Antidepressant-like Effect of Bacopaside I in Mice Exposed to Chronic Unpredictable Mild Stress by Modulating the Hypothalamic–Pituitary–Adrenal Axis Function and Activating BDNF Signaling Pathway

Preliminary studies conducted in our laboratory have confirmed that Bacopaside I (BS-I), a saponin compound isolated from Bacopa monnieri, displayed antidepressant-like activity in the mouse behavioral despair model. The present investigation aimed to verify the antidepressant-like action of BS-I using a mouse model of behavioral deficits induced by chronic unpredictable mild stress (CUMS) and further probe its underlying mechanism of action. Mice were exposed to CUMS for a period of 5 consecutive weeks to induce depression-like behavior. Then, oral gavage administrations with vehicle (model group), fluoxetine (12 mg/kg, positive group) or BS-I (5, 15, 45 mg/kg, treated group) once daily were started during the last two weeks of CUMS procedure. The results showed that BS-I significantly ameliorated CUMS-induced depression-like behaviors in mice, as characterized by an elevated sucrose consumption in the sucrose preference test and reduced immobility time without affecting spontaneous locomotor activity in the forced swimming test, tail suspension test and open field test. It was also found that BS-I treatment reversed the increased level of plasma corticosterone and decreased mRNA and protein expressions of glucocorticoid receptor induced by CUMS exposure, indicating that hypothalamic–pituitary–adrenal (HPA) axis hyperactivity of CUMS-exposed mice was restored by BS-I treatment. Furthermore, chronic administration of BS-I elevated expression levels of brain-derived neurotrophic factor (BDNF) (mRNA and protein) and activated the phosphorylation of extracellular signal-regulated kinase and cAMP response element-binding protein in the hippocampus and prefrontal cortex in mice subjected to CUMS procedure. Taken together, these results indicated that BS-I exhibited an obvious antidepressant-like effect in mouse model of CUMS-induced depression that was mediated, at least in part, by modulating HPA hyperactivity and activating BDNF signaling pathway.     

Effect of Prenatal Stress on the Pituitary–Adrenal Axis in Blue Foxes

Handling is a source of stress for farm bred blue foxes. The influence of handling during the late gestation period on the pituitary–adrenal axis was studied in 10-day old male and female blue foxes. Cortisol and progesterone were measured by radioimmunoassay in the plasma, adrenal homogenates, and in vitro incubates from animals of both sexes. Adrenals were incubated in vitro in the absence or presence of ACTH. In addition, the adrenal weight and plasma concentration of ACTH were assessed. In cubs of both sexes, the adrenal weight was decreased after prenatal stress treatment. The plasma concentration of progesterone and the adrenal cortisol in vitro production were elevated in the prenatally stressed female cubs, as compared to the control, along with the adrenal progesterone in vitro production in prenatally stressed male cubs. The adrenal cortisol and progesterone content and plasma ACTH and cortisol concentrations were not affected by prenatal stress. In conclusion, the results of this study suggest that the prenatal stress induced by handling pregnant vixens can affect the pituitary–adrenal axis in neonatal offspring, this effect being more pronounced in female cubs.     

Suppression of Hypothalamic–Pituitary–Adrenal Axis by Acute Heroin Challenge in Rats During Acute and Chronic Withdrawal from Chronic Heroin Administration

It is known that heroin dependence and withdrawal are associated with changes in the hypothalamic–pituitary–adrenal (HPA) axis. The objective of these studies in rats was to systematically investigate the level of HPA activity and response to a heroin challenge at two time points during heroin withdrawal, and to characterize the expression of associated stress-related genes 30 min after each heroin challenge. Rats received chronic (10-day) intermittent escalating-dose heroin administration (3 × 2.5 mg/kg/day on day 1; 3 × 20 mg/kg/day by day 10). Hormonal and neurochemical assessments were performed in acute (12 h after last heroin injection) and chronic (10 days after the last injection) withdrawal. Both plasma ACTH and corticosterone levels were elevated during acute withdrawal, and heroin challenge at 20 mg/kg (the last dose of chronic escalation) at this time point attenuated this HPA hyperactivity. During chronic withdrawal, HPA hormonal levels returned to baseline, but heroin challenge at 5 mg/kg decreased ACTH levels. In contrast, this dose of heroin challenge stimulated the HPA axis in heroin naïve rats. In the anterior pituitary, pro-opiomelanocortin (POMC) mRNA levels were increased during acute withdrawal and retuned to control levels after chronic withdrawal. In the medial hypothalamus, however, the POMC mRNA levels were decreased during acute withdrawal, and increased after chronic withdrawal. Our results suggest a long-lasting change in HPA abnormal responsivity during chronic heroin withdrawal.     

