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Mitochondria are involved in the pathogenesis of post-traumatic stress disorder (PTSD). Phosphodiesterase-4 (PDE-4) regulates mitochondrial-dependent intracellular cAMP levels in neuropsychiatric disorders. Inhibition of PDE-4 with rolipram (RPM) has anxiolytic and psycho-mimetic properties. However, the role of PDE-4 inhibitor in PTSD remains unclear. Therefore, it may be useful in the treatment of comorbidities that resemble PTSD. The effects of RPM (PDE-4 inhibitor) and paroxetine (PAX) on mitochondrial dysfunction in the amygdala were investigated using the stress re-stress (SRS) model of PTSD. On day 2 (D-2), male rats were exposed to foot shock at intensity 2 mA for 10-second followed by halothane anesthesia. The rats were then subjected to re-stress of foot shock on D-8 to D-32 at 6-day intervals. RPM (0.5, 1, and 2 mg/kg) and PAX (10 mg/kg) treatments given orally from D-8 to D-32. RPM (1 and 2mg/kg) significantly attenuated SRS-induced PTSD-like symptoms like fear response, anxiety-like behavior, cognitive deficits and hypocorticosteronism. The SRS-induced decrease in mitochondrial respiratory complex (I, II, IV, and V) activity, respiratory control rate (RCR) and cAMP level in the amygdala were ameliorated by RPM. Further, sub-chronic treatment with RPM reduced the SRS-induced rise in ADP/ATP ratio in the amygdala. RPM ameliorated the SRS-induced alteration in mitochondrial membrane potential (MMP) and cytochrome-c levels in the amygdala. Thus, findings suggested that cAMP-dependent regulation of ADP/ATP ratio and mitochondrial function could be a potential mechanism for the anti-PTSD-like effect of RPM in the SRS model. [ABSTRACT FROM AUTHOR]

Chronic D-galactose (D-gal) administration causes cognitive impairment and is used widely in animal models for anti-aging studies. Centella asiatica (CA), a traditional herbal medicine, has been used as a brain tonic to enhance memory. This study evaluates the neuroprotective role of an ethanolic extract of Centella asiatica (CAE) against D-gal-induced aging in rats. Healthy male rats were divided into three groups: Control, D-gal, and D-gal + CAE. The Control group received normal saline (i.p.), whereas the D-gal group received D-gal (120 mg/kg b.w., i.p.), and the D-gal + CAE group received D-gal (120 mg/kg b.w., i.p.) and CAE (300 mg/kg b.w., orally) daily for 42 days. Behavioral and brain biochemical and histopathological changes were assessed after treatment. The results of the behavioral study depicted that D-gal significantly reduces the spontaneous alternation and locomotor activity indicating behavioral and cognitive impairment. Biochemical studies showed that D-gal significantly increases the oxidative stress and acetylcholinesterase activity (AChE) in rat brain. Histopathological study showed that D-gal disturbs the normal architecture of hippocampal and cortical cells, indicating degeneration in these brain areas. D-gal and CAE co-treatment for 42 days attenuated the behavioral, biochemical, and neuroanatomical impairments caused by the D-gal; it markedly suppresses the D-gal-induced oxidative stress and AChE activity in the brain, and maintains the normal cellular architecture in hippocampal and cortical areas. Thus, this study shows that CAE can protect the brain from the adverse effects of D-gal (e.g., memory loss and cognitive impairment) by modulating AChE activity and oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Post-traumatic stress disorder (PTSD) develops after exposure to a severe traumatic event. Stress re-stress (SRS) model of PTSD using forced swim as a re-stress shows hypocortisolism, an index of hypothalamic–pituitary–adrenal (HPA) axis dysfunction. Despite this, the SRS model lacks development of hyperarousal and intrusive memory which are prominent symptoms of PTSD. Aim: Developing a model which shows more clinical similarities to PTSD. We used intense foot-shock (FS) (2 mA for 10 sec) instead of the forced-swim test (FST) as a re-stress cue. Methods: The stress session was performed on D-2 except control group. The FST group rats were forced to swim for 20 min, and FS group rats were exposed to foot shock of 2 mA for 10 sec. The re-stress sessions of FST and FS were performed on D-8, 14, 20, 26 and 32. The freezing behavior was evaluated after the FS re-stress cue, and remaining behavioral assessments such as anxiety and depressive-like behavior, and cognitive dysfunction were performed on last day of the experiment. Results: The FS-induced PTSD-like (anxiety and depressive-like behavior, and cognitive dysfunction) symptoms and a decrease in plasma corticosterone were more significant compared to FST. The hyperarousal and intrusive memory induced by FS were additional symptoms in the SRS model. Treatment with paroxetine significantly attenuated FST and FS-induced behavioral deficits in PTSD rats. Conclusion: FS as a re-stress model shows prominent PTSD-like symptoms with HPA axis dysfunction compared to FST. [ABSTRACT FROM AUTHOR]

