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Since genetic mutations during brain development play a significant role in the genesis of epilepsy, and such genetically determined epilepsies are the most difficult to treat, there is a need to study the mechanisms of epilepsy development with deletions of various transcription factors. We utilized heterozygous mice (Sip1wt/fl) with a neuronal deletion of the transcription factor Sip1 (Smad interacting protein 1) in the cerebral cortex. These mice are characterized by cognitive impairment and are prone to epilepsy. It is known that the brain-derived neurotrophic factor (BDNF) has a neuroprotective effect in various neurodegenerative diseases. Therefore, we created and applied an adeno-associated construct carrying the BDNF sequence selectively in neurons. Using in vitro and in vivo research models, we were able to identify a key gen, the disruption of whose expression accompanies the deletion of Sip1 and contributes to hyperexcitation of neurons in the cerebral cortex. Overexpression of BDNF in cortical neurons eliminated epileptiform activity in neurons obtained from heterozygous Sip1 mice in a magnesium-free model of epileptiform activity (in vitro). Using PCR analysis, it was possible to identify correlations in the expression profile of genes encoding key proteins responsible for neurotransmission and neuronal survival. The effects of BDNF overexpression on the expression profiles of these genes were also revealed. Using BDNF overexpression in cortical neurons of heterozygous Sip1 mice, it was possible to achieve 100% survival in the pilocarpine model of epilepsy. At the level of gene expression in the cerebral cortex, patterns were established that may be involved in the protection of brain cells from epileptic seizures and the restoration of cognitive functions in mice with Sip1 deletion. [ABSTRACT FROM AUTHOR]

Psychiatric conditions, such as depression, anxiety, bipolar disorder, and schizophrenia, are increasingly recognized as significant risk factors for cardiovascular disease (CVD). This review systematically analyzes evidence from various databases to provide a comprehensive understanding of the impact of psychiatric illnesses on the incidence, management, and prognosis of CVD. Key findings suggest a bidirectional relationship between psychiatric disorders and CVD, indicating that mental health conditions can predispose individuals to CVD, while CVD can exacerbate or trigger psychiatric symptoms. The review explores the underlying mechanisms of these associations, including behavioral factors, stress responses, and medication side effects. It also examines the challenges in managing CVD patients with comorbid psychiatric conditions, emphasizing the importance for integrated care approaches. This review underscores the necessity of considering mental health as an integral component of cardiovascular care and calls for further research to develop tailored management strategies for these complex conditions, ultimately aiming to improve patient outcomes and quality of life. This comprehensive analysis provides valuable insights for future investigations and guides clinicians in optimizing care for patients with both psychiatric and cardiovascular conditions. [ABSTRACT FROM AUTHOR]

Background: Emerging issues in the management of major depressive disorder (MDD) comprise a nonadherence to treatment and treatment failures, depressive recurrence and relapses, misidentification of incoming exacerbated phases and consequently, a chronification of depression. While antidepressant drugs constitute the standard of care for MDD, effective psychosocial interventions are needed to reduce rehospitalizations and other adverse events. The present study primarily investigated the effects and impact of implementing a structured psychoeducational intervention on the clinical course of MDD. Methods: A non-randomized comparative, pragmatic, pilot, single-center study of adults with nonpsychotic moderate or severe episode of MDD recently discharged from a psychiatric hospitalization. The consecutive subjects were allocated either to the intervention group (N=49) or to the attention control group (N=47), based on their preference. The psychoeducational intervention was based on a modified Munoz's Depression Prevention Course. Subjects were followed up prospectively for two years. Results: The absolute changes in Beck anxiety inventory scale, Zung's depression questionnaire, and Montgomery and Äsberg depression rating scale (MADRS) total scores at 6-month follow-up were comparable between the two groups. There were lower rates of the rehospitalization within one year (2.1% vs. 16.7%; P<0.001) and less rehospitalizations after one year (6.3% vs. 25%; P<0.001), lower rates of the ongoing sickness absence (11.5% vs. 29.2%; P<0.001), less persons with disability due to MDD at 1-year follow-up (1% vs. 11.5%; P=0.002), and less nonadherent subjects who self-discontinued treatment (6.3% vs. 28.1%; P<0.001) among participants in the intervention group compared to the control group. The disability due to MDD at 1-year follow-up was predicted by the absence of the psychoeducational intervention (P=0.002) and by the MADRS total score at 6-month follow-up (OR 1.10; 95% CI 1.003-1.195; P=0.044). Qualitative data indicated the intervention was desired and appreciated by the participants, as well as being practical to implement in Slovakian clinical settings. Conclusion: The results suggest the psychoeducational intervention based on a modified Munoz's Depression Prevention Course has beneficial effects in adults with MDD recently discharged from a psychiatric hospitalization. The findings implicate the psychoeducational intervention may offer a new approach to the prevention of depressive relapses. [ABSTRACT FROM AUTHOR]