Chronic Stress Suppresses the Expression of Cutaneous Hypothalamic–Pituitary–Adrenocortical Axis Elements and Melanogenesis

Chronic stress can affect skin function, and some skin diseases might be triggered or aggravated by stress. Stress can activate the central hypothalamic–pituitary–adrenocortical (HPA) axis, which causes glucocorticoid levels to increase. The skin has HPA axis elements that react to environmental stressors to regulate skin functions, such as melanogenesis. This study explores the mechanism whereby chronic stress affects skin pigmentation, focusing on the HPA axis, and investigates the role of glucocorticoids in this pathway. We exposed C57BL/6 male mice to two types of chronic stress, chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). Mice subjected to either stress condition showed reduced melanogenesis. Interestingly, CRS and CUMS triggered reductions in the mRNA expression levels of key factors involved in the HPA axis in the skin. In mice administered corticosterone, decreased melanin synthesis and reduced expression of HPA axis elements were observed. The reduced expression of HPA axis elements and melanogenesis in the skin of stressed mice were reversed by RU486 (a glucocorticoid receptor antagonist) treatment. Glucocorticoids had no significant inhibitory effect on melanogenesis in vitro. These results suggest that, high levels of serum corticosterone induced by chronic stress can reduce the expression of elements of the skin HPA axis by glucocorticoid-dependent negative feedback. These activities can eventually result in decreased skin pigmentation. Our findings raise the possibility that chronic stress could be a risk factor for depigmentation by disrupting the cutaneous HPA axis and should prompt dermatologists to exercise more caution when using glucocorticoids for treatment.     

Honokiol Exerts Antidepressant Effects in Rats Exposed to Chronic Unpredictable Mild Stress by Regulating Brain Derived Neurotrophic Factor Level and Hypothalamus–Pituitary–Adrenal Axis Activity

Honokiol (HNK), the main active component of Magnolia officinalis, has shown a variety of pharmacological activities. In the present study, we measured the antidepressant-like effects of HNK in a rat model of chronic unpredictable mild stress (CUMS) and explored its possible mechanisms. The antidepressant-like effects of HNK were assessed in rats by an open field test (OFT), sucrose preference test (SPT) and forced swimming test (FST). Then, serum levels of corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT) and hippocampal brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor α (GRα) levels were assessed to explore the possible mechanisms. We identified that HNK treatment (2, 4, and 8 mg/kg) alleviated the CUMS-induced behavioural deficits. Treatment with HNK also normalized the CUMS-induced hyperactivity of the limbic hypothalamic–pituitary–adrenal (HPA) axis, as indicated by reduced CRH, ACTH and CORT serum levels. In addition, HNK increased the expression of GRα (mRNA and protein) and BDNF (mRNA and protein) in the hippocampus. These data confirmed the antidepressant-like effects of HNK, which may be related to its normalizing the function of the HPA axis and increasing the BDNF level in the hippocampus.     

Effect of Cyanotoxins on the Hypothalamic–Pituitary–Gonadal Axis in Male Adult Mouse

Background

Microcystins LR (MC-LR) are hepatotoxic cyanotoxins that have been shown to induce reproductive toxicity, and Hypothalamic–Pituitary–Gonadal Axis (HPG) is responsible for the control of reproductive functions. However, few studies have been performed to evaluate the effects of MC-LR on HPG axis. This study aimed to investigate the MC-LR-induced toxicity in the reproductive system of mouse and focus on the HPG axis.