• Suvorexant attenuated the PTSD-like symptoms in SRS exposed rats. • Exposure of SRS caused peripheral and central activation of orexinergic system. • Suvorexant ameliorated the hyperactivity of serotonergic and orexinergic systems. • The abnormality in HPA axis and CRF-R1 up-regulation was significantly ameliorated by suvorexant and paroxetine. • Suvorexant at low and median doses attenuated the SRS-induced decrease in locomotion. Post-traumatic stress disorder (PTSD) is a psychological disorder affecting many around the world. Growing evidence suggests that orexin-A is involved in the pathophysiology of depression and panic anxiety disorder. However, the role of orexin-A in PTSD remains unclear. Therefore, pharmacological manipulation of orexin-A can be a potential approach for the treatment of PTSD. Male Wistar rats were subjected to stress re-stress (SRS) by restraining them for 2 h followed by foot shock (FS) and halothane exposure on day-2 (D-2). Then the rats were weekly exposed to FS as re-stress cue. Suvorexant, an orexin antagonist (10, 20 and 30 mg/kg p.o.) and paroxetine (10 mg/kg p.o.) were administered from D-8 to D-32. Plasma and cerebrospinal fluid (CSF) were collected for corticosterone and orexin-A measurement. The analysis of serotonin and corticotropin-releasing factor receptor-1 (CRF-R1) were performed in the amygdalar tissue. SRS-induced PTSD-like symptoms like fear response, anxiety-like behaviour and hypocorticosteronism were attenuated by suvorexant and paroxetine. Interestingly, SRS exposed rats showed activation of orexin-A and serotonergic systems, which were also attenuated by suvorexant. Additionally, suvorexant ameliorated the extrahypothalamic induced upregulation of CRH-R1 in SRS-exposed rats. Therefore, orexin-A may be considered as a neurochemical-marker for PTSD and suvorexant alleviated PTSD-like symptoms through modulating orexinergic, serotonergic and neuroendocrine systems. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that mitochondrial dysfunction plays a significant role in PTSD. However, the exact mechanism is still unclear. Mitochondrial dynamics could be one of the mechanisms, as it is crucial for mitochondrial homeostasis and is widely affected in traumatic situations. Mitochondrial dynamics regulate mitochondrial homeostasis via orexinergic receptors, and it is shown that antagonism of orexinergic receptors attenuates PTSD-like symptoms. Therefore, the present study aimed to determine how orexin antagonists affect mitochondrial dynamics in rats exhibiting PTSD-like symptoms. Using rats, a stress-re-stress (SRS) model with PTSD-like symptoms was established. On day 2 (D-2), the animals were exposed to variable stressors including 2 h of restraint followed by brief mild foot shock and exposure to 4%halothane. Foot shock was performed as a re-stress from D-8 to D-32 at six-day intervals. SRS exposure caused PTSD-like phenotype, hypothalamic-pituitary-adrenal axis dysfunction, activation of mammalian target of rapamycin (mTOR), and mitochondrial-fission-process-1 (MTFP-1). SRS-subjected rats exhibited enhanced expression of fission-regulating proteins, including dynamin-related protein-1 and mitochondrial-fission-protein-1 and reduced expression of fusion-regulating proteins, including optic-atrophy-1 and mitofusin-2, in the amygdala. TEM analysis revealed that SRS exposure further damaged the mitochondria. Treatment with suvorexant with rapamycin significantly mitigated PTSD-like symptoms and improved mitochondrial dynamics in SRS-exposed rats. However, their combination showed a more pronounced effect. Further, suvorexant in combination with rapamycin significantly mitigated mTOR and MTFP-1 activation. Sertraline attenuated PTSD-like symptoms without affecting SRS-induced activation of mTOR and disparity in mitochondrial dynamics. Suvorexant pharmacological effects on mitochondrial biogenesis also involve the mTOR pathway. The role of orexinergic pathway in SRS-induced mitochondrial mitophagy was not explored. Targeting both the orexinergic and mTOR pathways might exert a beneficial synergistic effect for treating PTSD. [Display omitted] • mTOR regulates MTFP1 translation and mitochondrial dynamics in SRS-exposed rats. • Suvorexant and rapamycin mitigate mTOR effect and stabilize the mitochondrial dynamics • Suvorexant and rapamycin ameliorate the SRS-induced mitochondrial damage in rats • SRS-induced PTSD-like phenotype ameliorated by suvorexant, rapamycin and sertraline • Suvorexant reduced the SRS-induced increased in plasma and CSF orexin-A level. [ABSTRACT FROM AUTHOR]

