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Background and Purpose: Diabetic patients have an increased risk of psychiatric disorders. Because hyperglycaemia increases L-lactate in the brain and L-lactate inhibits AMP-activated protein kinase (AMPK), this study investigated the role of L-lactate and AMPK in strengthened fear memory, a model for human psychiatric disorders, in diabetic mice., Experimental Approach: The diabetic model was mice injected with streptozotocin. Fear memory was measured using the conditioned fear test with low (0.45 mA) or high (0.50 mA) foot shock to cause low and high freezing, respectively. Protein levels of AMPK and phosphorylated AMPK (pAMPK) were measured by western blotting and immunohistochemistry., Key Results: At 0.45 mA, the AMPK inhibitor dorsomorphin increased freezing, which was inhibited by the AMPK activator acadesine. In contrast, at 0.50 mA, acadesine decreased freezing, which was inhibited by dorsomorphin. In diabetic mice, pAMPK was decreased in the amygdala and hippocampus. Diabetic mice showed increased freezing at 0.45 mA, which was inhibited by acadesine. In the amygdala and hippocampus, L-lactate was increased in diabetic mice and injection of L-lactate into non-diabetic mice increased freezing at 0.45 mA. In addition, L-lactate decreased pAMPK in the hippocampus, but not the amygdala, and increase in freezing induced by L-lactate was inhibited by acadesine. Dorsomorphin-induced increase in freezing was inhibited by the AMPA receptor antagonist NBQX., Conclusions and Interpretation: In diabetic mice, L-lactate is increased in the amygdala and hippocampus, possibly through hyperglycaemia, which strengthens fear memory through inhibition of AMPK and activation of glutamatergic function., (© 2024 British Pharmacological Society.)

Type 1 diabetes mellitus (T1D) is associated with cognitive impairments in humans. A well-established animal model of T1D is induced through the administration of streptozotocin (STZ), a glucose analog that induces pancreatic β-cell death, resulting in hyperglycemia and cognitive impairment linked to neuroinflammation and oxidative stress. Tumor necrosis factor (TNF)-α, a key inflammatory mediator, is elevated in the central nervous system (CNS) of diabetic animals. In this study, we utilized TNFR1 knockout mice to investigate the role of TNFR1 signaling in short-term T1D-related cognitive impairment. Our findings showed that diabetic animals did not develop cognitive damage within the first 2 weeks of T1D but exhibited reduced exploration in all behavioral tests. Our findings suggest that this reduction in exploration was attributable to motor impairment, as there was no reduction in motivated novelty-seeking behavior. Additionally, deletion of TNFR1 signaling attenuated gait speed impairment in diabetic mice, but did not affect other motor-related or exploratory behaviors., 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 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

The effects of tyrosol and nano-tyrosol on the modulation of anxiety-like behavior and memory processes were evaluated in streptozotocin-induced diabetic rats. Male diabetic rats were orally treated with 1 ml of saline, nano-niosome, tyrosol, and nano-tyrosol (20 mg/dl) for 30 days. Anxiety-like behavior and memory process were evaluated by an elevated plus-maze (EPM) test-retest paradigm. The results showed that a single intraperitoneal (i.p.) administration of streptozotocin (50 mg/kg) raised blood glucose. While daily intragastric administration of tyrosol and nano-tyrosol reduced blood glucose. Induction of type II diabetes produced a distorted cellular arrangement whereas treatment with tyrosol and nano-tyrosol showed a typical cellular arrangement in the liver. Furthermore, induction of type II diabetes decreased %OAT (%open-arm time) but daily intragastric application of tyrosol (20 mg/dl) and nano-tyrosol (20 mg/dl) enhanced %OAT and %OAE (%open-arm entry) in the EPM when compared to the saline groups, showing anxiogenic- and anxiolytic-like effects, respectively. Also, induction of type II diabetes increased %OAT while daily intragastric administration of tyrosol (20 mg/dl) and nano-tyrosol (20 mg/dl) decreased %OAT and %OAE in the EPM in comparison to the saline groups, displaying impairment and improvement of emotional memory, respectively. Interestingly, nano-tyrosol exhibited the highest significant effect rather than tyrosol. Upon these results, we proposed the beneficial effects of tyrosol and nano-tyrosol on the modulation of anxiety-like behavior and memory processes in streptozotocin-induced diabetic rats., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Depression is a multifaceted disorder that represents one of the most common causes of disability. The risk for developing depression is increased in women and among individuals with chronic diseases. For example, individuals in the United States with diabetes mellitus (DM) are at a twofold increased risk of developing depression compared to the general population and approximately one-quarter of women with diabetes have comorbid depression. The neurobiological mechanisms underlying this association between diabetes and depression is not fully understood and is particularly under-investigated in female models. We sought to explore the role of neuroinflammation in diabetes-induced depression in a female mouse model of hyperglycemia., Methods: To this end, we utilized female C57BL/6 J mice to (1) characterize the depressive-like symptoms in response to 75 mg/kg/day dose of streptozotocin (STZ) over 5 days, a dose reported to induce hyperglycemia in female mice (n=20), (2) determine if female hyperglycemic mice are sensitized to unpredictable chronic mild stress (UCMS)-induced depressive-like behavior and neuroinflammation (n=28), and (3) investigate if female hyperglycemic mice are primed to respond to a subthreshold dose of lipopolysaccharide (LPS), an acute inflammatory challenge (n=21)., Results: Our results demonstrate that female mice exhibit robust hyperglycemia but limited evidence of depressive-like behavior in response to 75 mg/kg STZ. Additionally, we observe that healthy female mice have limited response to our stress protocol; however, hyperglycemic mice display increased stress-sensitivity as indicated by increased immobility in the forced swim test. While STZ mice show evidence of mild neuroinflammation, this effect was blunted by stress. Further, STZ mice failed to display a sensitization to inflammation-induced depressive-like behavior., Conclusion: We interpret this data to indicate that while STZ-induced hyperglycemia does increase vulnerability to stress-induced depressive-like behavior, this effect is not a consequence of neuroinflammatory priming. Future studies will seek to better understand the mechanisms underlying this sensitization., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Rationale: Although diabetic peripheral neuropathic pain (DPNP) and depression have been recognized for many years, their co-morbidity relationship and effective treatment choices remain uncertain., Objectives: To evaluate the antidepressant effect of carvedilol on streptozotocin-induced DPNP mice, and the relationship with gut microbiota., Methods: The hyperalgesia and depressive behaviors of mice with comorbidity of DPNP and depression were confirmed by pain threshold of the mechanical sensitivity test (MST), immobility time of the tail suspension test (TST) and the forced swimming test (FST). The anti-depressive effect and fecal gut microbiota composition were studied in DPNP mice treated with carvedilol (10 mg/kg/day), and the relationships between them were analyzed by Spearman's correlation., Results: Depression was successfully induced in DPNP mice. Carvedilol can reverse the decreased mechanical pain threshold and relieve the depressive behaviors of DPNP mice, while increasing the abundance of Prevotella, Ruminococcus, Helicobacter and Desulfovibrio, and decreasing the abundance of Akkermansia and Allobaculum., Conclusions: Carvedilol can alleviate the mechanical hyperalgesia and alter gut microbiota to ameliorate the depression-like behaviors which induced by DPNP., Competing Interests: Declaration of competing interest The authors state no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: In view of the neuroprotective characteristic of cannabidiol (CBD) and its beneficial action on aversive memory in non-diabetic animals, we aimed to investigate in animals with experimentally induced type-1 diabetes mellitus (T1DM) whether CBD treatment would be able to impair the contextual fear memory consolidation, its generalisation and whether the effect would be lasting. We also investigated the CBD effect on anxiety-like responses., Methods: After T1DM induction, animals received single or more prolonged treatment with CBD and were submitted to the contextual fear conditioning test. As expression of activity-regulated cytoskeletal-associated (Arc) protein is necessary for memory consolidation, we evaluated its expression in the dorsal hippocampus (DH). For evaluating anxiety-related responses, animals were submitted to the elevated plus maze test (EPMT), in which the time and number of entries in the open arms were used as anxiety index., Results: A single injection of CBD impaired the contextual fear memory consolidation and its generalisation, which was evaluated by exposing the animal in a neutral context. This single injection was able to reduce the elevated expression of Arc in the DH from these animals. Interestingly, more prolonged treatment with CBD also impaired the persistence of context-conditioned fear memory and induced an anxiolytic-like effect, as the treated group spent more time in the open arms of the EPMT., Conclusion: CBD interferes with contextual fear memory and the dosage regimen of treatment seems to be important. Moreover, we cannot rule out the involvement of emotional aspects in these processes related to fear memory.

