group was not subjected to stress. The stress, DHMBA, and vitamin E groups were subjected to individual and overcrowding stress. Brain and hippocampal 8-hydroxy-2'-deoxyguanosine levels, hippocampal glucocorticoid receptor-α levels, plasma corticosterone levels and RNA levels of glutathione peroxidase 4, catalase, and glutathione reductase in the hippocampus were measured., Results: In Experiment 1, DHMBA was not detected in the plasma or brain before DHMBA administration but was detected in both after administration. In Experiment 2, brain and hippocampal 8-hydroxy-2'-deoxyguanosine levels and plasma corticosterone levels were significantly lower in the DHMBA than in the stress group. Glucocorticoid receptor-α levels were higher in the DHMBA than in the stress group. DHMBA increased RNA levels of antioxidant enzymes in the hippocampus., Conclusion: DHMBA was translocated to the brain after administration. DHMBA administration decreased 8-hydroxy-2'-deoxyguanosine levels in the brain and hippocampus, increased hippocampal glucocorticoid receptor-α levels, and decreased the plasma corticosterone concentration, suggesting that DHMBA inhibits hyperactivity of the HPA axis. Nrf2 pathway activity induced by DHMBA resulted in increased antioxidant enzyme levels in the hippocampus., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Part of this study was entrusted by Watanabe Oyster Laboratory Co., Ltd. to Material Research Center Co., Ltd., and conducted by Material Research Center Co., Ltd. The authors belong to Watanabe Oyster Laboratory Co., Ltd., and they had role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Watanabe Mitsugu reports a relationship with Watanabe Oyster Laboratory Co., Ltd., that includes: board membership and equity or stocks. Emiko Miki, Kuroki Katsuya and Kenji Yoshiike report a relationship with Watanabe Oyster Laboratory Co., Ltd., that includes: employment., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Post-traumatic stress disorder (PTSD) poses significant neurological and psychiatric challenges. Investigations into the glutamatergic system, particularly the N-methyl-D-aspartate (NMDA) receptor, are crucial for understanding PTSD mechanisms. This study aimed to evaluate the therapeutic potential of the non-competitive NMDA receptor antagonist memantine in mitigating PTSD symptoms and to explore its underlying cellular and molecular impacts. Male Sprague Dawley rats were subjected to inescapable foot shock stress (FS-stress) to model PTSD. Following stress exposure, memantine was administered at doses of 5 mg/kg and 10 mg/kg six hours post-stress. Behavioural assessments, including fear conditioning and sucrose preference tests, were conducted. Golgi-Cox staining was used to assess neuroanatomical changes related to synaptic plasticity. Western blotting was used to analyse molecular markers associated with synaptic plasticity, while immunoassays measured proinflammatory cytokines and cortisol levels. Memantine treatment improved behavioral outcomes, restoring sucrose preference and reducing freezing behavior. Morphological analysis demonstrated that memantine enhanced dendritic spine structure, particularly increasing the proportion of mature mushroom spines, which are critical for synaptic stability. Additionally, memantine normalized cortisol levels, suggesting a regulatory effect on the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, memantine treatment improved the inflammatory cytokine profile, reducing IL-6 and TNF-α levels. These results suggest that memantine has potential as a therapeutic intervention for PTSD by targeting critical pathways involved in stress responses.The findings indicate that memantine, an NMDA receptor antagonist, can counteract behavioral and functional disturbances induced by FS-stress., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Depression and osteoporosis are usually concurrent health problems. This study aimed to explore the development of osteoporosis in depressive mice model and investigate the beneficial effects of the classical herbal formula Chaihu-Shugan-San (CHSG) on the brain and bone., Methods: CHSG powder was prepared by spray-drying following extraction with water. The fingerprint of CHSG was analyzed using liquid chromatography. The depressive-like model was established by chronic unpredictable mild stress (CUMS) in female mice. The depressive behaviors and trabecular bone properties (measured by micro-CT) were detected at 2, 4, 6, and 8 weeks of CUMS. RT-PCR, immunoblotting and immunofluorescence were applied to measure expression of inflammatory cytokines and morphology of microglias in the hippocampus. Biochemical measurements and histological staining on the adrenal gland were carried out to assess the activity of hypothalamic-pituitary-adrenal (HPA) axis. Histological staining, three-point bending strength, and the expression of regulators involved in bone metabolism were determined., Results: The treatment with CHSG for 8 weeks could ameliorate depressive behaviors, and down-regulate mRNA expression and tissue content of inflammatory factors IL-1β and IL-6 in hippocampus of CUMS mice. The inhibition of CHSG on neuroinflammation might be attributed to its repression of activity in microglias and NLRP3-triggered inflammation pathway. The serum of rats dramatically alleviated LPS-induced phosphorylation of nuclear NFκB (P65) and IκBα and up-regulation of IL-1β and IL-6 proteins in microglia BV2 cells. CUMS induced over-activity of HPA axis shown by the elevation in serum level of ACTH and corticosterone and in area percentage of zona fasciculata, intriguingly, CHSG reversed those changes in HPA system, ameliorated the reduction in mechanical strength and bone mineral density, and regulated bone metabolism factors of CUMS mice., Conclusion: The chronic stress-induced depression resulted in bone disorders developing to osteoporosis. Chaihu-Shugan-San exerted beneficial effects on skeletal tissue by ameliorating neuroinflammation and HPA over-activity of mice with depression., Competing Interests: All authors declare that they have no competing interests., (© 2024 He et al.)

Depressive-cardiac disease is a comorbid state in which both cardiovascular diseases and mental disorders are present. Patients with depression are more likely to develop cardiovascular disease, which increases the risk of cardiovascular events, such as acute coronary syndrome. Cardiovascular diseases also exacerbate the poor mood of patients with psychiatric disorders. Kai-xin-san (KXS), a classic antidepressant formula, has potential antidepressive and cardioprotective effects. In the present study, we first evaluated the antidepressive and cardioprotective effects of KXS in two post-myocardial ischemic depressed rat models: a) isoproterenol (ISO) via intraperitoneal injection combined with chronic unpredictable mild stress (CUMS)-induced myocardial ischemia and depression and b) left anterior descending coronary artery ligation (LAD) combined with chronic restraint stress (CRS)-induced myocardial ischemia and depression. We then induced exogenous corticosterone in a rat model of depressive-cardiac disease. Our study revealed that chronic administration of corticosterone could induce depression-like syndromes accompanied by cardiac insufficiency. The potential mechanism involves parallel onset of HPA axis dysfunction and an imbalance in lipid metabolism. KXS treatment successfully reversed corticosterone-induced depression-like behaviors and cardiac insufficiency. The present study highlights the pivotal role of the HPA axis and lipid metabolism in the development of comorbid depression and cardiovascular disease. Thus, KXS could be a promising therapeutic option for depressive-cardiac disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Kisspeptin is an endogenous peptide hormone that is the most potent stimulator of the hypothalamo-pituitary-gonadal (HPG) axis. The HPG axis can be suppressed by the activation of the hypothalamo-pituitary-adrenal (HPA) axis. The physiological role of kisspeptin in the interaction of the HPG axis and the HPA axis is not fully understood yet. The purpose of the current study was to investigate the possible effects of peripheral injection (intraperitoneally) of kisspeptin on HPG axis and HPA axis activity as well. Adult male Wistar rats were randomly divided into seven groups as sham (control), kisspeptin (10 nmol), p234 (10 nmol), kisspeptin + p234, kisspeptin + antalarmin (10 mg/kg), kisspeptin + astressin2b (100 μg/kg), and kisspeptin + atosiban (0.250 mg/kg) (n = 10 each group). At the end of the experiment, the hypothalamus, pituitary gland, and serum samples of the rats were collected. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin and kisspeptin + astressin2b groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin, kisspeptin + antalarmin, kisspeptin + astressin2b, and kisspeptin + atosiban groups that compared to the control group. There was no a significant difference in corticotropic releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone and corticosterone concentrations among all groups. Moreover, no significant difference was found in the concentration of pituitary oxytocin. Our results suggest that peripheral kisspeptin injection induces an activation in the HPG axis, but not in the HPA axis in male rats., Competing Interests: Declarations. Conflict of interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2024. Akadémiai Kiadó Zrt.)