Depressive disorders are the most prevalent mental health conditions in the world. The commonly prescribed antidepressant medications can have serious side effects, and their efficacy varies widely. Thus, simple, effective adjunct therapies are needed. Vinegar, a fermented acetic acid solution, is emerging as a healthful dietary supplement linked to favorable outcomes for blood glucose management, heart disease risk, and adiposity reduction, and a recent report suggests vinegar may improve symptoms of depression. This randomized controlled study examined the 4-week change in scores for the Center for Epidemiological Studies Depression (CES-D) questionnaire and the Patient Health Questionnaire (PHQ-9) in healthy overweight adults ingesting 2.95 g acetic acid (4 tablespoons vinegar) vs. 0.025 g acetic acid (one vinegar pill) daily. A secondary objective explored possible underlying mechanisms using metabolomics analyses. At week 4, mean CES-D scores fell 26% and 5% for VIN and CON participants respectively, a non-significant difference between groups, and mean PHQ-9 scores fell 42% and 18% for VIN and CON participants (p = 0.036). Metabolomics analyses revealed increased nicotinamide concentrations and upregulation of the NAD+ salvage pathway for VIN participants compared to controls, metabolic alterations previously linked to improved mood. Thus, daily vinegar ingestion over four weeks improved self-reported depression symptomology in healthy overweight adults, and enhancements in niacin metabolism may factor into this improvement. [ABSTRACT FROM AUTHOR]

Importance: Approximately 9% of US adults experience major depression each year, with a lifetime prevalence of approximately 17% for men and 30% for women. Observations: Major depression is defined by depressed mood, loss of interest in activities, and associated psychological and somatic symptoms lasting at least 2 weeks. Evaluation should include structured assessment of severity as well as risk of self-harm, suspected bipolar disorder, psychotic symptoms, substance use, and co-occurring anxiety disorder. First-line treatments include specific psychotherapies and antidepressant medications. A network meta-analysis of randomized clinical trials reported cognitive therapy, behavioral activation, problem-solving therapy, interpersonal therapy, brief psychodynamic therapy, and mindfulness-based psychotherapy all had at least medium-sized effects in symptom improvement over usual care without psychotherapy (standardized mean difference [SMD] ranging from 0.50 [95% CI, 0.20-0.81] to 0.73 [95% CI, 0.52-0.95]). A network meta-analysis of randomized clinical trials reported 21 antidepressant medications all had small- to medium-sized effects in symptom improvement over placebo (SMD ranging from 0.23 [95% CI, 0.19-0.28] for fluoxetine to 0.48 [95% CI, 0.41-0.55] for amitriptyline). Psychotherapy combined with antidepressant medication may be preferred, especially for more severe or chronic depression. A network meta-analysis of randomized clinical trials reported greater symptom improvement with combined treatment than with psychotherapy alone (SMD, 0.30 [95% CI, 0.14-0.45]) or medication alone (SMD, 0.33 [95% CI, 0.20-0.47]). When initial antidepressant medication is not effective, second-line medication treatment includes changing antidepressant medication, adding a second antidepressant, or augmenting with a nonantidepressant medication, which have approximately equal likelihood of success based on a network meta-analysis. Collaborative care programs, including systematic follow-up and outcome assessment, improve treatment effectiveness, with 1 meta-analysis reporting significantly greater symptom improvement compared with usual care (SMD, 0.42 [95% CI, 0.23-0.61]). Conclusions and Relevance: Effective first-line depression treatments include specific forms of psychotherapy and more than 20 antidepressant medications. Close monitoring significantly improves the likelihood of treatment success. This narrative review uses data from network meta-analyses and systematic reviews to explore the prevalence, diagnosis, and treatment of major depression in US adults, including specific forms of psychotherapy and more than 20 antidepressant medications. [ABSTRACT FROM AUTHOR]