The relationship between diabetes mellitus type 2 (DM2) and sexual desire in women has not been systematically studied, therefore, animal models have been used for this purpose. When streptozotocin (STZ) is administered in the neonatal stage, the rat shows moderate chronic hyperglycemia and glucose intolerance in adulthood, resembling a DM2 model. These females show less alterations of sexual behavior (a slight decreased proceptivity and loss of paced mating) than their counterpart with severe hyperglycemia. However, the motivational components of copulation in female rats in this DM2 model have not been examined. The aim of this study was to evaluate female sexual motivation in a model of DM2 in three behavioral paradigms: the partner preference (PP), the sexual incentive motivation (SIM) and the odor preference test (OPT) tests. Neonatal females (3-4 days) were administered with streptozotocin (STZ, 70 mg/kg, intraperitoneally) or citrate buffer. At week 8, a glucose tolerance test was performed, females with blood glucose levels ≥ 250 mg/dl 60 min after a sucrose load (2 g/kg) were considered for the study. Behavioral tests were conducted at week 12, when the females were in natural proestrus. For PP we registered the time in each compartment and the sexual behavior, while in the SIM test, we calculated the time the females remained in each incentive zone. In these tests a castrated male and a sexually experienced male were used as stimuli. In OPT we evaluated the time the females spent sniffing the sawdust coming from cages housing these stimuli. In the PP and OPT hyperglycemic females behave similarly than controls, i.e., they retain a preference for sexually active males. In the SIM test there was a decrease in the time the hyperglycemic females remain in the vicinity of the sexually expert male. Data are discussed on the bases of the accessibility of the females to the stimuli., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1β and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Protectin DX (PDX), a specialized pro-resolving lipid mediator, presents potential therapeutic applications across various medical conditions due to its anti-inflammatory and antioxidant properties. Since type-1 diabetes mellitus (T1DM) is a disease with an inflammatory and oxidative profile, exploring the use of PDX in addressing T1DM and its associated comorbidities, including diabetic neuropathic pain, depression, and anxiety becomes urgent. Thus, in the current study, after 2 weeks of T1DM induction with streptozotocin (60 mg/kg) in Wistar rats, PDX (1, 3, and 10 ng/animal; i.p. injection of 200 μl/animal) was administered specifically on days 14, 15, 18, 21, 24, and 27 after T1DM induction. We investigated the PDX's effectiveness in alleviating neuropathic pain (mechanical allodynia; experiment 1), anxiety-like and depressive-like behaviors (experiment 2). Also, we studied whether the PDX treatment would induce antioxidant effects in the blood plasma, hippocampus, and prefrontal cortex (experiment 3), brain areas involved in the modulation of emotions. For evaluating mechanical allodynia, animals were repeatedly submitted to the Von Frey test; while for studying anxiety-like responses, animals were submitted to the elevated plus maze (day 26) and open field (day 28) tests. To analyze depressive-like behaviors, the animals were tested in the modified forced swimming test (day 28) immediately after the open field test. Our data demonstrated that PDX consistently increased the mechanical threshold throughout the study at the two highest doses, indicative of antinociceptive effect. Concerning depressive-like and anxiety-like behavior, all PDX doses effectively prevented these behaviors when compared to vehicle-treated T1DM rats. The PDX treatment significantly protected against the increased oxidative stress parameters in blood plasma and in hippocampus and prefrontal cortex. Interestingly, treated animals presented improvement on diabetes-related parameters by promoting weight gain and reducing hyperglycemia in T1DM rats. These findings suggest that PDX improved diabetic neuropathic pain, and induced antidepressant-like and anxiolytic-like effects, in addition to improving parameters related to the diabetic condition. It is worth noting that PDX also presented a protective action demonstrated by its antioxidant effects. To conclude, our findings suggest PDX treatment may be a promising candidate for improving the diabetic condition per se along with highly disabling comorbidities such as diabetic neuropathic pain and emotional disturbances associated with T1DM., Competing Interests: Declaration of competing interest The authors declare no conflicting interests., (Copyright © 2024. Published by Elsevier Inc.)

Background: In the present study, we investigated the effect of high-intensity interval training (HIIT) on cognitive behaviors in female rats with a high-fat diet + streptozotocin (STZ)-induced type 2 diabetes., Methods: Twenty-four female rats were divided into four groups randomly (n = 6): control (C), control + exercise (Co + EX), diabetes mellitus (type 2) (T2D), and diabetes mellitus + exercise (T2D + EX). Diabetes was induced by a two-month high-fat diet and a single dose of STZ (35 mg/kg) in the T2D and T2D + EX groups. The Co + EX and T2D + EX groups performed HIIT for eight weeks (five sessions per week, running on a treadmill at 80-100% of V Max , 4-10 intervals). Elevated plus maze (EPM) and open field test (OFT) were used for assessing anxiety-like behaviors, and passive avoidance test (PAT) and Morris water maze (MWM) were applied for evaluating learning and memory. The hippocampal levels of beta-amyloid (Aβ) and Tau were also assessed using Western blot., Results: An increase in fasting blood glucose (FBG), hippocampal level of Tau, and a decrease in the percentage of open arm time (%OAT) as an index of anxiety-like behavior were seen in the female diabetic rats which could be reversed by HIIT. In addition, T2D led to a significant decrease in rearing and grooming in the OFT. No significant difference among groups was seen for the latency time in the PAT and learning and memory in the MWM., Conclusions: HIIT could improve anxiety-like behavior at least in part through changes in hippocampal levels of Tau., (© 2024. The Author(s).)

Introduction: Type 1 diabetes (T1D) causes cognitive decline and has been associated with brain metabolic disorders, but its potential molecular mechanisms remain unclear., Objectives: The purpose of this study was to explore the molecular mechanisms underlying T1D-induced cognitive impairment using metabolomics and lipidomics., Methods: We developed an optimized integration approach of metabolomics and lipidomics for brain tissue based on UPLC-Q-TOF-MS and analyzed a comprehensive characterization of metabolite and lipid profiles in the hippocampus and frontal cortex of T1D male mice with cognitive decline (T1DCD) and age-matched control (CONT) mice., Results: The results show that T1DCD mice had brain metabolic disorders in a region-specific manner relative to CONT mice, and the frontal cortex exhibited a higher lipid peroxidation than the hippocampus in T1DCD mice. Based on metabolic changes, we found that microglia was activated under diabetic condition and thereby promoted oxidative stress and neuroinflammation, leading to neuronal injury, and this event was more pronounced in the frontal cortex than the hippocampus., Conclusion: Our results suggest that brain region-specific shifts in oxidative stress and neuroinflammation may contribute to diabetic cognitive decline, and the frontal cortex could be the more vulnerable brain region than the hippocampus., 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 © 2022. Production and hosting by Elsevier B.V.)

Background and Purpose: Post-stroke cognitive impairment (PSCI) has become a major public health issue, as a leading cause of dementia. The inflammation that develops soon after cerebral artery occlusion and may persist for weeks or months after stroke is a key component of PSCI. Our aim was to take advantage of the immunomodulatory properties of peripheral blood mononuclear cells (PB-MNC) stimulated with ephrin-B2/fc (PB-MNC + ) for preventing PSCI., Methods: Cortical infarct was induced by thermocoagulation of the middle cerebral artery in male diabetic mice (streptozotocin IP). PB-MNC were isolated from diabetic human donors, washed with recombinant ephrin-B2/Fc and injected into the mice intravenously on the following day. Infarct volume, sensorimotor deficit, cell death and immune cell densities were assessed on day 3. Six weeks later, cognitive assessment was performed using the Barnes maze., Results: PB-MNC + transplanted in post-stroke diabetic mice reduced the neurological deficit, infarct volume and apoptosis at D3, without modification of microglial cells, astrocytes and T-lymphocytes densities in the brain. Barnes maze assessment of memory showed that the learning, retention and reversal phases were not significantly modified by cell therapy., Conclusions: Intravenous PB-MNC + administration the day after stroke induction in diabetic mice improved sensorimotor deficit and reduced infarct volume at the short term, but was unable to prevent long-term memory loss. To what extent diabetes impacts on cell therapy efficacy will have to be specifically investigated in the future. Including vascular risk factors systematically in preclinical studies of cell therapy will provide a comprehensive understanding of the mechanisms potentially limiting cell efficacy and also to identify good and bad responders, particularly in the long term., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood., Methods: We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell' medium/HG-treated mouse hippocampal HT22 cells., Results: Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood-brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / -) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells., Conclusions: These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice., (© 2021. The Author(s).)

