Hypothalamic-pituitary-adrenal Research Articles

Exploring the Neuropharmacological Terrain of Depression and Anxiety: Mechanisms, Therapies, and Future Avenues

Depression and anxiety are prevalent mental health illnesses that have significant worldwide consequences, impacting millions of individuals who experience chronic feelings of melancholy, excessive worry, and significant limitations in their everyday activities. Major Depressive Disorder (MDD) and several anxiety disorders, such as Generalized Anxiety Disorder (GAD), panic disorder, and social anxiety disorder, are defined by severe symptoms that make their treatment more difficult, especially when these illnesses happen at the same time. Gaining a comprehensive understanding of the neuropharmacological mechanisms that are responsible for these illnesses is of utmost importance in order to facilitate the development of treatments that are very effective. The existing therapy approaches, such as Selective Serotonin Reuptake Inhibitors (SSRIs) and newer antidepressants, provide partial relief but do not work for everyone. This suggests that further research is necessary to explore the underlying neurological causes of these illnesses. Recent developments in the field of neuropharmacology have provided insights into the significance of imbalances in neurotransmitters, specifically serotonin, norepinephrine, and dopamine, in the underlying mechanisms of mood disorders. Disruption of the Hypothalamic-Pituitary-Adrenal (HPA) axis and neuroinflammation are also major factors in the development of these illnesses. This review offers a thorough examination of these pathways, emphasizing the functions of neurotransmitter systems, neurostimulation treatments, and developing pharmaceutical medicines. This study investigates the possibility of new neuropharmacological targets, including NMDA receptor antagonists, AMPA receptor modulators, and neurosteroids, to enhance the effectiveness of treatment. In addition, it discusses non-pharmacological methods such as Cognitive Behavioral Therapy (CBT), physical activity, and mindfulness, highlighting their neuropharmacological foundations and advantages.This review is to provide an in-depth investigation of the current understanding and approaches to addressing depression and anxiety by including latest research findings. The text discusses crucial therapeutic approaches and presents potential areas of future study that could improve treatment results for these prevalent mental health illnesses.

Ashwagandha as an Adaptogen: Its Influence on Sleep Patterns, Stress Response, and Anxiety in Modern Life

Background: Ashwagandha (Withania somnifera), a prominent adaptogen in traditional Ayurvedic medicine, has gained substantial attention for its potential to enhance resilience to modern stressors, improve sleep quality, and alleviate anxiety. Preclinical and clinical studies have demonstrated that Ashwagandha’s active compounds, particularly withanolides, influence the hypothalamic-pituitary-adrenal (HPA) axis, leading to reductions in cortisol levels and a more balanced stress response. Puropose: This review aims to consolidate current evidence on Ashwagandha’s efficacy in modulating stress response, improving sleep patterns, and reducing anxiety levels. Material and methods: The review was based on the analysis of materials collected in the databases "Pubmed", Google Scholar, ResearchGate, books and other scientific articles. The search was conducted using keywords: “Ashwagandha”, “Withania somnifera”, “adaptogen”, “stress”, “anxiety”, “sleep”, “cortisol”. “HPA axis”. Results: A review of the literature has shown Ashwagandha anxiolytic properties, with effects comparable to standard anti-anxiety medications but with fewer side effects. Additionally, Ashwagandha has been shown to significantly improve sleep onset latency, sleep duration, and overall sleep quality, particularly in individuals suffering from stress-induced sleep disorders. Conclusions: Ashwagandha shows significant potential as a natural therapy for managing stress, improving sleep quality, and reducing anxiety, primarily through its effects on the hypothalamic-pituitary-adrenal (HPA) axis and cortisol regulation. Clinical trials have demonstrated its efficacy in improving sleep patterns and reducing anxiety, with a generally favorable safety profile. However, there is a need for further research, particularly to better understand the long-term effects and safety of Ashwagandha supplementation.