Congenital adrenal hyperplasia (CAH) is characterized by impaired adrenal cortisol production. Hydrocortisone (synthetic cortisol) is the drug-of-choice for cortisol replacement therapy, aiming to mimic physiological cortisol circadian rhythm. The hypothalamic-pituitary-adrenal (HPA) axis controls cortisol production through the pituitary adrenocorticotropic hormone (ACTH) and feedback mechanisms. The aim of this study was to quantify key mechanisms involved in the HPA axis activity regulation and their interaction with hydrocortisone therapy. Data from 30 healthy volunteers was leveraged: Endogenous ACTH and cortisol concentrations without any intervention as well as cortisol concentrations measured after dexamethasone suppression and single dose administration of (i) 0.5-10 mg hydrocortisone as granules, (ii) 20 mg hydrocortisone as granules and intravenous bolus. A stepwise model development workflow was used: A newly developed model for endogenous ACTH and cortisol was merged with a refined hydrocortisone pharmacokinetic model. The joint model was used to simulate ACTH and cortisol trajectories in CAH patients with varying degrees of enzyme deficiency, with or without hydrocortisone administration, and healthy individuals. Time-dependent ACTH-driven endogenous cortisol production and cortisol-mediated feedback inhibition of ACTH secretion processes were quantified and implemented in the model. Comparison of simulated ACTH and cortisol trajectories between CAH patients and healthy individuals showed the importance of administering hydrocortisone before morning ACTH secretion peak time to suppress ACTH overproduction observed in untreated CAH patients. The developed framework allowed to gain insights on the physiological mechanisms of the HPA axis regulation, its perturbations in CAH and interaction with hydrocortisone administration, paving the way towards cortisol replacement therapy optimization., Competing Interests: Declarations. Conflict of interest: D.B., R.M., L.A. and M.J.W. have no conflict of interest. U.N. received a consultant and presentation fee from Diurnal Ltd., O.B. received a presentation fee from Diurnal Ltd., R.R. is a consultant to Neurocrine (Diurnal Ltd.). C.K. and W.H. report grants from an industry consortium (AbbVie Deutschland GmbH & Co. K.G., Astra Zeneca, Boehringer Ingelheim Pharma GmbH & Co. K.G., F. Hoffmann-La Roche Ltd., Merck KGaA, Novo Nordisk, and Sanofi) for the PharMetrX PhD program. C.K. reports an additional grant from the Innovative Medicines Initiative-Joint Undertaking (‘DDMoRe’), grants from the Federal Ministry of Education and Research within the Joint Programming Initiative on Antimicrobial Resistance Initiative (JPIAMR) and from the European Commission within in the Horizon 2020 framework programme (“FAIR”), all outside the submitted work., (© 2024. The Author(s).)

Rationale: Premenstrual dysphoric disorder (PMDD) is characterized by severe affective symptoms during the luteal phase of the menstrual cycle. There is some evidence of altered interactions between the hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary adrenal (HPA) axes in PMDD. There is also evidence that similar affective disorders such as major depression and perinatal depression are associated with dysregulation in immune factors, but this has not been characterized in PMDD., Aims: The goals of this exploratory study were to identify 1) whether HPA-HPG axis interactions and immune markers differ between PMDD patients and controls across the menstrual cycle; 2) how luteal phase sertraline treatment impacts stress and inflammatory markers., Methods: Participants were females age 18-50 with regular menstrual cycles, not using psychotropic or hormonal medications, and were assigned to a control group or PMDD group based on prospective daily symptom ratings and clinical interview. Blood was drawn in the follicular and luteal phases, during laboratory sessions involving a mildly stressful task. In a second luteal phase, PMDD participants received open-label sertraline (50 mg/d) from ovulation to menses. Serum cortisol and ACTH were measured via ELISA and operationalized as area under the curve with respect to ground (AUCg), and peak level following laboratory task. Serum TNF-α, IL-6, CXCL-8, and IL-1β were measured using multiplex kits. Serum allopregnanolone (ALLO) was measured by gas chromatography/mass spectroscopy. To characterize HPA-HPG axis interactions across the menstrual cycle in PMDD participants and controls, multilevel linear models predicted cortisol and ACTH from the interaction of cycle phase (controlling for sertraline treatment), ALLO, and group. To determine the effects of sertraline treatment on inflammatory markers and how groups might differ in cyclical change on each marker, multilevel linear models predicted inflammatory markers from cycle phase (controlling for sertraline treatment) and group. A final set of exploratory models tested whether inflammatory markers predict premenstrual symptom score severity., Results: The sample included n=77 participants (41 controls, 36 PMDD); 28 participants with PMDD completed sertraline treatment. Group x phase x ALLO interactions showed that higher ALLO levels predicted lower cortisol peak in the treated luteal phase (interaction between phase and ALLO, p=0.042), and there was a higher cortisol peak in the treated luteal phase than the untreated luteal phase (p=0.038). CXCL-8 was significantly associated with premenstrual symptom severity after controlling for group and cycle phase (p=0.011). There were no main effects of group, phase, or ALLO on cortisol AUCg, ACTH AUCg, IL-6, CXCL-8, IL-1β, nor TNF-α (p's>0.05)., Conclusion: Serum markers of HPA axis and immune function did not vary by menstrual cycle phase nor PMDD status. However, sertraline treatment in the luteal phase was associated with higher ALLO levels predicting lower cortisol peak in response to mild laboratory stress, suggesting that sertraline treatment may normalize HPG-HPA axis interactions among individuals with PMDD. Greater premenstrual symptomatology was associated with higher levels of the inflammatory marker CXCL-8, but further research is needed into the potential role of inflammation in PMDD., Competing Interests: Declaration of Competing Interest ALM holds a provisional patent on the anti-inflammatory effects of allopregnanolone and related neurosteroids, and has current and previous funding from Sage Therapeutics related to the anti-inflammatory actions of allopregnanolone. LH has consulted for PureTech Health and Flo Health. JLP has research funding from NIMH and Janssen Pharmaceuticals; served as a consultant to SAGE Therapeutics, Biogen, Merck, Brii Biologics, Pure Tech, Dionysus Health, and Flo Health; speaker for employees of Karuna Therapeutics; founder’s stock in Dionysus Health; two patents: “Epigenetic Biomarkers of Postpartum Depression” and “Epigenetic Biomarkers of PMDD and SSRI Response.” LMO reports no conflicts of interest, but has research funding from NIMH and NICHD and receives royalties and editorial fees from APA Publishing, Elsevier, and UpToDate., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Wuling capsule, composed of the traditional Chinese medicine Wuling mycelia powder, is made by fermenting and processing Xylaria nigripes (Kl.) Sacc. Clinically, it is commonly used to alleviate depression and anxiety. However, the mechanisms through which Wuling capsule exerts its therapeutic benefits have not been clearly defined., Aim of the Study: This study aims to elucidate the mechanisms by which Wuling capsule alleviates depression and anxiety like behaviors induced by chronic social defeat stress (CSDS) in mice., Materials and Methods: High-performance liquid chromatography-tandem mass spectrometry system was used to identify the components of the Wuling capsule. Mice were subjected to CSDS to induce depression and anxiety-like behaviors. The expression of hypothalamic corticotropin-releasing hormone (CRH) and Nesfatin-1, as well as serum levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were quantified. Behavioral assessments included the open field test, elevated plus maze, sucrose preference test, and forced swim test to evaluate depression and anxiety levels. Specific manipulation of Nesfatin-1 in the paraventricular nucleus of the hypothalamus (PVN) or cells was achieved through stereotaxic virus injection or plasmid transfection. Intracerebral cannula implantation was used for PVN-specific drug administration., Results: A total of 123 different components were identified in Wuling capsule. CSDS induced depression and anxiety-like behaviors in mice, along with hyperactivation of the HPA axis, increased hypothalamic Nesfatin-1 levels, and elevated nuclear factor kappa-B (NF-κB) phosphorylation. Overexpression of Nesfatin-1 in the hypothalamus mimicked the effects of CSDS. Conversely, knockdown of hypothalamic Nesfatin-1 or PVN-specific administration of Nesfatin-1 antibody or NF-κB antagonist mitigated CSDS-induced depression and anxiety-like behaviors and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. In neuroblastoma-2a (N2a) cells, overexpression of Nesfatin-1 led to increased NF-κB phosphorylation and CRH levels, whereas knockdown of Nesfatin-1 produced the opposite effects. Treatment with Wuling capsule alleviated CSDS-induced depression and anxiety-like behaviors, HPA axis hyperactivity, and activation of the hypothalamic Nesfatin-1/NF-κB pathway., Conclusions: The hypothalamic Nesfatin-1/NF-κB pathway plays a significant role in depression by modulating the HPA axis and is involved in the antidepressant and anxiolytic effects of Wuling capsule., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Depression weakens antitumor immunity, yet the underlying mechanisms linking depression and tumor growth remain unclear. This study examines the influence of depression on the hypothalamic-pituitary-adrenal (HPA) axis, immunological function, and effectiveness of immunotherapy in triple-negative breast cancer (TNBC) patients., Methods: A mouse model of comorbid TNBC and depression was established via chronic restraint stress (CRS) and 4T1 tumor transplantation. A programmed cell death ligand 1 (PD-L1) inhibitor was used to manage mice with TNBC, and the ability of metyrapone to reverse the immune system changes induced by HPA axis activation in depression was evaluated. Mouse peripheral blood was used to measure HPA axis activity, immune cell numbers and cytokine levels., Results: Depression activates the HPA axis, leading to increased levels of glucocorticoids. Depression led to an increase in the B-cell number and a reduction in the CD4 + T-cell and CD8 + T-cell numbers, without a statistically significant difference in the regulatory T (Treg) cell number. Furthermore, depression increased the levels of the cytokines interferon-gamma (IFN-γ), interleukin (IL)-1β, IL-4, IL-6, IL-8, and tumor necrosis factor (TNF)-α while decreasing the levels of IL-2 and IL-10. Similar results were observed in the context of PD-L1 inhibitor therapy. The depressed mice presented an increased tumor burden and a poor response to the PD-L1 inhibitor. The application of metyrapone during PD-L1 inhibitor treatment resulted in partial restoration of these depression-related alterations., Conclusions: Depression reduces the effectiveness of PD-L1 inhibitors by altering the number of immune cells and the levels of cytokines through activation of the HPA axis., Translational Relevance: Depression is common in breast cancer patients and is associated with reduced antitumor immunity. There is limited knowledge regarding the specific mechanisms through which depression impairs antitumor immunity. Immunotherapy, which promotes the restoration of antitumor immunity, represents a promising treatment strategy for TNBC patients. However, the efficacy of immunotherapy can be compromised by depressive symptoms and the administration of glucocorticoids during treatment. It is still uncertain whether increasing glucocorticoid levels can reduce the efficacy of immunotherapy in patients with depression. The potential benefits of combining immunotherapy with glucocorticoid inhibitors compared with immunotherapy alone need to be evaluated for TNBC patients with concurrent depressive symptoms. Therefore, further clarification of the specific mechanisms by which depression impairs antitumor immunity is needed to inform future optimization of immunotherapy strategies., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The hypothalamus-pituitary-adrenal axis (HPA axis) and the sympathetic-adrenal-medullary system (SAM system), two neuroendocrine systems associated with the stress response, have often been implicated to modulate decision-making in various domains. This systematic review summarizes the scientific evidence on the effects of pharmacological HPA axis and SAM system modulation on decision-making. We found 6375 references, of which 17 studies fulfilled our inclusion criteria. We quantified the risk of bias in our results with respect to missing outcome data, measurements, and selection of the reported results. The included studies administered hydrocortisone, fludrocortisone (HPA axis stimulants), yohimbine, reboxetine (SAM system stimulants), and/or propranolol (SAM system inhibitor). Integrating the evidence, we found that SAM system stimulation had no impact on risk aversion, loss aversion or intertemporal choice, while SAM system inhibition showed a tentative reduction in sensitivity to losses. HPA axis stimulation had no effect on loss aversion or reward anticipation but likely a time-dependent effect on decision under risk. Lastly, combined stimulation of both systems exhibited inconsistent results that could be explained by dose differences (loss aversion) and sex differences (risk aversion). Future research should address time-, dose-, and sex-dependencies of pharmacological effects on decision-making., (© The Author(s) 2024. Published by Oxford University Press.)