Methods

Adult male C57BL/6 mice were exposed to various concentrations of MC-LR (0, 3.75, 7.50, 15.00 and 30.00 µg/kg body weight per day) for 1 to 14 days, and it was found that exposure to different concentrations of MC-LR significantly disturbed sperm production in the mice testes in a dose- and time-dependent manner. To elucidate the associated possible mechanisms, the serum levels of testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were assessed. Meanwhile, PCR assays were employed to detect alterations in a series of genes involved in HPG axis, such as FSH, LH, gonadotropin-releasing hormone (GnRH) and their complement receptors. Furthermore, the effect of MC-LR on the viability and testosterone production of Leydig cells were tested in vitro. Results: MC-LR significantly impaired the spermatogenesis of mice possibly through the direct or indirect inhibition of GnRH synthesis at the hypothalamic level, which resulted in reduction of serum levels of LH that lead to suppression of testosterone production in the testis of mice.

Conclusions

MC-LR may be a GnRH toxin that would disrupt the reproductive system of mice.     

The Gut–Brain Axis and Peroxisome Proliferator-Activated Receptors in the Regulation of Epileptogenesis

Journal of Evolutionary Biochemistry and Physiology - A large proportion of patients with epilepsy suffer from pharmacoresistant forms of the disease, and this makes the search for new treatments...     

Chronic Piromelatine Treatment Alleviates Anxiety,Depressive Responses and Abnormal Hypothalamic–Pituitary–Adrenal Axis Activity in Prenatally Stressed Male and Female Rats

The prenatal stress (PNS) model in rodents can induce different abnormal responses that replicate the pathophysiology of depression. We applied this model to evaluate the efficacy of piromelatine (Pir), a novel melatonin analog developed for the treatment of insomnia, in male and female offspring. Adult PNS rats from both sexes showed comparable disturbance associated with high levels of anxiety and depressive responses. Both males and females with PNS demonstrated impaired feedback inhibition of the hypothalamic–pituitary–adrenal (HPA) axis compared to the intact offspring and increased glucocorticoid receptors in the hippocampus. However, opposite to female offspring, the male PNS rats showed an increased expression of mineralocorticoid receptors in the hippocampus. Piromelatine (20 mg/kg, i.p., for 21 days injected from postnatal day 60) attenuated the high anxiety level tested in the open field, elevated plus-maze and light–dark test, and depressive-like behavior in the sucrose preference and the forced swimming tests in a sex-specific manner. The drug reversed to control level stress-induced increase of plasma corticosterone 120 min later in both sexes. Piromelatine also corrected to control level the PNS-induced alterations of corticosteroid receptors only in male offspring. Our findings suggest that the piromelatine treatment exerts beneficial effects on impaired behavioral responses and dysregulated HPA axis in both sexes, while it corrects the PNS-induced changes in the hippocampal corticosteroid receptors only in male offspring.

     

Causal Relationship between Physiological and Pathological Processes in the Brain and in the Gastrointestinal Tract: The Brain–Intestine Axis

Biophysics - The brain and gastrointestinal tract are the most important organs responsible for detecting, transmitting, integrating, and responding to signals coming from the internal and external...     

Detachment of Brain Pericytes from the Basal Lamina is Involved in Disruption of the Blood–Brain Barrier Caused by Lipopolysaccharide-Induced Sepsis in Mice

The blood–brain barrier (BBB) is highly restrictive of the transport of substances between blood and the central nervous system. Brain pericytes are one of the important cellular constituents of the BBB and are multifunctional, polymorphic cells that lie within the microvessel basal lamina. The present study aimed to evaluate the role of pericytes in the mediation of BBB disruption using a lipopolysaccharide (LPS)-induced model of septic encephalopathy in mice. ICR mice were injected intraperitoneally with LPS or saline and were sacrificed at 1, 3, 6, and 24 h after injection. Sodium fluorescein accumulated with time in the hippocampus after LPS injection; this hyperpermeability was supported by detecting the extravasation of fibrinogen. Microglia were activated and the number of microglia increased with time after LPS injection. LPS-treated mice exhibited a broken basal lamina and pericyte detachment from the basal lamina at 6–24 h after LPS injection. The disorganization in the pericyte and basal lamina unit was well correlated with increased microglial activation and increased cerebrovascular permeability in LPS-treated mice. These findings suggest that pericyte detachment and microglial activation may be involved in the mediation of BBB disruption due to inflammatory responses in the damaged brain.     