Problem: Cardiorespiratory fitness (CRF) and mitochondrial function are important factors in health and disease. Even in immune cells, an effective metabolism is crucial for most major cellular functions, such as T-cell proliferation. Little is known about the relationship between CRF and mitochondrial metabolism of immune cells. Methods: In this narrative review, we collected the most recent literature in the field of exercise immunology and mitochondrial immune cell metabolism. We included studies, which used Oxygraph-or Seahorse techniques for measurement of mitochondrial function in various immune cell populations and subtypes associated with topics in the field of exercise in health and disease. Results: 20 studies were included in our analysis. Cell populations were PBMCs (peripheral blood mononuclear **cells), lymphocytes, T cells, NK cells, platelets, and neutrophils. While mitochondrial function was inconstantly affected through acute bouts of exercise, most of the studies, which included training interventions, reported a higher mitochondrial function in immune cells, which were in some studies correlated with the CRF. In various disease conditions, mitochondrial function of immune cells was impaired compared to healthy controls. Discussion: If a regular exercise training is followed by an improvement in immune cell mitochondrial respiration, regular exercise could become even more important in the context of optimizing immune function and immune regulation in prevention and therapy. [ABSTRACT FROM AUTHOR]

Background: Little is known about the prevalence of cellular senescence among immune cells (i.e., immune cells expressing senescence markers, iSCs) nor is there a gold-standard to efficiently measure iSCs. Major depressive disorder (MDD) in older adults has been associated with many hallmarks of senescence in whole blood, leukocytes, and plasma, supporting a strong connection between iSCs and MDD. Here, we investigated the prevalence and phenotype of iSCs in older adults with MDD. Using a single-cell phenotypic approach, circulating immune cells were examined for iSC biomarkers and their relationship to depression and inflammation. Results: PBMCs from older adults with MDD(aged 69.75 ± 5.23 years) and healthy controls (aged 71.25 ± 8.8 years) were examined for immune subset distribution and senescence biomarkers (i.e., lack of proliferation, senescence-associated heterochromatin foci (SAHF), and DNA damage). Dual-expression of SAHF and DNA damage was categorized by low, intermediate, and high expression. A significant increase in the number of high expressing total PBMCs (p = 0.01), monocytes (p = 0.008), a trending increase in the number of high expressing CD4 T cells (p = 0.06) was observed overall in those with MDD. There was also a significantly lower proportion of intermediate expressing cells in monocytes and CD4 T cells in MDD (p = 0.01 and p = 0.05, respectively). Correlation analysis revealed associations between iSCs and mRNA expression of factors related to SASP and immune cell function. Conclusion: MDD is associated with increased senescent cell biomarkers in immune cell populations delineated by distinct levels of SAHF and DNA damage. Inflammatory markers might serve as potent indicators of iSC burden in MDD. [ABSTRACT FROM AUTHOR]