Excessive stress can exceed the adjustment ability of body and cause injury and dysfunction, while elucidation of the mechanism and prevention measures of stress-related injury are still insufficient. The present study was to observe the effect of glucocorticoid (GC) on stress-induced hypothalamic nerve injury and elucidate the potential mechanism. The present study intended to establish a chronic restraint stress rat model for follow-up study. Open field test and elevated plus maze test were used to observe behavioral changes of stress rats; Enzyme-linked immunosorbent assay (ELISA) was used to detect changes in the levels of hypothalamus-pituitary-adrenal (HPA) axis-related hormones and inflammatory factors in hypothalamus; toluidine blue staining was used to observe pathological changes of hypothalamus. The results showed that stress rats showed obvious anxiety-like behaviors, the levels of HPA axis-related hormones and inflammatory factors showed abnormal fluctuations, and morphological results showed significant nerve injury in hypothalamus. Low-dose GC treatment significantly improved behavioral changes, alleviated hypothalamic nerve injury, and restored hypothalamic levels of inflammatory factors, serum levels of GC, corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH) and GC level in adrenal cortex of stressed rats, while GC receptor (GR) inhibitor, CRH receptor inhibitor, and adrenalectomy reversed the ameliorative effects of low-dose GC. Our study clarified that low-dose GC can restore stress coping ability by reshaping the homeostasis of the HPA axis, thus alleviating behavioral abnormalities and hypothalamic nerve injury in stressed rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Context: Glucocorticoids suppress the hypothalamic-pituitary-adrenal (HPA) axis, resulting in tertiary adrenal insufficiency (AI). When weaning patients off glucocorticoids there is no consensus on whether to maintain patients on prednisolone or convert to hydrocortisone., Objective: To investigate HPA axis recovery in patients on long-term prednisolone and assess outcome after hydrocortisone conversion., Methods: This was a retrospective cohort study at an outpatient endocrine steroid clinic. Patients were on long-term prednisolone and referred for HPA axis testing between 2015 and 2022. The main outcomes measured were (1) HPA axis recovery rate in patients on prednisolone demonstrated by a normal adrenocorticotrophic hormone (ACTH) stimulation test (AST) and (2) HPA axis recovery rate subanalysis of dose-matched patients with confirmed tertiary AI on prednisolone or hydrocortisone were measured., Results: In total, 206 patients on prednisolone were tested for tertiary AI. Of these, 176 remained on prednisolone while 30 were converted to hydrocortisone. The overall HPA axis recovery rate for patients on prednisolone after interval testing was 137/206 (66.5%). The HPA axis recovery rate in dose-matched prednisolone and hydrocortisone conversion groups was 7/10 (70%) and 2/13 (15%) (P = .008), respectively. There was no difference in mean (SD) age (67.1 [12.2] vs 63.4 [11.1] years; P = .464) and baseline cortisol (5.3 [4.2] vs 4.6 [3.1] µg/dL; P = .648) and median [interquartile, IQR] glucocorticoid duration (1213 [1114] vs 2316 [4808] days; P = .693) and baseline ACTH (20.5 [29.0] vs 16.3 [14.8] ng/L; P = .905) between dose-matched prednisolone and hydrocortisone groups. Follow-up duration in the prednisolone group was significantly lower (median [IQR] 348 [975] vs 667 [884] days; P = .012)., Conclusion: Patients with glucocorticoid-induced AI maintained on once-daily prednisolone can recover HPA axis function when weaning. There is no apparent advantage to recover HPA axis function in converting to multiple-dosing hydrocortisone., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Depressive pseudodementia (DPD) is a debilitating cognitive dysfunction that accompanies major and/or frequent depressive attacks. DPD has gained significant research attention owing to its negative effects on the patients' quality of life and productivity. This study tested the procognitive potential of Flibanserin (FBN), the serotonin (5HT) receptor modulator, against propranolol (PRP), as β/5HT1A receptors blocker. Serving this purpose, female Wistar Albino rats were subjected to chronic unpredictable stress (CUS) and subsequently treated with FBN only (3 mg/kg/day, p.o), PRP only (10 mg/kg/day, p.o), or PRP followed by FBN, using the same doses. FBN ameliorated the behavioral/cognitive alterations and calmed the hypothalamic-pituitary-adrenal (HPA) axis storm by reducing the levels of stress-related hormones, viz, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT) parallel to epinephrine (EPI) hyperstimulation. The maladaptive inflammatory response, comprising of interleukin (IL)-1β/6, and tumor necrosis factor (TNF)-α, was consequently blunted. This was contemporaneous to the partial restoration of the protein kinase-B (AKT)/glycogen synthase kinase (GSK)3β/signal transducer and activator of transcription (STAT)-3 survival trajectory and the reinstatement of the levels of brain derived neurotrophic factor (BDNF). Microscopically, FBN repaired the hippocampal architecture and lessened CD68/GFAP immunoreactivity. Pre-administration of PRP partially abolished FBN effect along the estimated parameters, except for 5HT2A receptor expression and epinephrine level, to prove 5HT1A receptor as a fulcrum initiator of the investigated pathway, while its sole administration worsened the underlying condition. Ultimately, these findings highlight the immense procognitive potential of FBN, offering a new paradigm for halting DPD advancement via synchronizing adrenergic/serotonergic circuitry., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Early postnatal administration of antibiotics has been linked to lasting effects on brain development and behavior. Research conducted on animals that are free from germs has demonstrated that the impact of microbiome colonization on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and neuroendocrine pathways is substantial, which play a crucial role in stress management. Nevertheless, it is still uncertain if the exposure to antibiotics in rat dams (F0-generation) before weaning is associated with neurobehavioral changes in rat offspring (F1-generation) during adulthood. In order to investigate the effects, we perturbed the intestinal microbiota of rat dams (F0 generation) by administering cefixime (CEF), an antibiotic commonly used for obstetric purposes, at clinically relevant doses (1 mg/kg, 2.5 mg/kg or 5 mg/kg). Anxiety-like behaviors in adult offspring was evaluated through the utilization of elevated plus maze (EPM) and open field paradigm (OFP) following a six-week interval from birth (PND42). Subsequent to behavioral assessments, the rats were euthanized, and their brains and blood was collected for biochemical analysis. Plasma corticosterone concentration was used to assess HPA activity, whereas the quantitative real-time polymerase chain reaction (PCR) was employed to determine the transcription levels of the glucocorticoid receptor (GR) Nr3c1. The offspring of F1 that were administered antibiotics before being weaned spent less time in the EPM open arm. The alterations were accompanied by increased levels of corticosterone in the bloodstream. The gene expression study revealed a decrease in the levels of mRNA transcription of Nr3c1. This research emphasizes the possible long-term effects of antibiotic exposure before weaning on the development of anxiety in offspring upon adulthood.