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by irreversible cognitive deficits and memory dysfunction. Dopamine is the most abundant catecholaminergic neurotransmitter in the brain which regulates motivation, reward, movement, and cognition. Recently, increasing evidences have shown that dopaminergic system is disturbed in AD conditions, and pharmacological interventions targeting dopamine D1 receptor (DRD1) exhibit certain therapeutic benefits in AD models. However, the underlying link between DRD1 and AD remains elusive. This study sought to test whether the selective DRD1 agonist A-68930 could improve streptozotocin (STZ)-induced cognitive impairment in mice. Here we found that A-68930 treatment through intraperitoneal injection efficiently alleviated STZ-induced cognitive deficits in mice. Moreover, our mechanism researches revealed that the DRD1 signaling induced by A-68930 significantly rescued STZ-induced mitochondrial biogenesis deficit, mitochondrial dysfunction, Aβ overexpression, and tau phosphorylation in mice hippocampus and cortex and SH-SY5Y cells, which may be mediated through stimulating AMPK/PGC-1α pathway. This study indicates that DRD1 agonist A-68930 can improve STZ-induced cognitive deficits and mitochondrial dysfunction in vivo and in vitro, and DRD1 may represent an appropriate target candidate for AD drug development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cognitive dysfunction is increasingly recognized as an important complication of diabetes mellitus (DM). Accumulating evidence indicates that the abnormality of cerebrovascular structure and function plays an essential role in diabetic cognitive impairment (DCI), however, changes in cerebrovascular factors have been blurred during the development of diabetes., Objective: To evaluate the changes in the structure and function of cerebrovascular in DCI mice and to investigate the changes of cerebral angiogenesis and stability factors during the development of DM., Methods: Diabetes was induced by feeding with high-fat diet combined with intraperitoneal injection of streptozotocin (STZ,120 mg/kg). Cognitive function was evaluated at different stages of DM, cerebral neovascularization, blood-brain barrier (BBB) permeability and hippocampal neurons were measured of DCI mice, and the expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor β (PDGFRβ) in hippocampus was detected during the development of DM., Results: With the progress of diabetes, the learning and memory ability of mice gradually decreased, and DCI mice showed neuronal degeneration, increased BBB permeability and pathological cerebral neovascularization. Moreover, the expression of VEGF in the hippocampus increased first and then decreased at DM+8week, PDGFRβ decreased continuously with the development of diabetes., Conclusions: Our results demonstrate that DCI may be attributed to the dynamic expression of VEGF/PDGFRβ in diabetic hippocampus, and pathological cerebral neovascularization, increased BBB permeability and neuronal degeneration are the key links., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Metabolic disorders are associated with a higher risk of psychiatric disorders. We previously reported that 20-week-old Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of progressive type 2 diabetes, showed increased anxiety-like behavior and regional area reductions and increased cholecystokinin-positive neurons in the corticolimbic system. However, in which stages of diabetes these alterations in OLETF rats occur remains unclear. We aimed to investigate anxiety-like behavior and its possible mechanisms at different stages of type 2 diabetes in OLETF rats. Eight- and 30-week-old OLETF rats were used as diabetic animal models at the prediabetic and progressive stages of type 2 diabetes respectively, and age-matched Long-Evans Tokushima Otsuka rats served as non-diabetic controls. In the open-field test, OLETF rats showed less locomotion in the center zone and longer latency to leave the center zone at 8 and 30 weeks old, respectively. The areas of the medial prefrontal cortex were smaller in the OLETF rats, regardless of age. The densities of cholecystokinin-positive neurons in OLETF rats were higher in the lateral and basolateral amygdala only at 8 weeks old and in the anterior cingulate and infralimbic cortices and hippocampal cornu ammonis area 3 at both ages. The densities of parvalbumin-positive neurons of OLETF rats were lower in the cornu ammonis area 2 at 8 weeks old and in the prelimbic and infralimbic cortices at both ages. No apoptotic cell death was detected in OLETF rats, but the percentage of neurons co-expressing activating transcription factor 4 and cholecystokinin and parvalbumin was higher in OLETF rats at both ages in the anterior cingulate cortex and basolateral amygdala, respectively. These results suggest that altered emotional behavior and related neurological changes in the corticolimbic system are already present in the prediabetic stage of OLETF rats., Competing Interests: No authors have competing interests.

Diabetes-related depression (DD) is a major complication of diabetes mellitus. Our previous studies indicated that glutamate (Glu) and hippocampal neuron apoptosis are key signal and direct factor leading to diabetes-related depression, respectively. However, the accurate pathogenesis remains to be unclear. We hypothesized that diabetes-related depression might be associated with the mitophagy-mediated hippocampal neuron apoptosis, triggered by aberrant Glu-glutamate receptor2 (GluR2)-Parkin pathway. To testify this hypothesis, here the rat model of DD in vivo and in vitro were both established so as to uncover the potential mechanism of DD based on mitophagy and apoptosis. We found that DD rats exhibit an elevated glutamate levels followed by monoamine neurotransmitter deficiency and depressive-like behaviour, and DD modelling promoted autophagosome formation and caused mitochondrial impairment, eventually leading to hippocampal neuron apoptosis via aberrant Glu-GluR2-Parkin pathway. Further, in vitro study demonstrated that the simulated DD conditions resulted in an abnormal glutamate and monoamine neurotransmitter levels followed by autophagic flux increment, mitochondrial membrane potential reduction and mitochondrial reactive oxygen species and lactic dehydrogenase elevation. Interestingly, both GluR2 and mammalian target of rapamycin (mTOR) receptor blocker aggravated mitophagy-induced hippocampal neuron apoptosis and abnormal expression of apoptotic protein. In contrast, both GluR2 and mTOR receptor agonist ameliorated those apoptosis in simulated DD conditions. Our findings revealed that mitophagy-mediated hippocampal neuron apoptosis, triggered by aberrant Glu-GluR2-Parkin pathway, is responsible for depressive-like behaviour and monoamine neurotransmitter deficiency in DD rats. This work provides promising molecular targets and strategy for the treatment of DD., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Introduction: Diabetes mellitus is related to cognitive impairments and molecular abnormalities of the hippocampus. A growing body of evidence suggests that Urtica dioica (Ud) and exercise training (ET) have potential therapeutic effects on diabetes and its related complications. Therefore, we hypothesized that the combined effect of exercise training (ET) and Ud might play an important role in insulin signaling pathway, oxidative stress, neuroinflammation, and cognitive impairment in diabetic rats., Methods: Forty animals were divided into five groups (N = 8): healthy-sedentary (H-sed), diabetes-sedentary (D-sed), diabetes-exercise training (D-ET), diabetes-Urtica dioica (D-Ud), diabetes-exercise training-Urtica dioica (D-ET-Ud). Streptozotocin (STZ) (Single dosage; 45 mg/kg, i.p.) was used to induce diabetes. Then, ET (moderate intensity/5day/week) and Ud extract (50 mg/kg, oral/daily) were administered for six weeks. We also investigated the effects of ET and Ud on cognitive performance (assessed through Morris Water Maze tests), antioxidant capacity, and lipid peroxidation markers in hippocampus. Furthermore, we measured levels of insulin sensitivity and signaling factors (insulin-Ins, insulin receptor-IR and insulin-like growth factor-1 receptor-IGF-1R), and neuroinflammatory markers (IL-1 β, TNF-α). This was followed by TUNEL assessment of the apoptosis rate in all regions of the hippocampus., Results: D-sed rats compared to H-sed animals showed significant impairments (P < 0.001) in hippocampal insulin sensitivity and signaling, oxidative stress, neuroinflammation, and apoptosis, which resulted in cognitive dysfunction. Ud extract and ET treatment effectively improved these impairments in D-ET (P < 0.001), D-Ud (P < 0.05), and D-ET-Ud (P < 0.001) groups compared to D-sed rats. Moreover, diabetes mediated hippocampal oxidative stress, neuroinflammation, insulin signaling deficits, apoptosis, and cognitive dysfunction was further reversed by chronic Ud+ET administration in D-ET-Ud rats (P < 0.001) compared to D-sed animals., Conclusions: Ud extract and ET ameliorate cognitive dysfunction via improvement in hippocampal oxidative stress, neuroinflammation, insulin signaling pathway, and apoptosis in STZ-induced diabetic rats. The results of this study provide new experimental evidence for using Ud+ET in the treatment of hippocampal complications and cognitive dysfunction caused by diabetes., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Gestational diabetes (GD) has a negative impact on neurodevelopment, resulting in cognitive and neurological deficiencies. Oxidative stress (OS) has been reported in the brain of the first-generation offspring of GD rats. OS has been strongly associated with neurodegenerative diseases. In this work, we determined the effect of GD on the cognitive behavior, oxidative stress and metabolism of second-generation offspring. GD was induced with streptozotocin (STZ) in pregnant rats to obtain first-generation offspring (F1), next female F1 rats were mated with control males to obtain second-generation offspring (F2). Two and six-month-old F2 males and females were employed. Anxious-type behavior, spatial learning and spatial working memory were evaluated. In cerebral cortex and hippocampus, the oxidative stress and serum biochemical parameters were measured. Male F2 GD offspring presented the highest level of anxiety-type behavior, whilst females had the lowest level of anxiety-type behavior at juvenile age. In short-term memory, adult females presented deficiencies. The offspring F2 GD females presented modifications in oxidative stress biomarkers in the cerebral cortex as lipid-peroxidation, oxidized glutathione and catalase activity. We also observed metabolic disturbances, particularly in the lipid and insulin levels of male and female F2 GD offspring. Our results suggest a transgenerational effect of GD on metabolism, anxiety-like behavior, and spatial working memory.