Glucose Metabolic Abnormality: A Crosstalk between Depression and Alzheimer's Disease.

Depression and Alzheimer's disease (AD) are two prevalent and debilitating conditions that significantly impact millions of people worldwide. Depressive disorders are characterized by persistent feelings of sadness, loss of interest, and impaired cognitive function. AD is a progressive neurodegenerative disorder that is accompanied by cognitive decline, memory loss, and behavioral changes. To date, the pathogenesis of AD and depression has not yet been fully explained. Recent studies have provided insights into the intricate relationship between these two disorders by emphasizing the role of glucose metabolic abnormalities as a potential link. This review explores the bidirectional association between depression and AD, focusing on common pathophysiological mechanisms involving glucose metabolism, such as hypothalamic-pituitary-adrenal (HPA) axis dysregulation, insulin resistance, glucose transporters, and oxidative stress. Understanding the crosstalk between glucose metabolic abnormalities, depression, and AD will open new avenues for therapeutic interventions. Finally, improving glucose metabolism through lifestyle modifications, pharmaceutical interventions or novel therapeutic approaches could provide a promising therapeutic strategy for managing both conditions simultaneously.

Dynamics of a pituitary–adrenal model with distributed time delays

This paper investigates the effects of distributed time delays on the dynamics of the pituitary–adrenal axis. Our two-dimensional model incorporates distributed time delays with general delay kernels, specifically illustrating interactions between adrenocorticotropic hormone (ACTH) and cortisol (CORT). We derive general theoretical results for general delay kernels, exemplified by Dirac and weak Gamma kernels, revealing stability transitions characterized by Hopf bifurcations. We establish conditions for the local asymptotic stability of the unique equilibrium and discuss the existence of periodic solutions. Numerical simulations demonstrate that periodic oscillations appear for appropriate values of the average time delays. Including an external input results in both ultradian and circadian rhythms, highlighting the system’s dynamic responsiveness to external stimuli.

Effects of Slow Breathing Exercises on Cardiac Autonomic Functions in Anxiety Disorder-A Randomised Control Trial.

Anxiety disorders are commonly associated with a higher risk of fatal cardiovascular diseases (CVD). Anxiety disorders lead to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, thus weakening the key neuronal components of the autonomic nervous system (ANS) that are involved in cardiovascular functions, leading to increased cardiovascular risk. Impaired ANS activity, as reduced parasympathetic tone is strongly associated with an increased risk of CVD in anxiety disorders. Slow pranayama influences the ANS by activating the parasympathetic tone and deactivating the sympathetic tone in healthy volunteers and various diseased conditions. Therefore, we aimed to study the effects of slow pranayama and savasana on cardiac autonomic function tests in anxiety disorder patients. Anxiety disorder patients (N = 140) of either sex between the age group 18 and 40 years attending the psychiatry outpatient department (OPD) in JIPMER were recruited for the study and were randomly assigned into the pranayama group and control group. The Pranayama group practised slow pranayama and savasana for 8 weeks along with routine psychiatric care, while the control group continued with routine psychiatric care only. Outcome measures were heart rate variability (HRV), baroreflex sensitivity (BRS), 30:15 ratio during lying to standing, E: I ratio during deep breathing, and ∇DBP during isometric handgrip, which were assessed before and after the intervention period. After 8 weeks in the Pranayama group, the HRV parameters showed significant improvement towards the parasympathetic domain. Also, there was a significant increase in parasympathetic reactivity with a decrease in sympathetic reactivity and significant improvement in BRS. Slow pranayama and savasana practice in anxiety disorder patients as an adjunct to routine psychiatric care effectively improves cardiac autonomic function with a shift towards parasympathetic predominance, with significant improvements in cardiovascular parameters. Slow pranayamas with savasana may be incorporated into the routine care of these patients to enhance their cardiovascular health.