Ubiquitin–Proteasome System Impairment and MPTP-Induced Oxidative Stress in the Brain of C57BL/6 Wild-type and GSTP Knockout Mice

The ubiquitin–proteasome system (UPS) is the primary proteolytic complex responsible for the elimination of damaged and misfolded intracellular proteins, often formed upon oxidative stress. Parkinson’s disease (PD) is neuropathologically characterized by selective death of dopaminergic neurons in the substantia nigra (SN) and accumulation of intracytoplasmic inclusions of aggregated proteins. Along with mitochondrial dysfunction and oxidative stress, defects in the UPS have been implicated in PD. Glutathione S-transferase pi (GSTP) is a phase II detoxifying enzyme displaying important defensive roles against the accumulation of reactive metabolites that potentiate the aggression of SN neuronal cells, by regulating several processes including S-glutathionylation, modulation of glutathione levels and control of kinase-catalytic activities. In this work we used C57BL/6 wild-type and GSTP knockout mice to elucidate the effect of both MPTP and MG132 in the UPS function and to clarify if the absence of GSTP alters the response of this pathway to the neurotoxin and proteasome inhibitor insults. Our results demonstrate that different components of the UPS have different susceptibilities to oxidative stress. Importantly, when compared to the wild-type, GSTP knockout mice display decreased ubiquitination capacity and overall increased susceptibility to UPS damage and inactivation upon MPTP-induced oxidative stress.     

Disruption to the 5-HT<Subscript>7</Subscript> Receptor Following Hypoxia–Ischemia in the Immature Rodent Brain

It has become increasingly evident the serotonergic (5-hydroxytryptamine, 5-HT) system is an important central neuronal network disrupted following neonatal hypoxic–ischemic (HI) insults. Serotonin acts via a variety of receptor subtypes that are differentially associated with behavioural and cognitive mechanisms. The 5-HT₇ receptor is purported to play a key role in epilepsy, anxiety, learning and memory and neuropsychiatric disorders. Furthermore, the 5-HT₇ receptor is highly localized in brain regions damaged following neonatal HI insults. Utilising our well-established neonatal HI model in the postnatal day 3 (P3) rat pup we demonstrated a significant decrease in levels of the 5-HT₇ protein in the frontal cortex, thalamus and brainstem one week after insult. We also observed a relative decrease in both the cytosolic and membrane fractions of 5-HT₇. The 5-HT₇ receptor was detected on neurons throughout the cortex and thalamus, and 5-HT cell bodies in the brainstem. However we found no evidence of 5-HT₇ co-localisation on microglia or astrocytes. Moreover, minocycline treatment did not significantly prevent the HI-induced reductions in 5-HT₇. In conclusion, neonatal HI injury caused significant disruption to 5-HT₇ receptors in the forebrain and brainstem. Yet the use of minocycline to inhibit activated microglia, did not prevent the HI-induced changes in 5-HT₇ expression.     

Altered GABAA Receptor Expression and Seizure Threshold Following Acute Ethanol Challenge in Mice Lacking the RIIβ Subunit of PKA