Centella asiatica (L.) Urban, is a medicinal herb with rich history of traditional use in Indian subcontinent. This herb has been valued for its diverse range of medicinal properties including memory booster, and also as a folk treatment for skin diseases, wound healing and mild diuretic. Aging is a gradual and continuous process of natural decay in the biological systems, including the brain. This work aims to evaluate the effectiveness of ethanolic extract of Centella asiatica (CAE) on age-associated cognitive impairments in rats, as well as the underlying mechanism. Rats were allocated into five distinct groups of 5 animals each: Young rats (3 months old rats), middle-aged (m-aged) rats (13–14 months old), and the remaining three groups were comprised of m-aged rats treated with different concentrations of CAE, viz., 150, 300, and 450 mg/kg b. w., orally for 42 days. Y-maze, open field, novel object recognition, and elevated plus maze tests were used to assess animal behavior. The malondialdehyde (MDA), superoxide dismutase (SOD), and acetylcholinesterase (AChE) assays; and H&E staining were done in the rat brain to assess the biochemical and structural changes. CAE was also subjected to HPLC analysis, in vitro antioxidant and anti-cholinergic activity. The active compounds of CAE were docked with AChE and BuChE in molecular docking study. The results showed that CAE treatment improves behavioral performance; attenuates the age-associated increase in MDA content, SOD, and AChE activity; and reduces neuronal loss. In vitro study showed that CAE has concentration-dependent antioxidant and anti-AChE activity. Furthermore, the presence of Asiatic acid and Madecassic acid in CAE and their good binding with cholinergic enzymes (in silico) also suggest the anticholinergic effect of CAE. The findings of the current study show that the anticholinergic and antioxidant effects of CAE are attributable to the presence of Asiatic acid and Madecassic acid, which not only provide neuroprotection against age-associated cognitive decline but also reverse it. [Display omitted] • Aging has a major impact on the brain, affecting memory and cognitive function. • CA improves hippocampus and cortex associated cognitive functions in m-aged rats. • CA reduces oxidative stress and improves cholinergic activity in m-aged rats. • The presence of Asiatic and Madecassic acid contributes to CA's beneficial effect. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Potentilla fulgens (Wall.) ex Hook. (Rosaceae) is a potent medicinal plant of the Western Himalayas, known under the name “Himalayan Cinquefoil or Bajradanti”, and has been used traditionally to treat ailments including peptic ulcers, mouth ulcers, diarrhea, diabetes and cancer. Objective: The aim of the present study was to scientifically evaluate the gastric-ulcer protective effect of P. fulgens ethanolic root extract (EPF) on experimental rats. Material and methods: The gastroprotective activity of EPF was evaluated on four gastric-ulcer models such as pyloric ligation (PL), ethanol (EtOH), cold restrain stress (CRS) and aspirin (ASP)-induced gastric ulcers. The gastric acid obtained from 4h PL-induced gastric ulcer rats was determined for total volume content, pH and total acid–pepsin output. Total carbohydrates and protein ratio, expressed as index of mucin activity, and DNA content were estimated in the gastric juice and gastric mucosal tissue. The microvascular permeability, H+K+–ATPase activity, gastric mucus and histamine content were also determined. The levels of antioxidant enzymes (superoxide dismutase, catalase, and glutathione) and malondialdehyde in the stomach tissue (mucosal scrapings) were quantified. A histopathological study of the stomach was evaluated using eosin–haematoxylin stain. Results: EPF (200–400mg/kg, p.o.) showed significant protection against acute gastric-ulcer induced by EtOH, PL and CRS (400mg/kg, p.o.), but was found to be ineffective against ASP-induced ulcerogens. The effect of EPF on gastric juice studies in 4h PL rats significantly produced an increased level in gastric pH, whereas the effect on gastric volume and acid–pepsin output was observed to decrease significantly. However, EPF was found to have no significant effect on the defensive factors, thus revealing its antisecretory property by inhibiting the aggressive factors. EPF, significantly decreased the histamine level, inhibited the H+K+–ATPase activity and prevented the microvascular injury caused by ethanol in the rat stomach. Moreover, it was also observed to have antioxidant effects by producing a significant increase in the levels of SOD, CAT, and GSH and decreased the LPO activity. Histopathological studies showed that EPF significantly prevented gastric lesions caused by ethanol. Conclusions: The present study showed that EPF has potent gastroprotective and antisecretory effects, thus justifying the traditional usage of this herb to treat gastric ulcers. [Copyright &y& Elsevier]