Echoes of conflict and displacement in maternal health: Life-course violence, timing, and maternal stress after childbirth at the northern Thailand-Myanmar border

Armed conflict, displacement, and related violence is escalating globally, concentrated among civilians and migrants in border areas, and poses grave harms to women and children. The current study investigates how women’s life-course experiences of conflict and displacement are linked to maternal stress and health outcomes after childbirth at the Thailand-Myanmar border, specifically stress, mental health, and cardiometabolic outcomes. Analyses are based on a cross-sectional population-based maternal and child health survey of 701 mothers, collected in 2017–18 in northern Thailand along the Myanmar border, including in camps, worksites, and residential homes. Results suggest that how conflict violence shapes contemporary stress and health depends on the outcome, level and timing of conflict violence exposure, and subsequent contextual threats and deprivation in displacement contexts. Past conflict violence was associated with symptoms of perceived stress (PS) and generalized anxiety disorder (GAD) but not depression. It was also associated with hypothalamic-pituitary-adrenal (HPA) axis activity (hair cortisol concentration) and adiposity (waist circumference and waist-to-hip ratio). Additionally, past conflict violence that began in childhood was particularly salient for PS, GAD, and adiposity; and level and timing of violence were salient jointly for HPA activity. Post-displacement factors also independently predicted higher blood pressure and played a potentially partial mediating role in the association between conflict exposure and both PS and GAD symptoms.

Abstract C068: Primary adrenocortical insufficiency as a presenting symptom of acute myeloid leukemia

Abstract Introduction: Primary Adrenal Insufficiency (PAI), also known as Addison's disease, is a rare endocrinopathy resulting from the destruction or dysfunction of the adrenal cortex. It has an estimated increasing prevalence between 100 and 140 cases/million and an incidence of 4 cases per million/year. On the other hand, Acute Myeloid Leukemia (AML) is the most common leukemia among adults and accounts for about 80% of all cases. Even though our case is exceptionally rare, it highlights the coexistence of both conditions in the same patient and that PAI can be the presenting symptom of AML. Case Report: A 52-year-old female with a history of lower extremity cellulitis presented for evaluation after experiencing fever, chills, fatigue, night sweats, nausea, and dysphagia. On arrival, she had pharyngeal erythema with cervical lymphadenopathy. Her white blood cell count was 33,000. A CT chest revealed bilateral neck adenopathy and an enlarged left hilar lymph node. Bone marrow flow cytometry results were consistent with AML, CD33 positive with 68% blasts. Induction chemotherapy with gemtuzumab ozogamicin and dexamethasone IV was initiated. Meanwhile, she developed acute abdominal pain. A CT abdomen/pelvis revealed bilateral adrenal symmetric thickening, indicating adrenal dysfunction, a new finding compared to prior imaging. Endocrinology was consulted. Physical examination revealed hyperpigmented palmar creases, fatigue, and nausea, raising suspicion of adrenal insufficiency. Laboratory work showed sodium 134, basal ACTH 10, and morning cortisol levels less than 1 mcg/dl. An ACTH stimulation test confirmed PAI, with ACTH increasing from 26 to 47, cortisol from 9.2 to 11.7, aldosterone from 2 to 15, and high plasma renin activity 2.64. She continued on steroid therapy with monitoring of blood pressure and sodium levels for two weeks. She was eventually discharged with a medication plan and follow-up appointments with endocrinology and hematology/oncology. Discussion: The coexistence of PAI and AML in the same patient is rare. Obscure clinical presentations complicated the diagnosis. Symptoms like fatigue, weakness, and nausea are common in AML patients, but hyperpigmentation of the palmar creases is not. We recommend evaluating adrenal function in acute leukemia patients to avoid adrenal insufficiency crises. If adrenal insufficiency was considered later, early steroid discontinuation could have provoked an adrenal crisis. Monitoring should continue to determine if the concern is permanent or transient. Conclusion: High suspicion and early evaluation of adrenal function in all acute leukemia patients should be considered to avoid adrenal insufficiency as a later complication. Due to the rarity of the disease and non-specific early symptoms, PAI is frequently not considered, leading to delayed diagnosis and increased risk for adrenal crisis. Successful long-term therapy relies on adequate patient education, frequent assessment of basal and stimulated cortisol levels, testing of HPA axis integrity, and various imaging techniques. Citation Format: Maria Toustsoglou, Aliya M. Khan, Mehmet Hepgur, John McDonald, Rubens Sievert. Primary adrenocortical insufficiency as a presenting symptom of acute myeloid leukemia [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C068.