Ethanol causes pathological changes in GABA_A receptor trafficking and function. These changes are mediated in part by ethanol activation of protein kinase A (PKA). The current study investigated the expression of the GABA_A α1 and α4 subunits and the kinase anchoring protein AKAP150, as well as bicuculline-induced seizure threshold, at baseline and following acute injection of ethanol (3.5 g/kg IP) in a mouse line lacking the regulatory RIIβ subunit of PKA. Whole cerebral cortices were harvested at baseline, 1 h, or 46 h following injection of ethanol or saline and subjected to fractionation and western blot analysis. Knockout (RIIβ?/?) mice had similar baseline levels of PKA RIIα and GABA_A α1 and α4 subunits compared to wild type (RIIβ+/+) littermates, but had deficits in AKAP150. GABA_A α1 subunit levels were decreased in the P2 fraction of RIIβ?/?, but not RIIβ+/+, mice following 1 h ethanol, an effect that was driven by decreased α1 expression in the synaptic fraction. GABA_A α4 subunits in the P2 fraction were not affected by 1 h ethanol; however, synaptic α4 subunit expression was increased in RIIβ+/+, but not RIIβ?/? mice, while extrasynaptic α4 and δ subunit expression were decreased in RIIβ?/?, but not RIIβ+/+ mice. Finally, RIIβ knockout was protective against bicuculline-induced seizure susceptibility. Overall, the results suggest that PKA has differential roles in regulating GABA_A receptor subunits. PKA may protect against ethanol-induced deficits in synaptic α1 and extrasynaptic α4 receptors, but may facilitate the increase of synaptic α4 receptors.     

The Influence of the Superoxide Dismutase Preparation Rexod® on Survival of CFU–S in С57ВL/6 Mice Exposed to Irradiation

Biology Bulletin - The radioprotective efficiency of the Rexod® drug (State Research Institute of Highly Pure Biopreparations of the Federal Medical-Biological Agency of Russia) containing...     

The associations of morningness–eveningness with anger and impulsivity in the general population

The aim of this study was to investigate the relationships among morningness–eveningness, impulsivity and anger in the general population. A total of 1000 community-dwelling subjects (500 males) aged 20–77 years (mean± SD age: 39.6 ± 11.6 years) completed the morningness–eveningness questionnaire (MEQ), Barratt impulsiveness scale (BIS), Spielberger State–Trait Anger Expression Inventory (STAXI) and Center for Epidemiologic Studies Depression Scale. Moderation and mediation analyses were performed to determine whether the relationship between two variables depended on the third variable, referred to as a moderator, and whether the third variable, known as a mediator, was associated with the other two variables establishing causation. The MEQ scores exhibited significant negative associations with BIS (p < 0.001) and STAXI (p < 0.001) scores, and high scores on the BIS were associated with high scores on the STAXI (p < 0.001). Impulsivity, as measured by the BIS, played a role as a moderator (p < 0.001) in the relationship between MEQ and STAXI, and anger, as measured by the STAXI, acted as moderator (p = 0.030) in the association between MEQ and BIS. However, after controlling for the interaction of the BIS and MEQ, the MEQ scores did not significantly predict STAXI scores (p = 0.070). Additionally, the effect size of the mediating effect of the BIS scores on the relationship between the MEQ and STAXI (percent mediation: 53.2%) was larger than that of the STAXI scores on the association between the MEQ and BIS (percent mediation: 31.8%). The present results demonstrate that morningness–eveningness was closely related with both impulsivity and anger in the general population. Furthermore, these findings suggest that impulsivity may exercise a great influence on the association between morningness–eveningness and anger in two ways: as a moderator by modulating this relationship based on the level of impulsivity and as a mediator by acting as an intermediary factor.     

Serotonin Depletion Does not Modify the Short-Term Brain Hypometabolism and Hippocampal Neurodegeneration Induced by the Lithium–Pilocarpine Model of Status Epilepticus in Rats

It has been reported that fluoxetine, a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, has neuroprotective properties in the lithium–pilocarpine model of status epilepticus (SE) in rats. The aim of the present study was to investigate the effect of 5-HT depletion by short-term administration of p-chlorophenylalanine (PCPA), a specific tryptophan hydroxylase inhibitor, on the brain hypometabolism and neurodegeneration induced in the acute phase of this SE model. Our results show that 5-HT depletion did modify neither the brain basal metabolic activity nor the lithium–pilocarpine-induced hypometabolism when evaluated 3 days after the insult. In addition, hippocampal neurodegeneration and astrogliosis triggered by lithium–pilocarpine were not exacerbated by PCPA treatment. These findings point out that in the early latent phase of epileptogenesis, non-5-HT-mediated actions may contribute, at least in some extent, to the neuroprotective effects of fluoxetine in this model of SE.     