Cannabidiol (CBD), a phytocannabinoid compound, presents antidepressant and anxiolytic-like effects in the type-1 diabetes mellitus(DM1) animal model. Although the underlying mechanism remains unknown, the type-1A serotonin receptor (5-HT1A) and cannabinoids type-1 (CB1) and type-2 (CB2) receptors seem to play a central role in mediating the beneficial effects on emotional responses. We aimed to study the involvement of these receptors on an antidepressant- and anxiolytic-like effects of CBD and on some parameters of the diabetic condition itself. After 2 weeks of the DM1 induction in male Wistar rats by streptozotocin (60 mg/kg; i.p.), animals were treated continuously for 2-weeks with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.), CB1 antagonist AM251 (1 mg/kg i.p.) or CB2 antagonist AM630 (1 mg/kg i.p.) before the injection of CBD (30 mg/kg, i.p.) or vehicle (VEH, i.p.) and then, they were submitted to the elevated plus-maze and forced swimming tests. Our findings show the continuous treatment with CBD improved all parameters evaluated in these diabetic animals. The previous treatment with the antagonists - 5-HT1A, CB1, or CB2 - blocked the CBD-induced antidepressant-like effect whereas only the blockade of 5-HT1A or CB1 receptors was able to inhibit the CBD-induced anxiolytic-like effect. Regarding glycemic control, only the blockade of CB2 was able to inhibit the beneficial effect of CBD in reducing the glycemia of diabetic animals. These findings indicated a therapeutic potential for CBD in the treatment of depression/anxiety associated with diabetes pointing out a complex intrinsic mechanism in which 5-HT1A, CB1, and/or CB2 receptors are differently recruited.

Diabetes mellitus is mainly associated with degeneration of the central nervous system, which eventually leads to cognitive deficit. Although some studies suggest that exercise can improve the cognitive decline associated with diabetes, the potential effects of endurance training (ET) accompanied by Matricaria chamomilla (M.ch) flowers extract on cognitive impairment in type 2 diabetes has been poorly understood. Forty male Wistar rats were randomized into 5 equal groups of 8: healthy-sedentary (H-sed), diabetes-sedentary (D-sed), diabetes-endurance training (D-ET), diabetes-Matricaria chamomilla. (D-M.ch), and diabetes-endurance training-Matricaria chamomilla. (D-ET-M.ch). Nicotinamide (110 mg/kg, i.p.) and Streptozotocin (65 mg/kg, i.p.) were utilized to initiate type 2 diabetes. Then, ET (5 days/week) and M.ch (200 mg/kg body weight/daily) were administered for 12 weeks. After 12 weeks of the experiment, cognitive functions were assessed using the Morris Water Maze (MWM) test and a passive avoidance paradigm using a shuttle box device. Subsequently, using crystal violet staining, neuron necrosis was examined in the CA3 area of the hippocampus. Diabetic rats showed cognitive impairment following an increase in the number of necrotic cells in region CA3 of the hippocampal tissue. Also, diabetes increased serum levels of lipid peroxidation and decreased total antioxidant capacity in serum and hippocampal tissue. ET + M.ch treatment prevented the necrosis of neurons in the hippocampal tissue. Following positive changes in hippocampal tissue and serum antioxidant enzyme levels, an improvement was observed in the cognitive impairment of the diabetic rats receiving ET + M.ch. Therefore the results showed that treatment with ET + M.ch could ameliorate memory and inactive avoidance in diabetic rats. Hence, the use of ET + M.ch interventions is proposed as a new therapeutic perspective on the death of hippocampal neurons and cognitive deficit caused by diabetes., (Copyright © 2021 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Type 1 diabetes (T1D) has been reported to cause cognitive decline, but brain metabolic changes during this process are still far from being fully understood. Here, we found that streptozotocin (STZ)-induced T1D mice exhibited impaired learning and memory at 11 weeks after STZ treatment but not at 3 weeks. Therefore, we studied metabolic alterations in six different brain regions of T1D mice with and without cognitive decline, and attempted to identify key metabolic pathways related to diabetic cognitive dysfunction. The results demonstrate that lactate had already increased in all brain regions of T1D mice prior to cognitive decline, but a decreased TCA cycle was only observed in hippocampus, cortex and striatum of T1D mice with cognitive impairment. Reduced N-acetylaspartate and choline were found in all brain regions of T1D mice, irrespective of cognitive decline. In addition, disrupted neurotransmitter metabolism was noted to occur in T1D mice before cognitive deficit. Of note, we found that the level of uridine was significantly reduced in cerebellum, cortex, hypothalamus and midbrain of T1D mice when cognitive decline was presented. Therefore, brain region-specific metabolic alterations may comprise possible biomarkers for the early-diagnosis and monitoring of diabetic cognitive decline. Moreover, down-regulated TCA cycle and pyrimidine metabolism could be closely related to T1D-associated cognitive impairment., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Recent studies raise the possibility that donepezil can delay the progression of Alzheimer's disease (AD). This research evaluated the efficacy of donepezil in an animal model with brain insulin resistance and AD-like alterations. Rats were fed with high-fat/high-fructose (HF/Hfr) diet during the study period (17 weeks) and received one injection of streptozotocin (STZ) (25 mg/kg) after 8 weeks of starting the study. Diabetic (T2D) rats were treated with donepezil (4 mg/kg; p.o.) or vehicle for 8 weeks after STZ injection. The influence of donepezil on AD-related behavioral, biochemical, and neuropathological changes was investigated in T2D rats. Treatment of diabetic rats with donepezil led to a significant decrease in both amyloid-β deposition and the raised hippocampal activity of cholinesterase (ChE). It significantly increased the suppressed glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). It also improved cognitive dysfunction in the passive avoidance and the Morris water maze tests. However, donepezil treatment did not significantly decrease the elevated levels of P-tau, caspase-3, GSK-3β, MDA, TNF-α, and IL-1β in the hippocampus of diabetic rats. Also, it did not restore the suppressed levels of glutathione and superoxide dismutase in the brain of these rats. Moreover, donepezil did not alter the elevated serum level of glucose, insulin, and total cholesterol. These findings suggest that donepezil treatment could ameliorate learning and memory impairment in T2D rats through reversal of some of the AD-related alterations, including reduction of amyloid-β burden and ChE activity as well as restoration of glutamate receptor expression. However, lack of any significant effect on P-tau load, oxidative stress, neuroinflammation, and insulin resistance raises the question about the ability of donepezil to delay the development or arrest the progression of T2D-induced AD and it is still a matter of debate that requires further studies., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Memory loss is a complication of diabetes which requires new approaches to its treatment. Shengmai San (SMS) is a famous traditional Chinese formula containing Panax ginseng, Ophiopogon japonicas, and Schisandra chinensis, whereas Radix puerariae has many reported pharmacological uses. In this study the combination, as Jiawei SMS (J-SMS) was screened for its ability to reverse diabetes-associated cognitive decline in rats. This was assessed behaviorally in diabetic rats (Streptozotocin, 45 mg/kg), with biochemical and western blot analysis (Akt and CREB). Diabetic rats showed fasting blood glucose (FBG) in the range of 13-15 mM throughout the study. J-SMS (0.5, 1.5, 4.5 g/kg) treatment significantly improved learning and memory deficit among diabetic rats as evidenced by preference for novel object, reduced escape latency and increased number of platform crossings (p < .05) in the NORT and MWM tests. Treatment with J-SMS also significantly improved the histopathological changes in the diabetic brain and increased the protein expression of AKT and CREB, required for proper memory function (p < .01). This study highlighted that J-SMS can reverse reference and working memory deficit among diabetic rats by modulating AKT and CREB proteins activation. Thus, J-SMS formulation might be possible candidate for further development., (© 2020 John Wiley & Sons, Ltd.)

Epidemiological studies have pointed at diabetes as a risk factor for Alzheimer's disease (AD) and this has been supported by several studies in animal models of both type 1 and type 2 diabetes. However, side-by-side comparison of the two types of diabetes is limited. We investigated the role of insulin deficiency and insulin resistance in the development of memory impairments and the effect of Exendin-4 (Ex4) treatment in a mouse model of AD. Three-4-month-old female wild type (WT) mice and mice overexpressing human tau and amyloid precursor protein (TAPP) were injected with streptozotocin (STZ) or fed a high-fat diet (HFD). A second study was performed in TAPP-STZ mice treated with Ex4, a long-lasting analog of GLP-1. Plasma and brain were collected at study termination for ELISA, Western blot, and immunohistochemistry analysis. Learning and memory deficits were impaired in TAPP transgenic mice compared with WT mice at the end of the study. Deficits were exaggerated by insulin deficiency in TAPP mice but 12 weeks of insulin resistance did not affect memory performances in either WT or TAPP mice. Levels of phosphorylated tau were increased in the brain of WT-STZ and TAPP-STZ mice but not in the brain of WT or TAPP mice on HFD. In the TAPP-STZ mice, treatment with Ex4 initiated after established cognitive deficits ameliorated learning, but not memory, impairments. This was accompanied by the reduction of amyloid β and phosphorylated tau expression. Theses studies support the role of Ex4 in AD, independently from its actions on diabetes., (© 2020 Wiley Periodicals LLC.)