Exploring the associations between momentary cortisol levels and psychotic-like experiences in young adults: Results from a temporal network analysis of daily-life data.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the development of psychosis and subthreshold psychotic symptoms commonly referred to as psychotic-like experiences (PLEs). The exact mechanisms linking the HPA axis responses with the emergence of PLEs remain unknown. The present study aimed to explore real-life associations between stress, negative affect, salivary cortisol levels (a proxy of the HPA axis activity) as well as PLEs together with their underlying cognitive biases (i.e., threat anticipation and aberrant salience). The study was based on the experience sampling method scheduled over 7 consecutive days in the sample of 77 drug-naïve, young adults (18-35 years). The saliva samples were collected with each prompt to measure cortisol levels. A temporal network analysis was used to explore the directed associations of tested variables. Altogether, 3234 data entries were analyzed. Data analysis revealed that salivary cortisol levels did not directly predict next-moment fluctuations of PLEs. However, higher salivary cortisol levels were associated with higher next-moment levels of PLEs through the effects on threat anticipation and negative affect. In turn, PLEs appeared to predict cortisol levels through the effects on negative affect and event-related stress. Negative affect and threat anticipation were the most central nodes in the network. There might be bidirectional associations between the HPA axis responses and PLEs. Threat anticipation and negative affect might be the most important mediators of these associations. Interventions targeting these mediators might hold promise for disrupting the connection between the HPA axis dysregulation and PLEs.

Links between ethnic discrimination, mental health, protective factors, and hair cortisol concentrations in asylum seekers living in Germany

ABSTRACT Objective: Asylum seekers often experience ethnic discrimination on the flight or in the host country, which may be associated with chronic stress and impaired mental health. Dysregulation of the hypothalamic–pituitary–adrenal axis, a known physiological correlate of chronic stress, can be assessed using hair cortisol concentrations (HCC). The present study aimed to investigate how different forms of perceived ethnic discrimination are associated with mental health outcomes, HCC, and protective factors in asylum seekers living in Germany. Methods: Somatic symptoms (PHQ-15), symptoms of posttraumatic stress (PDS), depressive symptoms (PHQ-9), different forms of ethnic discrimination (active harm, passive harm, institutional discrimination), and protective factors (in-group identification, social support) were assessed cross-sectionally in 144 asylum seekers (average age 32 years, average duration of stay in Germany nine months; 67% men). HCC were obtained from 68 participants. Multiple regression analyses were conducted and social support and in-group identification were tested as potential moderators. Results: Active ethnic discrimination was positively associated with all assessed mental health outcomes, and all forms of ethnic discrimination positively correlated with depressive symptoms. Ethnic discrimination was not associated with HCC. When controlling for other possible influences (e.g. age, gender, traumatic events), passive harm was negatively associated with depressive symptoms (β = −0.17, p = .033) and active harm was positively associated (β = 0.28, p = .022) with somatic symptoms. After the inclusion of the protective factors, the associations were no longer significant. Lower social support was associated with higher depressive symptoms (β = −0.35, p < .001), posttraumatic stress (β = −0.77, p < .001), and somatic symptoms (β = −0.32, p < .001), but did not moderate the associations between ethnic discrimination and the mental health outcomes. Conclusions: Perceived ethnic discrimination may negatively influence asylum seekers’ mental health but does not seem to be associated with HCC. Social support was associated with psychological symptom severity, but did not buffer the effects of ethnic discrimination on mental health.