L-type voltage-gated calcium channels (L-VGCCs) are thought to be involved in epileptogenesis and acute excitotoxicity. However, little is known about the role of L-VGCCs in neuroinflammation or delayed neuronal death following excitotoxic insult. We examined the effects of repeated treatment with the L-VGCC blocker nimodipine on neuroinflammatory changes and delayed neuronal apoptosis in the dentate gyrus following trimethyltin (TMT)-induced convulsions. Male C57BL/6 N mice were administered TMT (2.6 mg/kg, i.p.), and the expression of the Ca v 1.2 and Ca v 1.3 subunits of L-VGCC were evaluated. The expression of both subunits was significantly decreased; however, the astroglial expression of Ca v 1.3 L-VGCC was significantly induced at 6 and 10 days after TMT treatment. Furthermore, astroglial Ca v 1.3 L-VGCCs colocalized with both the pro-inflammatory phenotype marker C3 and the anti-inflammatory phenotype marker S100A10 of astrocytes. Nimodipine (5 mg/kg, i.p. × 5 at 12-h intervals) did not significantly affect TMT-induced astroglial activation. However, nimodipine significantly attenuated the pro-inflammatory phenotype changes, while enhancing the anti-inflammatory phenotype changes in astrocytes after TMT treatment. Consistently, nimodipine reduced the levels of pro-inflammatory astrocytes-to-microglia mediators, while increasing the levels of anti-inflammatory astrocytes-to-microglia mediators. These effects were accompanied by an increase in the phosphorylation of extracellular signal-regulated kinase (ERK), supporting our previous finding that p-ERK is a signaling factor that regulates astroglial phenotype changes. In addition, nimodipine significantly attenuated TMT-induced microglial activation and delayed apoptosis of dentate granule neurons. Our results suggest that L-VGCC blockade attenuates neuroinflammation and delayed neurotoxicity following TMT-induced convulsions through the regulation of astroglial phenotypic changes by promoting ERK signaling., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Depression and anxiety are the most frequent neuropsychiatric symptoms of multiple sclerosis (MS), an autoimmune-mediated demyelinating neurodegenerative disease. Their prevalence is 25-65% and 20-54%, respectively, often associated with chronic fatigue and cognitive impairment, but usually not correlated with motor and other deficits, suggesting different pathophysiological mechanisms. Both disorders often arise before MS diagnosis, lead to faster disability and impair the quality of life. Risk factors are (young) age, genetic and family history burden. While no specific neuropathological data for depression (and anxiety) in MS are available, modern neuroimaging studies showed bilateral fronto-temporal, subcortical and limbic atrophies, microstructural white matter lesions and disruption of frontoparietal, limbic and neuroendocrine networks. The pathogenesis of both depression and anxiety in MS is related to shared mechanisms including oxidative stress, mitochondrial dysfunction, neuroinflammation and neuroendocrine mechanisms inducing complex functional and structural brain lesions, but they are also influenced by social and other factors. Unfortunately, MS patients with anxiety, major depression or suicidal thoughts are often underassessed and undertreated. Current treatment, in addition to antidepressant therapy include transcranial magnetic stimulation, cognitive, relaxation, dietary and other healthcare measures that must be individualized. The present state-of- the-art review is based on systematic analysis of PubMed, Google Scholar and Cochrane Library until May 2024, with focus on the prevalence, clinical manifestation, neuroimaging data, immune mechanisms and treatment options. Depression and anxiety in MS, like in many other neuroimmune disorders, are related, among others, to multi-regional patterns of cerebral disturbances and complex pathogenic mechanisms that deserve further elucidation as a basis for early diagnosis and adequate management to improve the quality of life in this disabling disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

14-3-3 proteins are a family of regulatory proteins that are abundantly expressed in the brain and enriched at the synapse. Dysfunctions of these proteins have been linked to neurodevelopmental and neuropsychiatric disorders. Our group has previously shown that functional inhibition of these proteins by a peptide inhibitor, difopein, in the mouse brain causes behavioural alterations and synaptic plasticity impairment in the hippocampus. Recently, we found an increased cFOS expression in difopein-expressing dorsal CA1 pyramidal neurons, indicating enhanced neuronal activity by 14-3-3 inhibition in these cells. In this study, we used slice electrophysiology to determine the effects of 14-3-3 inhibition on the intrinsic excitability of CA1 pyramidal neurons from a transgenic 14-3-3 functional knockout (FKO) mouse line. Our data demonstrate an increase in intrinsic excitability associated with 14-3-3 inhibition, as well as reveal action potential firing pattern shifts after novelty-induced hyperlocomotion in the 14-3-3 FKO mice. These results provide novel information on the role 14-3-3 proteins play in regulating intrinsic and activity-dependent neuronal excitability in the hippocampus., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)