The incidence of depression doubles in diabetic patients and is associated with poor outcomes. Studies indicate that renin-angiotensin-aldosterone system inhibitors (RAASi) might relieve depression, however the mechanism of action is not well understood. We recently showed that angiotensin receptor blockers have antidepressant effects in experimental diabetes comorbid depression. Here we investigated whether all types of RAASi exhibit antidepressant and neuroprotective properties. Diabetes was induced by streptozotocin in adult male Wistar rats. After 5 weeks of diabetes, rats were treated per os with non-pressor doses of enalapril, ramipril, spironolactone or eplerenone for 2 weeks. Behavior was evaluated using forced swim test and open field test. Inflammatory response and brain-derived neurotrophic factor (BDNF) signaling were investigated in the hippocampus. Both ACEi and MR antagonists reversed diabetes-induced behavioral despair confirming their antidepressant-like effect. This may occur via alterations in hippocampal cytokine-mediated inflammatory response. Repressed BDNF production was restored by RAASi. Both ACEi and MR antagonists facilitated the BDNF-tropomyosin receptor kinase B-cAMP response element-binding protein signaling pathway as part of their neuroprotective effect. These data highlight the important benefits of ACEi and MR antagonists in the treatment of diabetes-associated depressive symptoms. Our novel findings support the link between diabetes comorbid depression, inflammation and repressed BDNF signaling. RAASi could provide new therapeutic options to improve the outcomes of both disorders., Competing Interests: Declaration of Competing Interest All other authors declare that they have no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Cognitive impairment and hyperalgesia are among the common manifestations of diabetes. Hyperglycemia may contribute to their developments but the exact pathophysiology underlying these complications is not fully understood. Flavonoids from plants original have beneficial effects on diabetes by improving glycemic control. Rutin (RUT) is a bioflavonoid found in many plants and foods with many biological activities including neuroprotective and antidiabetic effects. In this study, we hypothesized that administration of RUT (10, 25 and 50 mg/kg, i.g. ) for 30 days in rats would affect on hyperglycemia, cognitive dysfunction and hyperalgesia, which are common complications of diabetes type I. Methods: Diabetes was induced by streptozotocin (STZ) injection which destroys β-cells and induces clinical features in animals that resemble those in diabetes type I in humans. Therefore, STZ-treated animals are used for the evaluation of novel antidiabetic drugs. The animals received vehicle or RUT (10, 25 and 50 mg/kg, i.g., once daily) at the onset of hyperglycemia for 30 days. Learning and memory was assessed by passive avoidance learning and memory test in streptozocin-induced diabetic and non-diabetic rats. Chemical hyperalgesia was evaluated by the formalin test. Results: Diabetes-induced deficits in acquisition and retrieval processes. RUT (25 and 50 mg/kg) reversed learning and memory deficits in diabetic rats. These doses of RUT reversed chemical hyperalgesia during both phases of the formalin test in diabetic rats and induced antinociceptive effects in healthy animals. RUT 10 mg/kg did not alter behaviors in control and diabetic groups. RUT 50 mg/kg induced significant hypoglycemic effects in both diabetic and non-diabetic rats. Discussion: Prolonged oral administration of RUT (25 and 50 mg/kg) induced cognitive enhancing and antinociceptive effects in both control and diabetic rats. Therefore, it may represent a potential therapeutic option against diabetic neurological disorders which deserves consideration and further examination.

Aim: The purpose of this study was to investigate the possible effects of Myrtus communis subsp. communis (MC) on cognitive impairment in ovariectomized diabetic rats., Material and Method: Female Sprague-Dawley rats were divided into 5 groups consisting of 15 rats each; Control (C), Diabetes (D), Ovariectomy and diabetes (OVX + D), Ovariectomy, diabetes and donepezil (OVX + D + Don), Ovariectomy, diabetes and Myrtus communis subsp. communis (OVX + D + MC). Blood glucose measurements were made at the beginning and end of the experiments. The animals underwent the novel object recognition test (NORT) and their performance was evaluated. In hippocampal tissues; amyloid beta (Aβ) and neprilysin levels, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT) activities, polysialylated neural cell adhesion molecule (PSA-NCAM), α7 subunit of neuronal nicotinic acetylcholine receptor (α7-nAChR) and brain derived neurotrophic factor (BDNF) gene expressions were examined., Results: Animals with ovariectomy and diabetes showed increased levels of blood glucose, AChE activity and Aβ levels, and decreased neprilysin levels, ChAT activity, α7-nAChR, PSA-NCAM and BDNF gene expressions in parallel with a decrease in NORT performance score. On the other hand, in the MC-treated OVX + D group, there was a significant decrease observed in blood glucose levels and AChE activities while there was improvement in NORT performances and an increase in hippocampal ChAT activity, neprilysin levels, α7-nAChR, PSA-NCAM and BDNF expressions., Conclusion: These results suggest that MC extract could improve cognitive and neuronal functions with its anticholinesterase and antihyperglycemic properties., 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 © 2020 Elsevier B.V. All rights reserved.)

Diabetes mellitus (DM) is a highly prevalent chronic systemic disease, which may cause cognitive decline and degenerative change of the brain. Neuronal differentiation defects of neural stem cells (NSCs) played an important role in the development and progression of diabetes-associated cognitive decline (DACD), but the intrinsic pathological mechanism remains largely unclear. In the present study, we demonstrated that expression level of HDAC3 was upregulated in diabetic mice with reduced learning and memory abilities and in cultured NSCs after advanced glycation end products (AGEs) induction. In addition, AGEs interfered with normal differentiation of the cultured NSCs, and knocking down the expression of HDAC3 could partially attenuate the inhibitory effect of AGEs on NSCs differentiation. Findings in this study demonstrate that HDAC3 may serve as an experimental clue for revealing the pathogenesis of DACD., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Type 2 diabetes mellitus (T2DM) is a metabolic disease associated with chronic low-grade inflammation that is mainly associated with lifestyles. Exercise and healthy diet are known to be beneficial for adults with T2DM in terms of maintaining blood glucose control and overall health. We investigated whether a combination of exercise and curcumin supplementation ameliorates diabetes-related cognitive distress by regulating inflammatory response and endoplasmic reticulum (ER) stress. This study was performed using male Otsuka Long-Evans Tokushima Fatty (OLETF) rats (a spontaneous diabetes Type 2 model) and Long-Evans Tokushima Otsuka (LETO) rats (LETO controls) by providing them with exercise alone or exercise and curcumin in combination. OLETF rats were fed either a diet of chow (as OLETF controls) or a diet of chow containing curcumin (5 g/kg diet) for five weeks. OLETF rats exercised with curcumin supplementation exhibited weight loss and improved glucose homeostasis and lipid profiles as compared with OLETF controls or exercised OLETF rats. Next, we examined cognitive functions using a Morris water maze test. Exercise plus curcumin improved escape latency and memory retention compared to OLETF controls. Furthermore, OLETF rats exercised and fed curcumin had lower IL6, TNFα, and IL10 levels (indicators of inflammatory response) and lower levels of ER stress markers (BiP and CHOP) in the intestine than OLETF controls. These observations suggest exercise plus curcumin may offer a means of treating diabetes-related cognitive dysfunction.

Learning and memory deficits are obvious symptoms that develop over time in patients with poorly controlled diabetes. Hyperactivity of the renin-angiotensin system (RAS) is directly associated with β-cell dysfunction and diabetic complications, including cognitive impairment. Here, we investigated the protective and molecular effects of two RAS modifiers, aliskiren; renin inhibitor and captopril; angiotensin converting enzyme inhibitor, on cognitive deficits in the rat hippocampus. Injection of low dose streptozotocin for 4 days resulted in type 1 diabetes. Then, poorly controlled diabetes was mimicked with ineffective daily doses of insulin for 4 weeks. The hyperglycaemia and pancreatic atrophy caused memory disturbance that were identifiable in behavioural tests, hippocampal neurodegeneration, and the following significant changes in the hippocampus, increases in the inflammatory marker interleukin 1β, cholinesterase, the oxidative stress marker malondialdehyde and protein expression of phosphorylated extracellular-signal-regulated kinase and glycogen synthase kinase-3 beta versus decrease in the antioxidant reduced glutathione and protein expression of phosphorylated glycogen synthase kinase-3 beta. Blocking RAS with either drugs along with insulin amended all previously mentioned parameters. Aliskiren stabilized the blood glucose level and restored normal pancreatic integrity and hippocampal malondialdehyde level. Aliskiren showed superior protection against the hippocampal degeneration displayed in the earlier behavioural modification in the passive avoidance test, and the aliskiren group outperformed the control group in the novel object recognition test. We therefore conclude that aliskiren and captopril reversed the diabetic state and cognitive deficits in rats with poorly controlled STZ-induced diabetes through reducing oxidative stress and inflammation and modulating protein expression., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