Coenzyme Q10 and vitamin E alleviate heat stress-induced mood disturbances in male mice: Modulation of inflammatory pathways and the HPA axis

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

Neurobiological Implications of Chronic Stress and Metabolic Dysregulation in Inflammatory Bowel Diseases.

Chronic stress is a significant factor affecting modern society, with profound implications for both physical and mental health. Central to the stress response is cortisol, a glucocorticoid hormone produced by the adrenal glands. While cortisol release is adaptive in acute stress, prolonged exposure to elevated levels can result in adverse effects. This manuscript explores the neurobiological implications of chronic stress and its impact on metabolic dysregulation, particularly in the context of inflammatory bowel diseases (IBDs). The hypothalamic-pituitary-adrenal (HPA) axis regulates cortisol production, which influences metabolism, immune response, and neurobiology. Elevated cortisol levels are associated with the development and exacerbation of metabolic disorders like IBD and contribute to neurodegenerative processes, including cognitive impairments and increased susceptibility to psychiatric conditions. The interaction between cortisol and its receptors, particularly glucocorticoid receptors, underscores the complexity of these effects. This review aims to elucidate the mechanisms through which chronic stress and cortisol dysregulation impact metabolic health and neurobiological function, providing insights into potential therapeutic strategies for mitigating these effects.

Structural Basis for Antagonist Binding to Vasopressin V1b Receptor Revealed by the Molecular Dynamics Simulations.

The human V1b receptor (V1bR) is primarily expressed in the corticotropic cells of the anterior pituitary where it is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The activation of V1bR induces the secretion of adrenocorticotropin hormone (ACTH) from the anterior pituitary cells which, in turn, stimulates the production of cortisol via the adrenal cortex. Clinical studies have demonstrated the chronic dysfunction of the HPA axis in patients with several psychiatric disorders. Thus, the inhibition of the V1b receptor and normalizing the HPA axis hyperactivity is a promising approach to the treatment of many stress-related disorders such as anxiety and depression. Nelivaptan is a selective V1bR antagonist that can be used for this purpose and an excellent molecule to study how antagonists interact with V1bR, especially since in recent years the experimental structures of vasopressin V2 and oxytocin receptors were solved, providing high-similarity templates for homology modeling of V1bR. Therefore, in this work, six independent molecular dynamics simulations of a V1bR-nelivaptan complex in a fully hydrated lipid bilayer, yielding a total simulation time of 6.0 μs, have been conducted. In the lowest-energy complexes obtained in this work and proposed to be the most probable structure of the V1bR-nelivaptan complex, the location of the ligand inside the receptor pocket is very similar to that of the other ligands observed in the experimental structures of the vasopressin/oxytocin receptor family. The receptor-ligand interaction has been analyzed and described, revealing the details of the molecular mechanism of this antagonist binding to V1bR and a probable contribution of L2005×40 and T2035×43 to binding selectivity.

A brain-body feedback loop driving HPA-axis dysfunction in breast cancer.

Breast cancer patients often exhibit disrupted circadian rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality 1-3 . The exact cause of this phenomenon - whether due to treatments, stress, age, co-morbidities, lifestyle factors, or the cancer itself remains unclear. Here, we demonstrate that primary breast cancer alone blunts host GC rhythms by disinhibiting neurons in the hypothalamus, and that circadian phase-specific neuromodulation of these neurons can attenuate tumor growth by enhancing anti-tumor immunity. We find that mice with mammary tumors exhibit blunted GC rhythms before tumors are palpable, alongside increased activity in paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (i.e., PVN CRH neurons). Tumor-bearing mice have fewer inhibitory synapses contacting PVN CRH neurons and reduced miniature inhibitory post-synaptic current (mIPSC) frequency, leading to net excitation. Tumor-bearing mice experience impaired negative feedback on GC production, but adrenal and pituitary gland functions are largely unaffected, indicating that alterations in PVN CRH neuronal activity are likely a primary cause of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in breast cancer. Using chemogenetics (hM3Dq) to stimulate PVN CRH neurons at different circadian phases, we show that stimulation just before the light-to-dark transition restores normal GC rhythms and reduces tumor progression. These mice have significantly more effector T cells (CD8+) within the tumor than non-stimulated controls, and the anti-tumor effect of PVN CRH neuronal stimulation is absent in mice lacking CD8+ T cells. Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control output of the HPA axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression.