Depression, which affects millions of individuals worldwide, is associated with glucocorticoid (GC) impairment, with the FKBP51 protein playing a pivotal role. Ginsenosides, extracted from the root of Panax ginseng C.A. Mey, have demonstrated the potential to mitigate depression associated with GC dysregulation. This study evaluated the therapeutic efficacy of ethanol extract of P. ginseng (PG) in treating depression and its underlying FKBP51-linked mechanism. Using chronic unpredictable stress, a depression model was developed in Kunming mice to test the efficacy of PG by observing changes in behaviors and protein expression in depressed mice. The mechanism of action was investigated through transfection with HEK293T cells. Depressed mice treated with PG demonstrated notable improvements: the rate of weight loss was reduced, sucrose preference and open-field activity were enhanced, and the rate of apoptosis in hippocampal cells was decreased. Additionally, the HPA axis function appeared to be restored. These physiological adjustments coincided with an increase in GR levels and a decrease in FKBP51 levels. Altogether, these results suggested that PG treatment effectively alleviates depressive symptoms in mice. PG also moderated FKBP51-GR interaction, lessening FKBP51's restraint on GR nuclear entry. This modulation may enhance the sensitivity of the GR response, reinforcing the negative feedback regulation of the HPA axis and thereby reducing depressive symptoms in mice. These findings highlight the potential of PG as a promising curative treatment for depression, providing a basis for the development of innovative treatments targeting the FKBP51-GR pathway., (© 2024 John Wiley & Sons Ltd.)

Depression is a debilitating mood disorder that causes persistent feelings of sadness, emptiness, and a loss of joy. However, the clinical efficacy of representative drugs for depression, such as selective serotonin reuptake inhibitors, remains controversial. Therefore, there is an urgent need for more effective therapies to treat depression. Neuroinflammation and the hypothalamic-pituitary-adrenal (HPA) axis are pivotal factors in depression. Inulae Flos (IF), the flower of Inula japonica Thunb, is known for its antioxidant and anti-inflammatory effects. This study explored whether IF alleviates depression in both in vitro and in vivo models. For in vitro studies, we treated BV2 and PC12 cells damaged by lipopolysaccharides or corticosterone (CORT) with IF to investigate the mechanisms of depression. For in vivo studies, C57BL/6 mice were exposed to chronic restraint stress and were administered IF at doses of 0, 100, and 300 mg/kg for 2 weeks. IF inhibited pro-inflammatory mediators, such as nitric oxide, inducible nitric oxide synthase, and interleukins in BV2 cells. Moreover, IF increased the viability of CORT-damaged PC12 cells by modulating protein kinase B, a mammalian target of the rapamycin pathway. Behavioral assessments demonstrated that IF reduced depression-like behaviors in mice. We found that IF reduced the activation of microglia and astrocytes, and regulated synapse plasticity in the mice brains. Furthermore, IF lowered elevated CORT levels in the plasma and restored glucocorticoid receptor expression in the hypothalamus. Collectively, these findings suggest that IF can alleviate depression by mitigating neuroinflammation and recovering dysfunction of the HPA-axis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Diet-related factors are of great significance in the regulation of hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonad (HPG) axes. In this study, we aimed to investigate the effects of chronic exposure to a high fat diet (HFD), fructose or sucralose on the endocrine functions., Methods: Male, Sprague-Dawley rats received a normal chow diet, HFD, 10% fructose or 0.02% sucralose for 10 weeks. Behavioral changes were assessed by open field (OFT) and elevated plus-maze (EPM) tests at week 8. H&E staining was used to observe pathological changes in adrenal cortex, testis and perirenal adipose tissue. Serum hormone concentrations were quantified via enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of genes along the HPA and HPG axes were determined using real-time PCR., Results: All types of dietary interventions increased body weight and disturbed metabolic homeostasis, with anxiogenic phenotype in behavioral tests and damage to cell morphology of adrenal cortex and testis being observed. Along the HPA axis, significantly increased corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT) concentrations were observed in the HFD or 0.02% sucralose group. For HPG axis, gonadotropin-releasing hormone (GnRH) and estradiol (E2) concentrations were significantly increased in all dietary intervention groups, while decreased concentrations of follicle-stimulating hormone (FSH) and testosterone (T) were also detected. Moreover, transcriptional profiles of genes involved in the synthesis of hormones and corresponding hormone receptors were significantly altered., Conclusion: Long-term consumption of HFD, fructose or sucralose manifested deleterious effects on endocrine system and resulted in the dysregulation of HPA and HPG axes., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: As the second most risky environmental pollution, noise imposes threats to human health. Exposure to high-intensity noise causes hearing impairment, psychotic disorders, endocrine modifications. The relationship among low-intensity noise, obesity and lipid-regulating nuclear factor PPARα is not yet clear., Methods: In this study, male wild-type (WT) and Pparα-null (KO) mice on a high-fat diet (HFD) were exposed to 75 dB noise for 12 weeks to explore the effect of low-intensity noise on obesity development and the role of PPARα. 3T3-L1 cells were treated with dexamethasone (DEX) and sodium oleate (OA) to verify the down-stream effect of hypothalamic-pituitary-adrenal (HPA) axis activation on the adipose tissues., Results: The average body weight gain (BWG) of WT mice on HFD exposed to noise was inhibited, which was not observed in KO mice. The mass and adipocyte size of adipose tissues accounted for the above difference of BWG tendency. In WT mice on HFD, the adrenocorticotropic hormone level was increased by the noise challenge. The aggravation of fatty liver by noise exposure occurred in both mouse lines, and the transport of hepatic redundant lipid to adipose tissues were similar. The lipid metabolism in adipose tissue driven by HPA axis accorded with the BWG inhibition in vivo, validated in 3T3-L1 adipogenic stem cells., Conclusion: Chronic exposure to low-intensity noise aggravated fatty liver in both WT and KO mice. BWG inhibition was observed only in WT mice, which covered up the aggravation of fatty liver by noise exposure. PPARα mediates the activation of HPA axis by noise exposure in mice on HFD. Elevated adrenocorticotropic hormone (ACTH) promoted lipid metabolism in adipocytes, which contributed to the disassociation of BWG and fatty liver development in male WT mice. Summary of PPARα suppresses noise-induced body weight gain in mice on high-fat-diet. Chronic exposure to low-intensity noise exposure inhibited BWG by PPARα-dependent activation of the HPA axis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Biological sex affects the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, how androgen deprivation affects this axis remains largely unknown. In this study, we investigated the effect of androgen status on different components of the HPA axis in male mice. Two weeks of androgen deprivation did not affect total plasma corticosterone levels but led to increased pituitary ACTH levels. Stress-induced total plasma corticosterone levels were increased, whereas the suppression of corticosterone after dexamethasone treatment under basal conditions was attenuated. Androgen-deprived mice displayed a 2-fold increase in plasma levels of corticosteroid binding globulin (CBG). A similar increase in CBG was observed in global androgen receptor knock-out animals, compared to wild-type littermates. Androgen deprivation was associated with a 6-fold increase in CBG mRNA in the liver and enhanced transcriptional activity at CBG regulatory regions, as evidenced by increased H3K27 acetylation. We propose that the induction of CBG as a consequence of androgen deprivation, together with the unaltered total corticosterone levels, results in lower free corticosterone levels in plasma. This is further supported by mRNA levels of androgen-independent GR target genes in the liver. The reduction in negative feedback on the HPA axis under basal condition would suffice to explain the enhanced stress reactivity after androgen deprivation. Overall, our data demonstrate that, in mice, tonic androgen receptor activation affects CBG levels in conjunction with effects on gene expression and HPA-axis reactivity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Schizophrenia (SCH) is a mental disorder that requires long-term antipsychotic treatment. SCH patients are thought to have an increased sensitivity to stress. The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, observed in SCH, could include altered levels of glucocorticoids, glucocorticoid receptors (GRs), and associated proteins. The perinatal administration of phencyclidine (PCP) to rodents represents an animal model of SCH. This study investigated the effects of perinatal PCP exposure and subsequent haloperidol/clozapine treatment on corticosterone levels measured by ELISA and the expression of GR-related proteins (GR, pGR, HSP70, HSP90, FKBP51, and 11β-Hydroxysteroid dehydrogenase-11β-HSD) determined by Western blot, in different brain regions of adult rats. Six groups of male rats were treated on the 2nd, 6th, 9th, and 12th postnatal days (PN), with either PCP or saline. Subsequently, one saline and one PCP group received haloperidol/clozapine from PN day 35 to PN day 100. The results showed altered GR sensitivity in the rat brain after PCP exposure, which decreased after haloperidol/clozapine treatment. These findings highlight disturbances in the HPA axis in a PCP-induced model of SCH and the potential protective effects of antipsychotics. To the best of our knowledge, this is the first study to investigate the effects of antipsychotic drugs on the HPA axis in a PCP animal model of SCH.