Current pharmacotherapy for post-traumatic stress disorder (PTSD) is limited to few antidepressants. Mitochondrial dysfunction is observed in PTSD, along with altered potassium homeostasis. Nutritional supplementation of taurine can improve ionic homeostasis and thereby treat PTSD-like symptoms in rats. The purpose is to study the pharmacological effect of taurine in stress re-stress-induced PTSD in rats. As per protocol, animals were restrained for 2 h then exposed to footshock (FS) (2 mA/10 s) followed by halothane-induced anesthesia. Behavioral assessments such as elevated plus maze (EPM) and Y-maze tests were performed on days 2, 8, and 32 of experimental protocol after re-stress. In addition, daily oral administration of taurine (100, 200, and 300 mg/kg) and paroxetine (PAX) (10 mg/kg) was done from D-8 to D-32 followed by re-stress. The plasma concentration of taurine, corticosterone, and potassium was measured on Day-32 along with mitochondrial function in discrete brain regions. Sub-chronic administration of taurine in high and medium doses significantly ameliorated PTSD-like symptoms such as hyperarousal, anxiety, and improved spatial recognition memory. Taurine in all doses restored the plasma concentration of corticosterone and potassium. SRS-induced alterations in mitochondrial bioenergetics, complex enzyme activities, and reduced mitochondrial membrane potential in different brain regions were ameliorated by taurine. Nutritional supplementation of taurine improves potassium ionic homeostasis, mitochondrial function, and attenuated PTSD-like symptoms in SRS subjected rats. [Display omitted] [ABSTRACT FROM AUTHOR]

Long term exposure of electromagnetic radiations (EMR) from cell phones and Wi-Fi hold greater propensity to cause anxiety disorders. However, the studies investigating the effects of repeated exposure of EMR are limited. Therefore, we investigated the effects of repeated exposure of discrete frequencies of EMR in experimental animals. Male rats were exposed to EMR (900, 1800 and 2450 MHz) for 28 (1 h/day) days. Long term exposure of EMR (2450 MHz) induced anxiety like behavior. It deregulated the hypothalamic pituitary adrenal (HPA) axis in rats as observed by increase in plasma corticosterone levels apart from decreased corticotrophin releasing hormone-2 (CRH-2) and Glucocorticoid receptor (GR) expression in amygdala. Further, it impaired mitochondrial function and integrity. The expression of Bcl 2 showed significant decrease while Bax and ratio of Bax: Bcl 2 were increased in the mitochondria and vice versa in cytoplasm indicating altered regulation of apoptosis. EMR exposure caused release of cytochrome-c and expression of caspase-9 ensuing activation of apoptotic cell death. Additional set of experiments performed to estimate the pattern of cell death showed necrotic and apoptotic amygdalar cell death after EMR exposure. Histopathological studies also revealed a significant decrease in neuronal cells in amygdala. The above findings indicate that long-term exposure of EMR radiation (2450 MHz) acts as a stressor and induces anxiety-like behaviors with concomitant pathophysiological changes in EMR subjected rats. Image 1 • EMR-2450 MHz induces stress and aggravates anxiety-like symptoms in rats. • Exposure of EMR-2450 MHz increases plasma corticosterone level and, expression of CRH-2 and GR in amygdala. • Increased expression of cytochrome-C and caspase-9 indicating mitochondrial dysfunction and activation of apoptosis. • Change in expression of mitochondrial Bax: Bcl 2 ratio indicating modulation of apoptosis. • EMR-2450 MHz exposure causes both amygdalar necrotic and apoptotic cell death. [ABSTRACT FROM AUTHOR]