Daytime Dysfunction: Symptoms Associated with Nervous System Disorders Mediated by SIRT1.

Daytime dysfunction, including symptoms like sleepiness, poor memory, and reduced responsiveness, is not well researched. It is crucial to develop animal models and study the biological mechanisms involved. We simulated sleep disorders through sleep deprivation, and stressful stimuli were used to establish daytime functional animal models. We used tests like the sodium pentobarbital sleep synergy test and the DSI telemetry system to measure sleep duration and structure. We also used tests like the Morris water maze, open field test, grip test, and baton twirling test to assess mental and physical fatigue. To assess the intrinsic biological mechanisms, we measured sleep-wake-related neurotransmitters and related receptor proteins, circadian rhythm-related proteins and cognition-related proteins in hypothalamus tissue, and oxidative stress, inflammatory factors, S100β, and HPA axis-related indexes in serum. Multi-factor sleep deprivation resulted in the disruption of sleep-wakefulness structure, memory-cognitive function degradation, decreased grip coordination, and other manifestations of decreased energetic and physical strength. The intrinsic biological mechanisms were related to the disturbed expression of sleep-wake, circadian rhythm, memory-cognition-related proteins, as well as the significant elevation of inflammatory factors, oxidative stress, the HPA axis, and other related indicators. Intrinsically related biological mechanisms and reduced sirt1 expression can lead to disruption of circadian rhythms; resulting in disruption of their sleep-wake-related neurotransmitter content and receptor expression. Meanwhile, the reduced expression of sirt1 also resulted in reduced expression of synapse-associated proteins. This study prepared an animal model of daytime dysfunction by means of multi-factor sleep deprivation. With sirt1 as a core target, the relevant biological mechanisms of neurological disorders were modulated.

5,7,3',4',5'-Pentamethoxyflavone, a Flavonoid Monomer Extracted From Murraya paniculata (L.) Jack, Alleviates Anxiety Through the A2AR/Gephyrin/GABRA2 Pathway.

The sedative and hypnotic properties of 5,7,3',4',5'-pentamethoxyflavone (PMF), a monomer extracted from the leaves of Murraya paniculata (L.) Jack, have been reported. However, the role of PMFs in the development of anxiety remains uncertain. An anxiety model was developed using chronic unpredictable mild stimulation (CUMS). Kunming mice were randomly allocated to the following groups: control, CUMS, PMF (50 mg/kg), PMF (100 mg/kg), and diazepam (3 mg/kg). The anxiolytic effects of PMFs were evaluated using elevated plus maze (EPM) test and open field test (OFT). Enzyme-linked immunosorbent assay (ELISA) kits were used to analyze the serum levels of corticosterone (CORT), 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), and cyclic adenosine monophosphate (cAMP) in the hippocampus. High-throughput-16S rRNA sequencing was performed to investigate its effect on the composition of the gut microbiota. Subsequently, western blotting was performed to assess the expression of GABAergic synaptic-associated proteins. PMF effectively mitigated CUMS-induced anxiety-like behavior. Further examination revealed that PMF treatment ameliorated dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and increased 5-HT and GABA levels in the hippocampus. Notably, the ability of PMF to maintain the stability of GABAergic synapses by enhancing the species composition of the gut microbiota and acting on the adenosine a2a receptor (A2AR)/gephyrin/gamma-aminobutyric acid A receptor alpha 2 (GABRA2) pathway revealed a previously unrecognized mechanism for the anxiolytic effect of PMF. These findings suggest that PMF enhances the expression of A2AR, preserves GABAergic synaptic stability, and reduces anxiety by modulating the microbiota composition. Thus, it holds promise as an anxiolytic agent.