Stressful life event is closely associated with depression, thus strategies that blunt or prevent the negative effect stress on the brain might benefits for the treatment of depression. Although previous study showed the role of protein kinase R (PKR)-like ER kinase (PERK) in inflammation related depression, its involvement in the neuropathology of chronic stress induced depression is still unknown. We tried to explore whether block the PERK pathway would alleviate the animals' depression-like behavior induced by chronic restraint stress (CRS) and investigate the underlying mechanism. The CRS-exposed mice exhibited depression-like behavior, including anhedonia in the sucrose preference test (SPT), and increased immobility time in tail suspension test (TST) and forced swim test (FST). ISRIB administration for 2 weeks significantly improved the depression-like behavior in male mice exposed to CRS, which was manifested by markedly increasing the sucrose preference and reducing the immobility time in the FST and TST. However, we observed that exposure to the same dose of ISRIB in CRS female mice only showed improved anhedonia-like deficits,leaving unaltered improvement in the FST and TST. Mechanically, we found that ISRIB reversed the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, indicating decreased levels of serum corticosterone, reduced hippocampal glucocorticoidreceptor (GR) expression and expression of FosB in hypothalamic paraventricularnucleus (PVN), which was accompanied by preserved hippocampal neurogenesis. The present findings further expand the potential role of ER stress in depression and provide important details for a therapeutic path forward for PERK inhibitors in mood disorders., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to report, nor any involvements to disclose, financial or otherwise, that may bias the conduct, interpretation or presentation of this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tao-Hong-Si-Wu-Tang (THSWT), a traditional Chinese herbal remedy, is commonly utilized for the treatment of female perimenopausal depression through regulating menstruation, but the mechanism remains unknown. In this study, ICR mice were randomly divided into six groups: low, medium, and high dose of THSWT (0.5, 1.5, and 4.5 g/kg), soy isoflavone (250 mg/kg), ovariectomy group, and control group. All mice, except the control group, had ovaries removed and were exposed to hypoxic stimulation for 28 days to establish a perimenopausal depression mice model. The mice, having unrestricted access to food and water, were administered THSWT treatment for a duration of 14 days. The Western blotting and Enzyme linked immunosorbent assay kits were used to determine protein and hormone levels, respectively. Experimental results showed that THSWT reduced the immobility time of mice from 150.8 s to 104.9 s in the tail suspension test, and it decreased the immobility time of mice from 165.7 s to 119.0 s in the forced swimming test, outperforming the results obtained with soy isoflavones. In addition, THSWT upregulated the protein expression of follicle-stimulating hormone receptor and downregulated the protein expression of corticotropin-releasing hormone-receptor 1 in the hippocampus. Compared with the oophorectomized group, treatment with THSWT decreased the levels of corticosterone and adrenocorticotropic hormone in serum by 173.7 and 23.4 ng/mL, respectively. These findings showed that THSWT could stimulate the perimenopausal nerve tissue and regulate the level of serum hormones in mice. THSWT exhibited promising potential as a viable alternative drug for hormone treatment of perimenopause in clinical use.

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is linked to the pathophysiology of depression. Although exogenous adrenocorticotropic hormone (ACTH) is associated with a depressive-like phenotype in rodents, comprehensive neurobehavioral and mechanistic evidence to support these findings are limited. Sprague-Dawley rats (male, n = 30; female, n = 10) were randomly assigned to the control (male, n = 10) or ACTH (male, n = 20; female n = 10) groups that received saline (0.1 ml, sc.) or ACTH (100 μg/day, sc.), respectively, for two weeks. Thereafter, rats in the ACTH group were subdivided to receive ACTH plus saline (ACTH&#95;S; male, n = 10; female, n = 5; 0.2 ml, ip.) or ACTH plus imipramine (ACTH&#95;I; male, n = 10; female, n = 5;10 mg/kg, ip.) for a further four weeks. Neurobehavioral changes were assessed using the forced swim test (FST), the sucrose preference test (SPT), and the open field test (OFT). Following termination, the brain regional mRNA expression of BDNF and CREB was determined using RT-PCR. After two-weeks, ACTH administration significantly increased immobility in the FST (p = 0.03), decreased interaction with the center of the OFT (p < 0.01), and increased sucrose consumption (p = 0.03) in male, but not female rats. ACTH administration significantly increased the expression of BDNF in the hippocampus and CREB in all brain regions in males (p < 0.05), but not in female rats. Imipramine treatment did not ameliorate these ACTH-induced neurobehavioral or molecular changes. In conclusion, ACTH administration resulted in a sex-specific onset of depressive-like symptoms and changes in brain regional expression of neurotrophic factors. These results suggest sex-specific mechanisms underlying the development of depressive-like behavior in a model of ACTH-induced HPA axis dysregulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: It has been reported that central adrenal insufficiency (CAI) in pediatric patients (pts) with Prader-Willi syndrome (PWS) may be a potential cause of their sudden death. In addition, the risk of CAI may increase during treatment with recombinant human growth hormone (rhGH)., Objective: To prevent both over- and undertreatment with hydrocortisone, we evaluated the prevalence of CAI in a large multicenter cohort of pediatric pts with PWS analyzing adrenal response in the low-dose ACTH test (LDAT) and/or the glucagon stimulation test (GST) and reviewing the literature., Methods: A total of 46 pts with PWS were enrolled to the study, including 34 treated with rhGH with a median dose of 0.21 mg/kg/week. LDAT was performed in 46 pts, and GST was carried out in 13 pts. Both tests were conducted in 11 pts. The tests began at 8:00 a.m. Hormones were measured by radioimmunoassays. Serum cortisol response >181.2 ng/mL (500 nmol/L) in LDAT and >199.3 ng/mL (550 nmol/L) in GST was considered a normal response. Additionally, cortisol response delta (the difference between baseline and baseline) >90 ng/mL and doubling/tripling of baseline cortisol were considered indicators of normal adrenal reserve., Results: Three GSTs were not diagnostic (no hypoglycemia obtained). LDAT results suggested CAI in four pts, but in two out of four pts, and CAI was excluded in GST. GST results suggested CAI in only one patient, but it was excluded in LDAT. Therefore, CAI was diagnosed in 2/46 pts (4.3%), 1 treated and 1 untreated with rhGH, with the highest cortisol values of 162 and 175 ng/dL, but only in one test. However, in one of them, the cortisol delta response was >90 ng/mL and peak cortisol was more than tripled from baseline. Finally, CAI was diagnosed in one patient treated with rhGH (2.2%)., Conclusion: We present low prevalence of CAI in pediatric pts with PWS according to the latest literature. Therefore, we do not recommend to routinely screen the function of the hypothalamic-pituitary-adrenal axis (HPAA) in all pts with PWS, both treated and untreated with rhGH. According to a review of the literature, signs and symptoms or low morning ACTH levels suggestive of CAI require urgent and appropriate diagnosis of HPAA by stimulation test. Our data indicate that the diagnosis of CAI should be confirmed by at least two tests to prevent overtreatment with hydrocortisone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wędrychowicz, Doleżal-Ołtarzewska, Zygmunt-Górska, Kalicka-Kasperczyk, Tyrawa, Wojcik, Janus, Kot, Lecka-Ambroziak, Petriczko, Wielopolska and Starzyk.)

Background: Clascoterone cream 1% is a topical androgen receptor inhibitor approved to treat acne vulgaris in patients =&gt;12 years of age. This report provides details of patients who developed laboratory signs of hypothalamic-pituitary-adrenal (HPA) axis suppression without clinical signs of adrenal suppression during the clascoterone development program., Methods: Two open-label, multicenter, Phase 2 trials evaluated HPA axis suppression in patients with moderate-to-severe acne vulgaris. Study 1 (NCT01831960) enrolled cohorts of adults =&gt;18 years of age and adolescents =&gt;12 to &lt;18 years of age. Study 2 (NCT02720627) enrolled adolescents 9 to &lt;12 years of age. Patients applied clascoterone twice daily at maximum-exposure dosages for 14 days. Adrenal suppression was evaluated via cosyntropin stimulation test (CST) at baseline and day 14. Patients with an abnormal CST result (serum cortisol level =&lt;18 &micro;g/dL) had a follow-up CST approximately 4 weeks later. Blood was collected for pharmacokinetic analysis. Other safety assessments included adverse events (AEs), physical examination/vital signs, and electrocardiography., Results: Overall, 5/69 clascoterone-treated patients had an abnormal CST result on day 14, including 1/20 adults, 2/22 patients aged =&gt;12 to &lt;18 years, and 2/27 patients aged 9 to &lt;12 years. All patients had normal cortisol levels at follow-up testing approximately 4 weeks later. No relationship was observed between abnormal CST results and clascoterone plasma concentrations or the amount of study drug applied. No clinically relevant AEs or clinically significant changes in safety measures were observed in patients with adrenal suppression., Conclusion: Clascoterone induced laboratory evidence of mild, reversible HPA axis suppression under maximum-use exposure. J Drugs Dermatol. 2024;23(6):433-437.&nbsp; &nbsp;&nbsp; doi:10.36849/JDD.7997.