Diabetic rats display cognition impairments accompanied by activation of NF-κB signalling and increased Aβ expression. Ghrelin has been suggested to improve cognition in diabetic rats. In this study, we investigated the role of ghrelin on cognition and NF-κB mediated Aβ production in diabetic rats. A diabetic rat model was established with streptozotocin (STZ) injection, and diabetic rats were intracerebroventricularly administered with ghrelin or (D-lys3)-GHRP-6 (DG). Our results showed that diabetic rats had cognition impairment in the Morris water maze test, accompanied by the higher expression of Aβ in the hippocampus. Western blot analysis showed that diabetic rats exhibited significantly decreased levels of GHSR-1a and protein phosphatase 1 (PP1) in the hippocampus and increased activation of the IKK/NF-κB/BACE1 pathway. Chronic ghrelin administration upregulated hippocampal PP1 expression, suppressed IKK/NF-κB/BACE1 mediated Aβ production, and improved cognition in STZ-induced diabetic rats. These effects were reversed by DG. Then, primary rat hippocampal neurons were isolated and treated with high glucose, followed by Ghrelin and DG, PP1 or IKK. Similar to the in vivo results, high glucose suppressed the expression levels of GHSR-1a and PP1, activated the IKK/NF-κB/BACE1 pathway, increased Aβ production. Ghrelin suppressed IKK/NF-κB/BACE1 induced Aβ production. This improvement was reversed by DG and a PP1 antagonist and was enhanced by the IKK antagonist. Our findings indicated that chronic ghrelin administration can suppress IKK/NF-κB/BACE1 mediated Aβ production in primary neurons with high glucose treatment and improve the cognition via PP1 upregulation in diabetic rats., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Depression is a chronic and progressive syndrome and commonly associated with several neuropsychiatric comorbidities, of which depression is the most studied. It has been demonstrated that statins also have anti-inflammatory and immunomodulatory properties, which being explored for potential benefits in depression. However, the role of statins in the treatment of diabetes-related depression has not been well examined. Herein, we investigated the effects of atorvastatin on depressive behaviors and neuroinflammation in streptozotocin-induced diabetic mice. Our data indicated that oral administration of atorvastatin at 10 or 20 mg/kg for 3 weeks markedly ameliorated diabetes-associated depressive behaviors reflected by better performance in sucrose preference test (SPT), tail suspension test (TST), and novelty-suppressed feeding test (NSFT). The study further showed that atrovastatin decreased the expression of nucleus NF-κB p65 expression and ameliorated neuroinflammatory responses in prefrontal cortex as evidenced by less Iba-1-positive cells and lower inflammatory mediators including IL-1β and TNF-α. As expected, atorvastatin-treated diabetic mice exhibited significant improvement of hyperlipidemia rather than hyperglycemia. These results suggest that atorvastatin has the potential to be employed as a therapy for diabetes-related depression.

Rationale: Studies point out a higher prevalence of posttraumatic stress disorder (PTSD) in individuals with diabetes mellitus. It is known that glucocorticoid (GR) and mineralocorticoid (MR) receptors are implicated in fear memory processes and PTSD. However, there is no preclinical studies addressing the involvement of these receptors on abnormal fear memories related to diabetic condition., Objectives: By inducing a contextual conditioned fear memory, we generate a suitable condition to investigate the extinction and the generalization of the fear memory in streptozotocin-induced diabetic (DBT) rats alongside the expression of the cytosolic and nuclear GR and MR in the hippocampus (HIP) and prefrontal cortex (PFC). Moreover, we investigated the involvement of the MR or GR on the acquisition of fear memory extinction and on the generalization of this fear memory. When appropriate, anxiety-related behavior was evaluated., Methods: Male Wistar rats received one injection of steptozotocin (i.p.) to induce diabetes. After 4 weeks, the animals (DBTs and non-DBTs) were subjected to a conditioned contextual fear protocol., Results: The expression of MR and GR in the HIP and PFC was similar among all the groups. The single injection of MR agonist was able to facilitate the acquisition of the impaired fear memory extinction in DBTs animals together with the impairment of its generalization. However, the GR antagonism impaired only the generalization of this fear memory which was blocked by the previous injection of the MR antagonist. All treatments were able to exert anxiolytic-like effects., Conclusions: The results indicate that MR activation in DBT animals disrupts the overconsolidation of aversive memory, without discarding the involvement of emotional behavior in these processes.

: Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive impairment. Ranolazine, an anti-ischemic drug used in the treatment of angina pectoris, has been shown to possess hypoglycemic properties in pre-clinical and clinical studies. The aim of this study was to evaluate the effects of ranolazine on glucose metabolism and cognitive function in a T2DM model of Wistar rats. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ). The control group received a normal caloric diet (NCD) and sodium citrate buffer. Metformin, an effective hypoglycemic drug, was employed as a positive control. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine, and NCD + Metformin. Rats received ranolazine (20 mg/kg), metformin (300 mg/kg), or water, for 8 weeks. At the end of the treatments, all animals underwent to an intraperitoneal glucose tolerance test (IPGTT) and behavioral tests, including passive avoidance, novel object recognition, forced swimming, and elevate plus maze tests. Interleukin-6 plasma levels in the six treatment groups were assessed by Elisa assay. Body mass composition was estimated by nuclear magnetic resonance (NMR). Glucose responsiveness significantly improved in the HFD/STZ + Ranolazine ( p < 0.0001) and HFD/STZ + Metformin ( p = 0.003) groups. There was a moderate effect on blood glucose levels in the NCD + Ranolazine and NCD + Metformin groups. Lean body mass was significantly increased in the HFD/STZ + Ranolazine and HFD/STZ + Metformin animals, compared to HFD/STZ + Vehicle animals. Ranolazine improved learning and long-term memory in HFD/STZ + Ranolazine compared to HFD/STZ + Vehicle ( p < 0.001) and ameliorated the pro-inflammatory profile of diabetic mice. These results support the hypothesis of a protective effect of ranolazine against cognitive decline caused by T2DM., Competing Interests: The Authors declare no conflict of interests.

Background: Diabetes mellitus is a metabolic disease which also causes cognitive deficits. Betaine (N,N,N-trimethylglycine), also known as trimethylglycine, has been shown to ameliorate diabetic symptoms in diabetic animals and improve cognitive ability in Alzheimer disease (AD) animals. However, the effects of betaine on cognitive deficits in diabetic animals have not been described yet. Therefore, in the current study, the effects of betaine on cognition in diabetic rats were evaluated., Methods: We established a diabetic rat model by injecting streptozotocin (STZ) into rats and administrated betaine to these diabetic rats. We monitored the metabolism index, and glucose and insulin levels in blood and cerebrospinal fluid. We measured inflammatory cytokine levels, including TNF-α, IL-1β, and IL-6, in serum and hippocampus. We also monitored oxidative stress in the hippocampus by measuring malondialdehyde (MDA) level and superoxide dismutase (SOD) activity. We measured the learning and memory ability of diabetic rats using the Morris water and Y maze tests and tested the phosphatidylinositol 3-kinase (PI3K)/Akt activation and p-mTOR level in the hippocampus., Results: Betaine improved glucose metabolism and suppressed the production of inflammatory cytokines, including TNF-α, IL-1β, and IL-6. Also, betaine decreased MDA concentration and increased SOD activity in the hippocampus of diabetic rats. Betaine ameliorated cognitive deficits in diabetic rats, and it promoted PI3K expression and Akt activation and decreased p-mTOR expression., Conclusion: Betaine alleviates cognitive deficits in STZ-induced diabetic rats via regulating the PI3K/Akt signaling pathway., (© 2020 S. Karger AG, Basel.)