Early life stress influences epilepsy outcomes in mice.

Stress is a common seizure trigger that has been implicated in worsening epilepsy outcomes. The neuroendocrine response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and HPA axis dysfunction worsens epilepsy outcomes, increasing seizure burden, behavioral comorbidities, and risk for sudden unexpected death in epilepsy (SUDEP) in mice. Early life stress (ELS) reprograms the HPA axis into adulthood, impacting both the basal and stress-induced activity. Thus, we propose that ELS may influence epilepsy outcomes by influencing the function of the HPA axis. To test this hypothesis, we utilized the maternal separation paradigm and examined the impact on seizure susceptibility. We show that ELS exerts a sex dependent effect on seizure susceptibility in response to acute administration of the chemoconvulsant, kainic acid, which is associated with an altered relationship between seizure activity and HPA axis function. To further examine the impact of ELS on epilepsy outcomes, we utilized the intrahippocampal kainic acid model of chronic epilepsy in mice previously exposed to maternal separation. We find that the relationship between corticosterone levels and the extent of epileptiform activity is altered in mice subjected to ELS. We demonstrate that ELS impacts behavioral outcomes associated with chronic epilepsy in a sex-dependent manner, with females being more affected. We also observe reduced mortality (presumed SUDEP) in female mice subjected to ELS, consistent with previous findings suggesting a role for HPA axis dysfunction in SUDEP risk. These data demonstrate for the first time that ELS influences epilepsy outcomes and suggest that previous life experiences may impact the trajectory of epilepsy.

Role of stress and early-life stress in the pathogeny of inflammatory bowel disease.

Numerous preclinical and clinical studies have shown that stress is one of the main environmental factor playing a significant role in the pathogeny and life-course of bowel diseases. However, stressful events that occur early in life, even during the fetal life, leave different traces within the central nervous system, in area involved in stress response and autonomic network but also in emotion, cognition and memory regulation. Early-life stress can disrupt the prefrontal-amygdala circuit thus favoring an imbalance of the autonomic nervous system and the hypothalamic-pituitary adrenal axis, resulting in anxiety-like behaviors. The down regulation of vagus nerve and cholinergic anti-inflammatory pathway favors pro-inflammatory conditions. Recent data suggest that emotional abuse at early life are aggravating risk factors in inflammatory bowel disease. This review aims to unravel the mechanisms that explain the consequences of early life events and stress in the pathophysiology of inflammatory bowel disease and their mental co-morbidities. A review of therapeutic potential will also be covered.

Parenting stress, dyadic coping and endocrine markers of stress and resilience in foster and biological mothers.

Foster parents have been shown to report higher levels of parenting stress but also more dyadic coping (DC) behaviors in their partnership than biological parents, which might be an important protective factor that helps them cope with daily stressors. Here, we examined how parenting stress and DC are related in foster and biological parents and whether these are reflected in long-term alterations of hypothalamic-pituitary-adrenocortical (HPA) axis activity. A total of 79 foster mothers and 131 biological mothers participated in a longitudinal study. At the initial assessment, children were aged 2-7 years and lived for an average of 18 months in their current foster family. Mothers' cortisol and dehydroepiandrosterone (DHEA) concentrations and their cortisol/DHEA ratios were assessed in scalp hair twice with approximately 11 months in between, while their perceived parenting stress and DC were measured by self-report questionnaires. Results showed no significant differences between foster mothers and biological mothers in cortisol, DHEA and cortisol/DHEA concentrations. While more DC was longitudinally related to lower levels of parenting stress across both study groups, no significant associations were found to endocrine markers. Thus, these findings indicate that increased parenting stress levels were not, or not strongly, reflected in HPA axis alterations as assessed in hair. Our findings thus add evidence for non-significant associations between self-reported perceived stress and chronic HPA axis markers. Future studies may explore whether early interventions, including those aimed at promoting and maintaining positive DC, are beneficial in preventing the development of stress-related illnesses in foster parents.

Efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Bulimia Nervosa (BN): A Review and Insight into Potential Mechanisms of Action.

Bulimia nervosa (BN) is a disorder primarily affecting adolescent females, characterized by episodes of binge eating followed by inappropriate compensatory behaviors aimed at preventing weight gain, including self-induced vomiting and the misuse of diuretics, laxatives, and insulin. The precise etiology of BN remains unknown, with factors such as genetics, biological influences, emotional disturbances, societal pressures, and other challenges contributing to its prevalence. First-line treatment typically includes pharmacotherapy, which has shown moderate effectiveness. Neuroimaging evidence suggests that altered brain activity may contribute to the development of BN, making interventions that directly target the brain extremely valuable. One such intervention is repetitive transcranial magnetic stimulation (rTMS), a non-invasive stimulation technique that has been garnering interest in the medical community for many years. This review explores the use of rTMS in the treatment of BN. Searches were conducted in the PubMed/Medline, ResearchGate, and Cochrane databases. Twelve relevant studies were identified. Analysis of the results from these studies reveals promising findings, particularly regarding key parameters in the pathophysiology of BN. Several studies assessed the impact of rTMS on binge episodes. While some studies did not find significant reductions, most reported decreases in binge eating and purging behaviors, with some cases showing complete remission. Reductions in symptoms of depression and food cravings were also demonstrated. However, results regarding cognitive improvement were mixed. The discussion focused heavily on potential mechanisms of action, including neuromodulation of brain networks, induction of neuroplasticity, impact on serotonergic dysfunction, anti-inflammatory action, and HPA axis modulation. rTMS was found to be a safe intervention with no serious side effects. rTMS in the treatment of BN appears to be a promising intervention that alleviates some symptoms characteristic of the pathophysiology of this disorder. An additional effect is a significant reduction in depressive symptoms. However, despite these findings, further research is required to confirm its effectiveness and elucidate the mechanisms of action. It is also recommended to further investigate the potential mechanisms of action described in this review.

An overview of Centella asiatica and its therapeutic applications

Globally, medicinal herb intervention has become popular in treating many illnesses. Centella asiatica (C. asiatica), a plant native to Southeast Asia, is utilized extensively due to its pharmacological and therapeutic benefits attributed by its triterpenoids and saponins. It has been widely researched for a variety of medicinal properties, including antidiabetic, antioxidant, wound healing, reproductive, sedative, anxiolytic, digestive, gastric ulcer, cognitive, antidepressant, and anti-inflammatory effects. The sedative qualities are associated with regulating the HPA axis to mitigate stress and modulate GABAergic activity, while its capacity to promote collagen production, provide antioxidant protection, and lower inflammation aids in the healing of wounds. Owing to a wide range of literature on C. asiatica, the significant discoveries about various diseases are occasionally overlooked. Hence, more concise and succinct information is warranted. This review aimed to summarize the potential medicinal aspects of C. asiatica, highlighting the medicinal properties, physicochemical properties and health benefits along with future direction of the therapeutic potential. While many of the well-established properties and effects have been proven, the procurement of further clinical trials must be attended to involving the determination of standardized procedures and investigate the ultimate possible function of C. asiatica in treating diverse medical diseases, thus, to fully comprehend the therapeutic benefits of the herb. By possessing numerous pharmacological properties, C. asiatica could potentially offer greater assistance in the medical world for treating the patients while minimizing risks and mitigating degenerative effects.