There is an increasing overdependence and use of atrazine herbicide for the control of pre-and post-emergence broad leaf weeds on maize farms in rural agricultural communities in Nigeria. We carried out a survey of atrazine residue in 69 hand-dug wells (HDW), 40 boreholes (BH) and 4 streams from all the 6 communities (Awa, Mamu, Ijebu-Igbo, Ago-Iwoye, Oru and Ilaporu) in Ijebu North Local Government Area, Southwest Nigeria. The effect of the highest concentration of atrazine detected in the water from each of the communities on the hypothalamic-pituitary-adrenal (HPA) axis of albino rats was investigated. Varying concentrations of atrazine were detected in the HDW, BH and stream waters sampled. The highest concentration of atrazine recorded in the water from the communities ranged from 0.01 to 0.08 mg/L. Although there were no significant differences ( p  > 0.05) in serum levels of corticosterone, aldosterone and ROS of rats exposed to 0.01, 0.03 and 0.04 mg/L concentrations of atrazine compared to control, a significant increase ( p  < 0.05) was observed at 0.08 mg/L. Catalase activity increased significantly ( p  < 0.05) only at 0.03 and 0.04 mg/L of atrazine exposure. Butyrylcholinesterase activity, lipid peroxidation and serum ACTH of rats exposed to all the atrazine concentrations were not significantly different ( p  > 0.05) compared to control. Atrazine at environmentally relevant concentrations of 0.01, 0.03 and 0.04 mg/L detected in the water may not affect the HPA axis, attention should be given to 0.08 mg/L, which increases the serum corticosterone and aldosterone of the exposed rats.

In sexually mature male Wistar rats with modeled post-traumatic stress disorder, personalized characteristics of neurobiological reactions in the population of predator-induced stress-resilient and stress-susceptible heparinized animals were determined. Characteristics of the systemic response of immune mechanisms, hypothalamic-pituitary-adrenal axis, behavioral manifestations, as well as basic properties of the CNS (excitation/inhibition) are presented. The study demonstrated encouraging positive results of the course administration of unfractionated heparin at a dose below the therapeutic and prophylactic doses. The inclusion of heparin drugs into the clinical practice for the treatment of post-traumatic stress disorder will not require large-scale clinical trials, because many effects of heparin as a nonspecific adaptogen are well studied. Moreover, these properties were confirmed at a higher technological level during the COVID-19 pandemic., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Cafeteria diet (CD) model for in-vivo studies mimics the western diet having imbalanced nutritional value, high caloric-density and palatability. Uncontrolled eating leads to the development of childhood obesity, poor self-esteem and depression due to its effects on brain development. Herbal supplements are novel inclusion in the management of obesity and mental well-being. Pterostilbene (PTE) found in blueberries and Pterocarpus marsupium heartwood, is known to prevent obesity in invivo models. Adolescent Swiss albino male mice were fed on CD for 70 days and the development of obesity was assessed by gain in body weight, abdominal circumference. Forced swim and tail suspension test confirmed depression in CD fed mice. Obesity induced depressed (OID) mice were treated with PTE (10, 20, 40 mg/kg), standard antiobesity drug cetilistat (10 mg/kg), antidepressant fluoxetine (10 mg/kg) for 28 days. Post treatment, PTE-treated mice showed reduction in BW and depression-like behavior analysed using paradigms such as sucrose preference, open field, marble burying, and resident intruder test in comparison to the CD group. Insulin resistance, lipid profile, antioxidant enzyme, inflammatory cytokines (NF-κB, IL-6, TNF α) and cortisol levels were mitigated by PTE. It also restored normal cellular architecture of the brain and adipose tissue and increased the Silent mating type information regulation 2 homolog1 (SIRT1), leptin and ghrelin receptors gene expression in the brain. Thus, it can be concluded that PTE might have inhibited OID like behavior in mice via inhibition of IR, modulating neuroinflammation and hypothalamic-pituitary-adrenal axis dysfunction and upregulating SIRT1 mediated leptin-ghrelin signaling., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The biological pathways linking lead exposure to adverse outcomes are beginning to be understood. Rodent models suggest lead exposure induces dysfunction within the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid regulation, a primary physiological stress response system. Over time, HPA axis and glucocorticoid dysfunction has been associated with adverse neurocognitive and cardiometabolic health, much like lead exposure. This systematic review utilized PRISMA guidelines to synthesize the literature regarding associations between lead exposure and downstream effector hormones of the HPA axis, including cortisol, a glucocorticoid, and dehydroepiandrosterone (DHEA), a glucocorticoid antagonist. We additionally determined the state of the evidence regarding lead exposure and allostatic load, a measure of cumulative body burden resultant of HPA axis and glucocorticoid dysfunction. A total of 18 articles were included in the review: 16 assessed cortisol or DHEA and 3 assessed allostatic load. Generally, the few available child studies suggest a significant association between early life lead exposure and altered cortisol, potentially suggesting the impact of developmental exposure. In adulthood, only cross sectional studies were available. These reported significant associations between lead and reduced cortisol awakening response and increased cortisol reactivity, but few associations with fasting serum cortisol. Two studies reported significant associations between increasing lead exposure and allostatic load in adults and another between early life lead exposure and adolescent allostatic load. The paucity of studies examining associations between lead exposure and allostatic load or DHEA and overall heterogeneity of allostatic load measurements limit conclusions. However, these findings cautiously suggest associations between lead and dysregulation of physiological stress pathways (i.e., glucocorticoids) as seen through cortisol measurement in children and adults. Future research would help to elucidate these associations and could further examine the physiological stress pathway as a mediator between lead exposure and detrimental health outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise to the activation of the hypothalamo-pituitary-adrenal (HPA) axis. However, the physiological role of kisspeptin in the interaction of HPG and HPA axis is not fully understood yet. This study was conducted to investigate the possible effects of central kisspeptin injection on HPG axis as well as HPA axis activity. Adult male Wistar rats were randomly divided into seven groups as followed: sham (control), kisspeptin (50 pmol), P234 (1 nmol), kisspeptin + p234, kisspeptin + antalarmin (0.1 μg), kisspeptin + astressin 2B (1 μg), and kisspeptin + atosiban (300 ng/rat) ( n  = 10 each group). At the end of the experiments, the hypothalamus, pituitary, and serum samples of the rats were collected. There was no significant difference in corticotropic-releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone, and corticosterone levels among all groups. Moreover, no significant difference was detected in pituitary oxytocin level. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin, and kisspeptin + astressin 2B groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin kisspeptin + antalarmin, kisspeptin + astressin 2B, and kisspeptin + atosiban groups compared to the control group. Our findings suggest that central kisspeptin injection causes activation in the HPG axis, but not the HPA axis in male rats.

The study objective was to investigate the effect of repeated hypothalamic-pituitary-adrenal (HPA) axis stimulation using synthetic adrenocorticotropic hormone (ACTH) intramuscular injections on hair cortisol concentration, growth, and behavior in preweaned dairy calves. Twenty-seven Holstein calves were assigned to nine triads (based on sex and birth order) and randomly assigned to 1 of 3 treatments: 1) control (CON; 2 mL saline weekly); 2) moderate (MOD; alternating Cosyntropin [2 mcg/kg body weight (BW)] and saline weekly); or 3) frequent (FREQ; Cosyntropin [2 mcg/kg BW] weekly). Calves received their first injection on study day 0 (7 ± 1 d of age). Hair was collected from the tail switch between days -5 and -3 (baseline), 21, and 49 and analyzed for cortisol concentration. To verify the endogenous cortisol release by Cosyntropin during the treatment period, saliva was collected on days 0, 14, 28, and 42 before injection and every 15 min for 2 h after injection for analysis of salivary cortisol concentration. Calves were fitted with accelerometers to continuously monitor lying time, number of lying bouts, and lying bout duration throughout the study. Growth measures (BW, hip height, hip width) were recorded weekly. Data were analyzed using repeated measures ANOVA (SAS, Version 9.4), and models included the fixed effects of treatment, time (min or study day), and interaction between treatment and time. Temperature humidity index was included as a continuous covariate in all models. We observed a treatment × min interaction (P < 0.0001), whereby salivary cortisol concentration was lower in CON calves compared to MOD and FREQ calves 15 to 120 min postinjection. While hair cortisol concentration was not influenced by treatment, concentration decreased from day 21 (1.28 ± 0.03 ng/mL) to 49 (0.93 ± 0.03 ng/mL). Average BW was similar across treatments (CON [59.4 ± 1.09 kg], MOD [58.6 ± 0.98 kg], and FREQ [57.6 ± 0.96 kg]; P = 0.50). There was no evidence to suggest a difference in average daily lying time (CON [18.5 ± 0.23 h/d], MOD [18.6 ± 0.23 h/d], and FREQ [18.5 ± 0.23 h/d]; P = 0.99). These results suggest that repeated HPA axis stimulation through Cosyntropin administration increased salivary cortisol concentration, but did not influence hair cortisol concentration, growth, or behavior in preweaned dairy calves., (Published by Oxford University Press on behalf of the American Society of Animal Science 2024.)