Diabetes mellitus (DM) is a common health problem, which manifests itself with chronic hyperglycemia and impaired insulin action. The prevalence of anxiety disorders tends to be high in the diabetic population. Exercise has a well-known anxiolytic effect, also demonstrated on rodents, but the effect of exercise on the DM-induced anxiety is still unknown. Female, Wistar albino rats were randomly divided into four groups (n=8) (C; EX; DM; DM+EX). DM was induced by injection (i.p.; 50 mg/kg) of Streptozotocin (STZ). Rats exercised in moderate intensity on the treadmill (15m/min; 5°; 30 min) for 5 weeks. Anxiety-like behavior (ALB) was evaluated by Open field test (OFT) and Elevated Plus Maze (EPM). According to OFT, central time and central entry have increased with in EX but not in DM+EX. There was no difference between C and DM. Central latency time didn't differ among groups. Unsupported rearing increased in both EX and DM+EX. There was no significant decrease in DM. Freezing time was significantly increased in the DM group. Exercise training reduced freezing time both in diabetic and non-diabetic animals. EPM results were similar. Time spent in open arm was increased significantly in exercise groups compared to their sedentary matches, and freezing time data were also parallel to OFT. Our study revealed that diabetes had shown an anxiogenic effect, which was not severe, and it only manifested itself on some behavioral parameters. Exercise training was reduced anxiety-like behavior both in diabetic and non-diabetic rats. However, because of the nature of exercise studies, it is hard to separate the anxiolytic effect of exercise from the alteration of locomotion., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Several studies have suggested the association between neurodegenerative diseases and diabetes mellitus (DM), DM causes cognitive impairment with age, but its effect is not well known in Parkinson's disease (PD). As a member of the incretin family, Glucagon-like peptide-1 (GLP-1) has glycemic regulation functions. It also exerts many additional effects on different tissues through its receptor's widespread expression., Objective: our aim is to investigate the effect of pre-existing diabetes on the severity of PD in male albino rats, and to find out whether GLP-1 could improve PD symptoms in diabetic animals in addition to its hypoglycemic effect, and how it could do that., Methods: 75 adult male albino rats were equally divided into: Control, Parkinson's, Diabetic Parkinson's, Diabetic Parkinson's + low dose exenatide (GLP-1 receptor agonist), Diabetic Parkinson's + high dose exenatide group. Blood glucose and insulin, striatal dopamine, some striatal oxidative stress and inflammatory markers, and the catalepsy score were measured., Results: Pre-existing of diabetes before initiation of PD raises the severity of PD shown by the more significant increase in catalepsy score, and the more significant decrease in striatal dopamine level. GLP-1 effects extend beyond their hypoglycemic effects only since it has a direct anti-oxidant, and anti-inflammatory neuronal effect with increasing the striatal dopamine and improving the catalepsy score in a dose dependent manner., Conclusions: Diabetes increases the severity of impairment in PD, and GLP-1 improve it through its direct neuronal effect in addition to its indirect effect through producing hypoglycemia., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Rationale: Sugar has addictive potential owing to increase in monoaminergic-transmission at pleasure and reward centers of brain. Insulin dysfunction triggered synaptic monoamine deficit is associated with sugar overeating and craving-related psychological changes in diabetic patients. Sugar-substitute (saccharin) is non-caloric artificial sweetener that may alleviate brain disorders in diabetes., Objectives: In present study, effects of sucrose and sugar-substitute (saccharin) exposures and withdrawal on depression and anxiety-like behavior in type 2 diabetic mice were assessed., Methods: Swiss albino mice were injected with streptozotocin (135 mg/kg). After induction of diabetes, mice were exposed to a two-bottle water-water, 10% sucrose-water, or 10% saccharin-water choice paradigm for 28 days. Separate groups were employed to assess withdrawal effect of sucrose or saccharin in diabetic mice. Monoamine oxidase (MAO), corticosterone, thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH) were quantified after behavioral tests., Results: Diabetic mice manifested preference towards 10% sucrose or saccharin over water. Sucrose-overeating by diabetic mice amplified symptoms of depression and anxiety; however, withdrawal further exaggerated these behavioral abnormalities. Substitution of sucrose by 10% saccharin attenuated the depressive and anxiety-like behavior in comparison to diabetic mice that were exposed separately to water-water or sucrose-water alone, and with respect to normal mice. Although withdrawal from saccharin resurfaced behavioral anomalies in diabetic mice, however, these were significantly low in comparison with withdrawal from sucrose or normal group. Reinstatement of exposure to saccharin mitigated symptoms of depression and anxiety in diabetic mice., Conclusion: Preference of sucrose overeating augments while saccharin mitigates depressive and anxiety behavior during diabetes.

Impaired executive function is a major peril for patients with type 2 diabetes, reducing quality of life and ability for diabetes management. Despite the significance of this impairment, few animal models of type 2 diabetes examine domains of executive function such as cognitive flexibility or working memory. Here, we evaluated these executive function domains in db/db mice, an established model of type 2 diabetes, at 10 and 24 weeks of age. The db/db mice showed impaired cognitive flexibility in the Morris water maze reversal phase. However, the db/db mice did not show apparent working memory disturbance in the spatial working memory version of the Morris water maze or in the radial water maze. We also examined axon initial segments (AIS) and nodes of Ranvier, key axonal domains for action potential initiation and propagation. AIS were significantly shortened in medial prefrontal cortex and hippocampus of 26-week-old db/db mice compared with controls, similar to our previous findings in 10-week-old mice. Nodes of Ranvier in corpus callosum, previously shown to be unchanged at 10 weeks, were elongated at 26 weeks, suggesting an important role for this domain in disease progression. Together, the findings help establish db/db mice as a model of impaired cognitive flexibility in type 2 diabetes and advance our understanding of its pathophysiology., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Brain is a site of diabetic end-organ damage. Diabetes-associated cognitive dysfunction, referred as "diabetic encephalopathy" (DE) has been coined for the patients with type 2 diabetes mellitus showing decline in their cognitive function, especially weak episodic memory, cognitive inflexibility and poor psychomotor performance leading towards Alzheimer's disease. Current evidence supported that aberrant synapses, energy metabolism imbalance, advanced glycation end products (AGEs) accumulation and Tau hyperphosphorylation are associated with cognition deficits induced by diabetes. Oleoylethanolamide (OEA), an endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonist, has anti-hyperlipidemia, anti-inflammatory and neuroprotective activities. However, the effect of OEA on DE is unknown. Therefore, we tested its influence against cognitive dysfunction in high fat diet and streptozotocin (HFD + STZ)-induced diabetic C57BL/6J and PPARα - -/- mice using Morris water maze (MWM) test. Neuron staining, dementia markers and neuroplasticity in the hippocampus were assessed to evaluate the neuropathological changes. The results showed that chronic OEA treatment significantly lowered hyperglycemia, recovered cognitive performance, reduced dementia markers, and inhibited hippocampal neuron loss and neuroplasticity impairments in diabetic mice. In contrast, the changes in MWM performance and neuron loss were not observed in PPARα knockout mice via OEA administration. These results indicated that OEA may provide a potential alternative therapeutic for DE by activating PPARα signaling., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The study was designed to find out the effect of thymoquinone (TQ) alone and combination of TQ + fluoxetine in depression of type-2 diabetic rats. Glucose level was significantly decreased in TQ alone treated group, whereas no significant change was recorded when TQ was combined with fluoxetine. Administration of TQ alone and combination of TQ and fluoxetine significantly decreased immobility time, increased latency to immobility and increased locomotor activity. Treatment with TQ alone significantly decreased level of TBARS, increased GSH and restored the activities of antioxidant enzymes (GPx, GR & CAT). However, TQ and fluoxetine combination reduced TBARS level, increased GSH content but no change in the antioxidant enzymes activities. Inflammatory markers (IL-1β, IL-6 & TNF-α) levels were significantly reduced after the administration of TQ alone and TQ + fluoxetine. The study suggests that combination of TQ and fluoxetine can be used to control depression in type-2 diabetes mellitus.

Introduction: Our previous study has confirmed that a novel curcumin derivate nicotinate-curcumin (NC) can facilitate autophagic flux in THP-1 cells induced by oxidized low-density lipoprotein., Aims: Given that autophagy plays critical roles in neurodegenerative diseases, the present study was carried out to investigate whether NC can improve cognitive function of rats with diabetes mellitus (DM) via restoring autophagic flux in CA1 hippocampus., Results: Our results showed that NC treatment improved cognitive deficit and attenuated neuronal loss as well as cellular ultrastructure impairment in the CA1 region of DM rats induced by streptozotocin. Moreover, NC lowered the expressions of the apoptosis-related proteins Bcl-2, Bax, Cyt-c, and cleaved Caspase-3. Notably, NC treatment reversed autophagic flux impairment as evidenced by the deceases in LC3-II and p62 protein levels, and autophagosome accumulation in the hippocampal CA1 region of DM rats. However, these protective effects of NC were abolished by cotreatment with 3-methyladenine (an autophagy inhibitor) and chloroquine (an autophagic flux inhibitor), respectively. Furthermore, NC treatment decreased the expressions of phosphorylated mammalian target of rapamycin (mTOR) and p70 ribosomal protein S6 kinase (p70S6k) proteins in the CA1 region of DM rats., Conclusions: These results indicate that NC ameliorates DM-induced cognitive function impairment via restoring autophagic flux might by inhibiting mTOR/p70S6k activation in the CA1 region, and NC may be a promising agent for diabetic cognitive dysfunction prevention and treatment., (© 2018 John Wiley & Sons Ltd.)