Melatonin Increases Interleukin-1β and Decreases Tumor Necrosis Factor Alpha in the Brain of Mice Infected with the Venezuelan Equine Encephalomyelitis Virus

The effect of melatonin (MLT) on the brain levels of tumor necrosis factor alpha (TNF-) and interleukin-1 (IL-1) in Venezuelan equine encephalomyelitis (VEE) virus infection was determined. Brain homogenates from mice inoculated with 10 LD₅₀ of VEE virus, untreated or treated with 500g MLT/kg body weight were assayed by ELISA to measure the levels of TNF- and IL-1. MLT was injected daily starting 3 days before and continuing to 7 days after virus inoculation. Infected mice treated with MLT showed decreased levels of TNF- when compared to the untreated infected mice on days 1, 3, 4, and 5 postinoculation (P < 0.001). In contrast, IL-1 levels increased from days 1 to 5 in the infected mice treated with MLT when compared with the untreated infected animals (P < 0.01). The results suggest that the protective effect of MLT on the VEE virus infection could be due, among other factors, to a decrease in TNF- synthesis along with an increase in the production of IL-1.     

The Effects of Antidepressants “Fluoxetine and Imipramine” on Vascular Abnormalities and Toll Like Receptor-4 Expression in Diabetic and Non-Diabetic Rats Exposed to Chronic Stress

Several studies reveal that diabetes doubles the odds of comorbid depression with evidence of a pro-inflammatory state underlying its vascular complications. Indeed, little information is available about vascular effects of antidepressant drugs in diabetes. Method: We investigated the effect of chronic administration of fluoxetine “FLU” and imipramine “IMIP” on behavioral, metabolic and vascular abnormalities in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS). Results: Both diabetes and CRS induced depressive-like behavior which was more prominent in diabetic/depressed rats; this was reversed by chronic treatment with FLU and IMIP in a comparable manner. Diabetic and non-diabetic rats exposed to CRS exhibited abnormalities in glucose homeostasis, lipid profile and vascular function, manifested by decreased endothelium-dependent relaxation, increased systolic blood pressure and histopathological atherosclerotic changes. Vascular and metabolic dysfunctions were associated with significant increase in aortic expression of TLR-4, and pro-inflammatory cytokines (TNF-α and IL-1ß). FLU ameliorated these metabolic, vascular and inflammatory abnormalities, while IMIP induced either no change or even worsening of some parameters. Conclusion: FLU has favorable effect over IMIP on metabolic, vascular and inflammatory aberrations associated with DM and CRS in Wistar rats, clarifying the preference of FLU over IMIP in management of comorbid depression in diabetic subjects.     

The Interaction of Amyloid β and the Receptor for Advanced Glycation Endproducts Induces Matrix Metalloproteinase-2 Expression in Brain Endothelial Cells

The pathological hallmarks of Alzheimer’s disease (AD) include formation of extracellular amyloid-β peptide (Aβ) and inflammatory responses. Numerous studies have reported that cerebral microvascular Aβ deposition promotes neuroinflammation in AD. Matrix metalloproteinases (MMPs) are involved in the cleavage of extracellular matrix proteins and regulation of growth factors, receptors, and adhesion molecules. Relatively little is known about the involvement of MMPs as inflammatory mediators in the pathological processes of AD. In this study, we explored the signaling pathway of MMP-2 up-regulation by Aβ in brain endothelial cells (BECs) of mice. Using Western blots, we found that inhibitors of extracellular-signal-regulated kinases (ERK) and c-Jun N-terminal kinase (JNK) significantly decreased Aβ-induced MMP-2 expression in BECs. Furthermore, antibody neutralization of the receptor for advanced glycation endproducts effectively blocked Aβ-induced activation of ERK and JNK and their contribution to elevated MMP-2 expression in BECs. Our results suggest that increased MMP-2 expression induced by the interaction of Aβ with RAGE in BECs may contribute to enhanced vascular inflammatory stress in Aβ-related vascular disorders, such as cerebral amyloid angiopathy and AD. This study offers new insights into neuroinflammation in the progression of AD.