Background: It was known since the 1940s that pharmacological administration of glucocorticoids can inhibit inflammatory and immune processes, and these hormones are still today among the most widely used therapeutic tools to treat diseases with immune components. However, it became clear later that endogenous glucocorticoids can either support or restrain immune processes., Summary: Early studies showed that (a) endogenous levels of glucocorticoids can modulate immune cell activity; (b) the immune response itself can stimulate the hypothalamus-pituitary-adrenal (HPA) axis to release glucocorticoids to levels that can exert immunoregulatory effects; (c) immune products, later identified as cytokines, mediate this effect. On these bases, the existence of a glucocorticoid-mediated immunoregulatory circuit was proposed. It was also shown that increased levels of endogenous glucocorticoids exert protective effects during infections and other diseases with immune components. However, it was found in animal models and in humans that these effects can be blunted in several immune-linked diseases by defects at several levels, for example, by glucocorticoid resistance or by adrenal insufficiency. Evidence was later provided that the glucocorticoid-mediated immunoregulatory circuit can also be activated by cytokines produced not only as consequence of immune stimulation but also following psycho/sensorial and physical stimuli. Thus, this circuit can be integrated at brain levels and, besides stimulating the HPA axis, cytokines can also affect synaptic plasticity, most likely via a tripartite synapse, with astrocytes as neuro-immune cells acting as the third component., Key Messages: It is now well established that the glucocorticoid-mediated immunoregulatory circuit plays a central role in maintaining health. However, several variables can condition the efficacy of the effect of endogenous glucocorticoids. Furthermore, since cytokines and other immune products have many other neuroendocrine and metabolic effects, other neuroendocrine-immune circuits could simultaneously operate or become predominant during different pathologies. The consideration of these aspects might help to implement strategies to eventually decrease therapeutic doses of exogenous glucocorticoids., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients - potentially with substantial exposure to early-life adversity (ELA) - show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories. Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration. Method: The observational study ( n  = 160 PTSD group, n  = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study ( n  = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts. Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies. Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

Introduction: Alzheimer's disease (AD) alters neurocognitive and emotional function and causes dysregulation of multiple homeostatic processes. The leading AD framework pins amyloid beta plaques and tau tangles as primary drivers of dysfunction. However, many additional variables, including diet, stress, sex, age, and pain tolerance, interact in ways that are not fully understood to impact the onset and progression of AD pathophysiology. We asked: (1) does high-fat diet, compared to low-fat diet, exacerbate AD pathophysiology and behavioral decline? And, (2) can supplementation with eicosapentaenoic (EPA)-enriched fish oil prevent high-fat-diet-induced changes?, Methods: Male and female APPswePSdE9 mice, and their non-transgenic littermates, were randomly assigned to a diet condition (low-fat, high-fat, high-fat with EPA) and followed from 2 to 10 months of age. We assessed baseline corticosterone concentration during aging, pain tolerance, cognitive function, stress coping, and corticosterone response to a stressor., Results: Transgenic mice were consistently more active than non-transgenic mice but did not perform worse on either cognitive task, even though we recently reported that these same transgenic mice exhibited metabolic changes and had increased amyloid beta. Mice fed high-fat diet had higher baseline and post-stressor corticosterone, but diet did not impact cognition or pain tolerance. Sex had the biggest influence, as female mice were consistently more active and had higher corticosterone than males., Conclusion: Overall, diet, genotype, and sex did not have consistent impacts on outcomes. We found little support for predicted interactions and correlations, suggesting diet impacts metabolic function and amyloid beta levels, but these outcomes do not translate to changes in behaviors measured here., (© 2024 S. Karger AG, Basel.)

Major depression disorder is a debilitating psychiatric disease affecting millions of people worldwide. This disorder is the leading cause of morbidity and mortality in high-income countries. Selective serotonin reuptake inhibitors such as fluoxetine are first-line drugs for treating depression-related disorders, but not all patients respond well to these antidepressants. This study aimed to evaluate whether fluoxetine combined with aerobic exercise can affect lipopolysaccharide (LPS)-induced depressive-like behavior, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and brain inflammation in mice. Male mice were exposed to fluoxetine, swimming exercise, or a combination of both and finally treated with LPS. We measured depression-related symptoms such as anhedonia, behavioral despair, weight gain, and food intake. Hormones (corticosterone and testosterone) and cytokines (IL-1β, IL-6, TNF-α, IL-10) were also measured in serum and brain (hippocampus and prefrontal cortex), respectively. The findings indicated that LPS induced anhedonia and behavioral despair and increased corticosterone, hippocampal IL-1β, TNF-α, and decreased testosterone and hippocampal IL-10 in mice. Fluoxetine and exercise separately reduced LPS-induced depressive-like behavior, while their combination synergistically reduced these symptoms in LPS-treated mice. We found fluoxetine alone increased food intake and body weight in LPS-treated mice. Fluoxetine and exercise combination reduced corticosterone, hippocampal TNF-α, and prefrontal IL-6 and TNF-α levels and increased testosterone and hippocampal and prefrontal IL-10 levels more effectively than fluoxetine alone in LPS-treated mice. This study suggests that swimming exercise combined with fluoxetine can affect depression-related behavior, HPA axis, and brain inflammation more effectively than when they are used separately., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To examine the prevalence and risk factors for hypothalamus-pituitary-adrenal axis suppression (HPA axis suppression) in infants receiving glucocorticoid (GC) eye drops after ocular surgery., Methods: This was a clinical observational cohort study. Children under the age of two receiving GC eye drops after cataract or glaucoma surgery between 1 January 2017 and 31 December 2021 were included at one centre. Medical history and results of the adrenocorticotropic hormone (ACTH) stimulation tests were obtained through patient charts., Results: Forty-nine infants were included in the study. Ten out of 22 patients (45.5%) tested during treatment and two out of 27 patients (7.4%) tested after treatment cessation were diagnosed with HPA axis suppression. The duration of HPA axis suppression extended beyond 3 months in 8 out of 12 patients. Logistic regression showed that infants with HPA axis suppression had received a higher GC dose/body weight/day before the first ACTH test (p < 0.001). There was a 79% (95% CI:1.28;2.50) increase in the odds of having HPA axis suppression for a 0.01 mg GC increase/kg/day corresponding to an additional daily eye drop for an infant weighing 5 kg. There was an association between HPA axis suppression and number of days from surgery to test (p = 0.003), age at surgery (p = 0.035) and cumulated GC dose (p = 0.005). Three infants with HPA axis suppression had affected growth and one had Cushing-like features, but there were no cases of Addisonian crisis., Conclusion: Infants are at risk of having hypothalamus-pituitary-adrenal axis suppression if they receive a high daily glucocorticoid dose per weight by topical ocular administration. Infants receiving glucocorticoids after ocular surgery should be monitored clinically or by ACTH testing., (© 2022 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Objectives: The action of stress hormones, mainly glucocorticoids, starts and coordinates the systemic response to stressful events. The HPA axis activity is predicated on information processing and modulation by upstream centres, such as the hippocampus where adult-born neurons (hABN) have been reported to be an important component in the processing and integration of new information. Still, it remains unclear whether and how hABN regulates HPA axis activity and CORT production, particularly when considering sex differences., Materials and Methods: Using both sexes of a transgenic rat model of cytogenesis ablation (GFAP-Tk rat model), we examined the endocrinological and behavioural effects of disrupting the generation of new astrocytes and neurons within the hippocampal dentate gyrus (DG)., Results: Our results show that GFAP-Tk male rats present a heightened acute stress response. In contrast, GFAP-Tk female rats have increased corticosterone secretion at nadir, a heightened, yet delayed, response to an acute stress stimulus, accompanied by neuronal hypertrophy in the basal lateral amygdala and increased expression of the glucocorticoid receptors in the ventral DG., Conclusions: Our results reveal that hABN regulation of the HPA axis response is sex-differentiated., (© 2021 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.)

Purpose: Sepsis is hallmarked by high plasma cortisol/corticosterone (CORT), low adrenocorticotropic hormone (ACTH), and high pro-opiomelanocortin (POMC). While corticotropin-releasing hormone-(CRH) and arginine-vasopressin (AVP)-driven pituitary POMC expression remains active, POMC processing into ACTH becomes impaired. Low ACTH is accompanied by loss of adrenocortical structure, although steroidogenic enzymes remain expressed. We hypothesized that treatment of sepsis with hydrocortisone (HC) aggravates this phenotype whereas CRH infusion safeguards ACTH-driven adrenocortical structure., Methods: In a fluid-resuscitated, antibiotics-treated mouse model of prolonged sepsis, we compared the effects of HC and CRH infusion with placebo on plasma ACTH, POMC, and CORT; on markers of hypothalamic CRH and AVP signaling and pituitary POMC processing; and on the adrenocortical structure and markers of steroidogenesis. In adrenal explants, we studied the steroidogenic capacity of POMC., Results: During sepsis, HC further suppressed plasma ACTH, but not POMC, predominantly by suppressing sepsis-activated CRH/AVP-signaling pathways. In contrast, in CRH-treated sepsis, plasma ACTH was normalized following restoration of pituitary POMC processing. The sepsis-induced rise in markers of adrenocortical steroidogenesis was unaltered by CRH and suppressed partially by HC, which also increased adrenal markers of inflammation. Ex vivo stimulation of adrenal explants with POMC increased CORT as effectively as an equimolar dose of ACTH., Conclusions: Treatment of sepsis with HC impaired integrity and function of the hypothalamic-pituitary-adrenal axis at the level of the pituitary and the adrenal cortex while CRH restored pituitary POMC processing without affecting the adrenal cortex. Sepsis-induced high-circulating POMC may be responsible for ongoing adrenocortical steroidogenesis despite low ACTH., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Epilepsy is a common chronic neurological disease that manifests as recurrent seizures. The incidence and prevalence of epilepsy in women are slightly lower than those in men. Polycystic ovary syndrome (PCOS), a reproductive endocrine system disease, is a complication that women with epilepsy are susceptible to, and its total prevalence is 8%-13% in the female population and sometimes as high as 26% in female epilepsy patients. The rate of PCOS increased markedly in female patients who chose valproate (VPA), to 1.95 times higher than that of other drugs. In addition, patients receiving other anti-seizure medications (ASMs), such as lamotrigine (LTG), oxcarbazepine (OXC), and carbamazepine (CBZ), also have reproductive endocrine abnormalities. Some scholars believe that the increase in incidence is related not only to epilepsy itself but also to ASMs. Epileptiform discharges can affect the activity of the pulse generator and then interfere with the reproductive endocrine system by breaking the balance of the hypothalamic-pituitary-ovarian (HPO) axis. ASMs may also cause PCOS-like disorders of the reproductive endocrine system through the HPO axis. Moreover, other factors such as hormone metabolism and related signalling pathways also play a role in it., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Zhang, Wei, Tai, Yu and Xu.)