Diabetes is one of the risk factors for the development of vascular dementia (VD), leading to endothelial dysfunction and cognitive impairment. Resveratrol has been shown to have antioxidant, antiinflammatory, and neuroprotective effects. The previous studies have also reported that resveratrol improves cognitive and vascular endothelial functions in several pathological conditions. In the present study we aimed to evaluate the effect of resveratrol on cognitive and vascular endothelial function and to explore the mechanisms of its effects in the streptozotocin-induced diabetic rat model of VD. Male Wistar rats were divided into 3 groups (n = 10 in each group): Control, diabetes (DM), DM + resveratrol (DM + RSV) groups. Rats from the DM + RSV group received resveratrol (20 mg/kg/day, ip) for 4 weeks after induction of diabetes and then cognitive functions of the rats were tested by the Morris water maze and a passive avoidance tests. After behavioral tests, endothelial function of thoracic aorta (the endothelium-dependent and -independent vasorelaxant responses) was investigated. To explore the mechanisms of resveratrol, endothelial eNOS, aortic superoxide dismutase (SOD), NADPH oxidase, heme oxygenase-1 (HO-1) levels, TNF-α and IL-1β expressions; serum SOD and NADPH oxidase levels and, hippocampal BDNF, TNF-α and IL-1β expressions were measured. It was shown that DM resulted in severe learning and memory deficits associated with endothelial dysfunction, increased expression of TNF-α and IL-1β, increased oxidative stress levels and decreased expression of eNOS and BDNF. In contrast, resveratrol treatment improved the cognitive decline. It was also found that chronic treatment with resveratrol ameliorated the impaired vascular reactivity. Reveratrol significantly reversed diabetes-induced changes of protein expression. Our data suggest that resveratrol prevents memory deficits, endothelial dysfunction, increased oxidative stress, inflammation and impairment of neurotrophin expression in a VD rat model. Thus, the vasculoprotective and neuroprotective effects of resveratrol may be beneficial in DM patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Despite the strong association between diabetes and dementia, it remains to be fully elucidated how insulin deficiency adversely affects brain functions. We show that insulin deficiency in streptozotocin-induced diabetic mice decreased mitochondrial ATP production and/or citrate synthase and cytochrome oxidase activities in the cerebrum, hypothalamus, and hippocampus. Concomitant decrease in mitochondrial fusion proteins and increased fission proteins in these brain regions likely contributed to altered mitochondrial function. Although insulin deficiency did not cause any detectable increase in reactive oxygen species (ROS) emission, inhibition of monocarboxylate transporters increased ROS emission and further reduced ATP production, indicating the causative roles of elevated ketones and lactate in counteracting oxidative stress and as a fuel source for ATP production during insulin deficiency. Moreover, in healthy mice, intranasal insulin administration increased mitochondrial ATP production, demonstrating a direct regulatory role of insulin on brain mitochondrial function. Proteomics analysis of the cerebrum showed that although insulin deficiency led to oxidative post-translational modification of several proteins that cause tau phosphorylation and neurofibrillary degeneration, insulin administration enhanced neuronal development and neurotransmission pathways. Together these results render support for the critical role of insulin to maintain brain mitochondrial homeostasis and provide mechanistic insight into the potential therapeutic benefits of intranasal insulin.-Ruegsegger, G. N., Manjunatha, S., Summer, P., Gopala, S., Zabeilski, P., Dasari, S., Vanderboom, P. M., Lanza, I. R., Klaus, K. A., Nair, K. S. Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes.

Estrogen receptors (ERs) are thought to be associated with the onset and progression of neurodegenerative injuries and diseases, but the relationship and mechanisms underlying between ERs and cognition in type 2 diabetes remain elusive. In the current study, we investigated the effects of ERα and ERβ on the cognition, neurogenesis and apoptosis in high-fat diet and streptozocin-induced diabetic mice. We found that ERα and/or ERβ activation using their agonists (0.5 mg/kg E2, PPT or DPN) ameliorate memory impairment in the Morris water maze and Y-maze tests, increase hippocampal neurogenesis and prevent hippocampal apoptotic responses. Importantly, treatment with the pharmacologic ERs agonists caused significant increases in the membrane ERα and ERβ expression and subsequent PI3K/Akt, CREB and BDNF activation in the hippocampus of type 2 diabetes mellitus mice. Our data indicate that ERα and ERβ are involved in the cognitive impairment in type 2 diabetes, and that activated ERs, such as application of ERs agonists, could be a novel and promising strategy for the treatment of diabetic cognitive impairment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

An emerging body of evidence consistently suggests that compromised blood-brain barrier integrity may be causally associated with cognitive decline induced by type-2 diabetes. Our previous studies demonstrated that selected anti-inflammatory/anti-oxidative agents can preserve the integrity of blood-brain barrier and prevent neuroinflammation in mouse models of dysfunctional blood-brain barrier. Therefore, we have tested whether the previously proven blood-brain barrier protective agent, probucol, can prevent blood-brain barrier breakdown and cognitive decline in a dietary-induced murine model of diabetic insulin resistance. After 6-month chronic ingestion of a diet high in fat and fructose, the mice became insulin resistant. The high-fat and high-fructose-fed mice showed significant cognitive decline assessed by Morris water maze, concomitant with significant elevations in cortical and hippocampal glial acidic fibrillary protein and Fluoro Jade-C staining, indicating heightened neuroinflammation and neurodegeneration, respectively. The integrity of blood-brain barrier in high-fat and high-fructose-fed mice was substantially compromised, and this showed a significant association with heightened neurodegeneration. Co-provision of probucol with high-fat and high-fructose diet completely prevented the cognitive decline and blood-brain barrier dysfunction. Similarly, metformin was able to restore the cognitive function in high-fat and high-fructose-fed mice, while its blood-brain barrier protective effects were modest. These data suggest that probucol may prevent cognitive decline induced by insulin resistance by preserving the integrity of blood-brain barrier, whereas metformin's neuroprotective effects may be mediated through a separate pathway.

This study examined the potency and efficacy of ascorbic acid (AA) in the management of depression-like behavior in diabetic rats. Diabetes mellitus was induced by single intraperitoneal injections of nicotinamide (120 mg/kg) and streptozotocin (65 mg/kg) administered 15 min apart. Diabetic (blood glucose ≥250 mg/dL) rats were subjected to intermittent foot-shocks to induce comorbid depression. Seven groups of diabetes comorbid depressed rats received vehicle (1 mL/kg) or AA (10, 25, 50, 100, 200, or 400 mg/kg) orally for eleven days. Three control groups namely- nondiabetic, diabetic, and depressed rats received the vehicles only. The potency (ED 50 ) and efficacy (E max ) of AA against immobility period, hypercorticosteronemia, adrenal hyperplasia, hyperglycemia, hypoinsulinemia, oxidative stress, and inflammatory response were estimated. AA administration caused a dose-dependent decrease (P < 0.05) in immobility period with maximum inhibition of 69% (efficacy) at 200 mg/kg and ED 50 of 14 mg/kg (potency). AA at 200 mg/kg produced the maximal reduction in hypercorticosteronemia (55.1%) and adrenal hyperplasia (52.6%) with ED 50 of 9.8 and 14.4 mg/kg, respectively. AA at 400 mg/kg produced the maximal reduction in hyperglycemia (35.5%), hypoinsulinemia (32.7%), and lipid peroxidation (82%) with ED 50 of 18.6, 13.7, and 20.7 mg/kg, respectively. Moreover, AA at 400 mg/kg produced the maximal increase in SOD content (83%), CAT activity (77.9%), and IL-10 level (63%) with ED 50 of 21.5, 21, and 21 mg/kg, respectively. In conclusion, the present results suggest that AA has therapeutic potential against diabetes comorbid depression but better regulation of hyperglycemia and hypoinsulinemia is required to achieve maximal benefits., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Diabetes mellitus can induce impairment in learning and memory. Cognitive and memory deficits are common in older adults and especially in those with diabetes. This is mainly because of hyperglycemia, oxidative stress, and vascular abnormalities. Coenzyme Q10 (CoQ10) can decrease oxidative stress, hyperglycemia, and inflammatory markers, and improve vascular function. Therefore, the aim of the present study was to investigate the possible effects of CoQ10 on cognitive function, learning, and memory in middle-aged healthy and diabetic rats. Adult middle-aged male Wistar rats (390-460 g, 12-13 months old) were divided into 6 experimental groups. Diabetes was induced by a single i.p. injection of streptozotocin (60 mg/kg). CoQ10 (20 or 120 mg/kg, orally by gavage) was administered for 45 days. The cognitive function and learning memory of rats were evaluated using novel object recognition (NOR) and passive avoidance tests. The discrimination index of the NOR test in the diabetic groups receiving CoQ10 (20 or 120 mg/kg) and the healthy group receiving CoQ10 (120 mg/kg) was significantly higher than that in the control group. In addition, the step through latency was significantly longer and the time spent in the dark compartment was significantly shorter in the diabetic groups receiving CoQ10 than in the control group. CoQ10 supplementation can improve learning and memory deficits induced by diabetes in older subjects. In addition, CoQ10 at higher doses can improve cognitive performance in older healthy subjects., (© 2018 S. Karger AG, Basel.)

Recurrent nonsevere hypoglycemia (RH) can lead to cognitive dysfunction in patients with diabetes, although the involved mechanisms remain unclear. Here, we aimed to investigate the mechanism underlying RH-induced cognitive deficits with a focus on mitochondrial homeostasis. To establish a model that mimicked RH in patients with type 1 diabetes (T1DM) receiving insulin therapy, streptozotocin-induced mice with T1DM were subjected to recurrent, twice-weekly insulin injections over 4 wk. We found that RH disrupted the mitochondrial fine structure, reduced the number of mitochondria, and upregulated the expression of mitochondrial dynamics and mitophagy markers, including dynamin-related protein 1 (Drp1), Bcl-2/adenovirus E1B 19-kDa-interacting protein-3 (BNIP3), and microtubule-associated protein 1 light-chain 3 (LC3) in the hippocampus of T1DM mice. Moreover, RH and chronic hyperglycemia synergistically promoted the production of reactive oxygen species, impaired mitochondrial membrane potential, and suppressed mitochondrial energy metabolism. Under diabetic conditions, RH also altered the synaptic morphology and reduced the expression of synaptic marker proteins. Long-term recognition memory and spatial memory, assessed with the Morris water maze test, were also impaired. However, these effects were largely prevented by mitochondrial division inhibitor 1, a potent and selective Drp1 inhibitor. Thus, it appears that RH exacerbates the imbalance of mitochondrial homeostasis, leading to synapse injury and cognitive deficits in diabetes. The adjustment of mitochondrial homeostasis could serve as an effective neuroprotective approach when addressing low blood sugar conditions.