Overt expression of brain glucocorticoid receptor (GR) leads to elevation of glutamate release causes cerebral excitotoxicity which in turn produce neuropsychological disorders. The aim of our work is to study the consequence of 3-O-Acetyl-11-keto-β-boswellic acid (AKBA) on chronic unpredictable mild stress (CUMS) induced HPA axis dysregulation in relative to glutamate and GABA irregularity in depressive rats. AKBA (5, 10 &15mg/kg) was administered for 28 days parallel with CUMS induction in rats. Behavioural studies, tail suspension test (TST), open field exploratory (OFT) and forced swim test (FST) were performed. Biochemical studies including plasma corticosterone, glutamate GABA and glutamic acid decarboxylase (GAD) enzyme activity were studied. Glucocorticoid receptor expression and brain histology were studied to observe the effect of AKBA. CUMS induction results in depressive state of the animals were confirmed by the sucrose preference test. The administration of AKBA significantly reduced the immobility time and improved the exploratory behaviour. Plasma corticosterone and brain glutamate level was decreased and GABA level were increased significantly evident with GAD activation in AKBA-treated animals, further confirmed with decreased GR expression improves architecture of prefrontal cortex region. Correlation study illustrates behavioural improvements undeviating the biochemical alteration and GR expression after AKBA treatment during depression. AKBA significantly reversed the CUMS-induced glutamate/GABA abnormalities through the adaptation of central HPA axis regulation. Hence this study concludes that AKBA can be a better alternative to treat depressive disorders., (© 2021 John Wiley & Sons Australia, Ltd.)

(1) Background: Prolonged feeding with a high-fat diet (HFD) acts as a stressor by activating the functions of the hypothalamic-pituitary-adrenal gland (HPA) stress axis, accompanied of hypertension by inducing the renin-angiotensin-aldosterone system. Angiotensinases enzymes are regulatory aminopeptidases of angiotensin metabolism, which together with the dipeptidyl peptidase IV (DPP-IV), pyroglutamyl- and tyrosyl-aminopeptidase (pGluAP, TyrAP), participate in cognitive, stress, metabolic and cardiovascular functions. These functions appear to be modulated by the type of fat used in the diet. (2) Methods: To analyze a possible coordinated response of aminopeptidases, their activities were simultaneously determined in the hypothalamus, adenohypophysis and adrenal gland of adult male rats fed diets enriched with monounsaturated (standard diet (S diet) supplemented with 20% virgin olive oil; VOO diet) or saturated fatty acids (diet S supplemented with 20% butter and 0.1% cholesterol; Bch diet). Aminopeptidase activities were measured by fluorimetry using 2-Naphthylamine as substrates. (3) Results: the hypothalamus did not show differences in any of the experimental diets. In the pituitary, the Bch diet stimulated the renin-angiotensin system (RAS) by increasing certain angiotensinase activities (alanyl-, arginyl- and cystinyl-aminopeptidase) with respect to the S and VOO diets. DPP-IV activity was increased with the Bch diet, and TyrAP activity decrease with the VOO diet, having both a crucial role on stress and eating behavior. In the adrenal gland, both HFDs showed an increase in angiotensinase aspartyl-aminopeptidase. The interrelation of angiotensinases activities in the tissues were depending on the type of diet. In addition, correlations were shown between angiotensinases and aminopeptidases that regulate stress and eating behavior. (4) Conclusions: Taken together, these results support that the source of fat in the diet affects several peptidases activities in the HPA axis, which could be related to alterations in RAS, stress and feeding behavior.

DNA methylation shifts in Hypothalamic-pituitary-adrenal (HPA) axis related genes is reported in psychiatric disorders including hypersexual disorder. This study, comprising 20 dexamethasone suppression test (DST) non-suppressors and 73 controls, examined the association between the HPA axis dysregulation, shifts in DNA methylation of HPA axis related genes and importantly, gene expression. Individuals with cortisol level ≥ 138 nmol/l, after the low dose (0.5 mg) dexamethasone suppression test (DST) were classified as non-suppressors. Genome-wide methylation pattern, measured in whole blood using the EPIC BeadChip, investigated CpG sites located within 2000 bp of the transcriptional start site of key HPA axis genes, i.e.: CRH, CRHBP, CRHR-1, CRHR-2, FKBP5 and NR3C1. Regression models including DNA methylation M-values and the binary outcome (DST non-suppression status) were performed. Gene transcripts with an abundance of differentially methylated CpG sites were identified with binomial tests. Pearson correlations and robust linear regressions were performed between CpG methylation and gene expression in two independent cohorts. Six of 76 CpG sites were significantly hypermethylated in DST non-suppressors (nominal P < 0.05), associated with genes CRH, CRHR1, CRHR2, FKBP5 and NR3C1. NR3C1 transcript AJ877169 showed statistically significant abundance of probes differentially methylated by DST non-suppression status and correlated with DST cortisol levels. Further, methylation levels of cg07733851 and cg27122725 were positively correlated with gene expression levels of the NR3C1 gene. Methylation levels of cg08636224 (FKBP5) correlated with baseline cortisol and gene expression. Our findings revealed that DNA methylation shifts are involved in the altered mechanism of the HPA axis suggesting that new epigenetic targets should be considered behind psychiatric disorders., (© 2021. The Author(s).)

We studied the effect of constant illumination on the effects of administration of arginine vasopressin (AVP), one of the most important regulators of the key adaptive hypothalamic-pituitary-adrenal (HPA) axis under basal conditions and during stress, as well as on the circadian rhythm of activity of HPA axis and the pineal gland in laboratory primates. In young adult female rhesus monkeys exposed to constant illumination for 7 weeks, the rise in the concentration of ACTH and cortisol in response to administration of AVP was markedly reduced in comparison with both the basal period and with the control group of animals. In addition, a destructive effect of constant lighting on circadian rhythm of cortisol secretion was observed in the absence of significant circadian changes in melatonin secretion. The inhibitory effect of constant illumination on the function of the HPA axis under basal conditions and under conditions of its activation can reduce the body's adaptive abilities., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is characterized by hypothalamus-pituitary-adrenal axis dysfunction. As the neuroendocrinological axis has been shown to react under the regulation of the central nerve system through the corticotropin-releasing factor (CRF) releasing from the hypothalamic paraventricular nucleus. Whether one of the neuromodulation therapies, vagus nerve stimulation, is able to treat this neuroendocrinological disorder remains unknown. In this study, we explored the effects of vagus nerve stimulation (VNS) on CRF-induced serum ACTH level change in normal rats. After the vagus nerve electrode placement, the ACTH and corticosterone levels were measured multiple times before and after the administration of CRF (2 μg/kg) in switched-ON and -OFF groups, respectively, compared to the control group. Our results showed that 2 h continuous stimulation on the vagus nerve inhibited CRF-induced ACTH release up to 1 h compared with the control group, while the corticosterone level was not influenced. The vagus nerve might be a potential therapeutic target in the treatment of ACTH-dependent Cushing's syndrome disorders involving hypothalamus-pituitary-adrenal axis dysfunction., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are antidiabetic drugs with effects beyond antihyperglycemic action. The aim of the study was to examine whether a single dose of exenatide could be used as a stimulation test for the pituitary-adrenal axis. We carried out a single-group, open-label pilot clinical trial in an ambulatory setting. Ten healthy volunteers of both sexes with body weight>65 kg and age between 18-50 years were recruited. After fasting for 12 hours the subjects received 10 μg of exenatide solution subcutaneously. Blood samples were taken before the administration of exenatide and up to 150 minutes thereafter. The primary outcome was the maximal level of cortisol after the administration of exenatide. Single administration of exenatide 10 μg resulted in a modest increase in ACTH and cortisol levels, as compared to untreated values, and a decrease in blood glucose levels. Remarkably, a robust suppression of both renin and aldosterone levels occurred. We showed that acute administration of exenatide in a full therapeutic dose modestly stimulates the hypothalamic-pituitary-adrenal axis but inhibits the renin-aldosterone system. Further research is warranted to confirm this finding in the placebo-controlled study., Competing Interests: Vallo Volke has served at speakers’ bureau and received travel grants from Astra Zeneca, Eli Lilly, Aventis, and Novo Nordisk. Other authors declare that they have no conflicts of interest in the authorship or publication of this contribution., (Thieme. All rights reserved.)