Indole-3-carbinol (I3C) is reported to have hepatic and neuroprotective properties. However, the I3C role in the protection of the liver and brain in the pathological condition of hepatic encephalopathy has not been investigated. Therefore, in the present study, we have assessed the hepatic and neuroprotective roles of I3C against thioacetamide (TAA)- induced hepatic encephalopathy in Wistar rats. TAA (300 mg/kg) was intraperitoneally administered to Wistar rats to induce hepatic encephalopathy. The elevated levels of ammonia in the blood, liver, and brain were substantially lowered by I3C treatment (25, 50, and 100 mg/kg, oral, 7 days). I3C significantly ameliorated the TAA-induced liver dysfunction by decreasing the alanine transaminase, aspartate transaminase, and alkaline phosphatase enzymes and reduced the elevated cytochrome P4502E1 (CYP2E1) activity in the liver and brain. Further, I3C alleviated mitochondrial dysfunction and oxidative stress in the brain. I3C treatment improved the anti-inflammatory cytokine interleukin (IL)− 10 while reducing inflammatory cytokines such as tumor necrosis factor-1 and IL-6 in hepatic encephalopathy rats. I3C reduced the levels of apoptotic indicators mediated by the mitochondria, including cytochrome c, caspase 9, and caspase 3. Concurrently, I3C mitigated the liver and brain histological abnormalities in hepatic encephalopathy rats. Therefore, the present study concluded that the I3C protected the liver and brain from TAA-induced hepatic encephalopathy injury by inhibiting CYP2E1 enzyme activity and decreasing ammonia, oxidative stress, inflammation, and apoptosis. The present study provides preclinical validation of I3C use as hepatic and neuroprotective for hepatic encephalopathy management. [Display omitted] • Indole-3-carbinol (I3C) alleviated hyperammonemia by inhibiting CYP2E1 enzyme activity. • I3C ameliorated brain edema and neurological deficits in TAA rats. • I3C mitigated mitochondrial dysfunction, inflammation, oxidative stress, and apoptosis in TAA rats. • I3C mitigated liver and brain histological abnormalities in HE rats. • I3C exhibited hepatoprotection and neuroprotection in TAA rats. [ABSTRACT FROM AUTHOR]

[Display omitted] • The study provides structural insight into rGCase and its mechanism of interactions with chaperone. • Residues TYR 263, GLN 266, TYR 331, and GLU 358 play a major role in rGCase-chaperone interactions. • Chaperone shows stronger inhibitory activity and binding affinity for rGCase at pH 7.0 than pH 4.5. • AMB acted as a potent rGCase stabilizer, which improved rGCase thermostability. Disease-modifying treatment strategy for Parkinson's disease (PD) by stabilization of Glucocerebrosidase (GCase) enzyme by chaperones is of particular interest. Wild-type rat is a widely used animal model for PD; however, the in-silico model to elucidate the nature of rat GCase (rGCase)-chaperone interactions, mechanisms, and structural stability is still unavailable. Hence, we have developed pH-dependent rGCase homology models, in-silico (docking and molecular dynamics), and in-vitro techniques (enzyme kinetics and thermal stability) to address this gap. The homology modeling results revealed ≥ 90% rGCase residues were in the favored regions, representing adequate models quality. In-silico studies showed an interaction between chaperone (Ambroxol, AMB) and the active site residues TYR 331, TYR 263, GLN 266, and GLU 358 with the higher affinity at neutral pH than acidic pH. In-vitro studies showed higher inhibitory activity (IC 50) and binding affinity (K i) of AMB at neutral pH (IC 50 : 8.2 ± 2.6 µM and K i : 4.3 ± 1.2 µM) than acidic pH (IC 50 and K i : not identified). AMB improved rGCase thermostability was confirmed by thermal denaturation assay. We have developed the homology model for rGCase, which provides a perspective for designing and screening the chaperones at the initial phases of drug discovery to ameliorate PD. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Shilajit has been used as a rejuvenator for ages in Indian ancient traditional medicine and has been validated for a number of pharmacological activities. Aim of the study: The effect of processed shilajit which was standardized to dibenzo-α-pyrones (DBPs;0.43% w/w), DBP-chromoproteins (DCPs; 20.45% w/w) and fulvic acids (56.75% w/w) was evaluated in a rat model of chronic fatigue syndrome (CFS). The mitochondrial bioenergetics and the activity of hypothalamus–pituitary–adrenal (HPA) axis were evaluated for the plausible mechanism of action of shilajit. Materials and Methods: CFS was induced by forcing the rats to swim for 15mins for 21 consecutive days. The rats were treated with shilajit (25, 50 and 100mg/kg) for 21 days before exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility and the climbing period. The post-CFS anxiety level was assessed by elevated plus maze (EPM) test. Plasma corticosterone and adrenal gland weight were estimated as indices of HPA axis activity. Analysis of mitochondrial complex chain enzymes (Complex I, II, IV and V) and mitochondrial membrane potential (MMP) in prefrontal cortex (PFC) were performed to evaluate the mitochondrial bioenergetics and integrity respectively. Results: Shilajit reversed the CFS-induced increase in immobility period and decrease in climbing behavior as well as attenuated anxiety in the EPM test. Shilajit reversed CFS-induced decrease in plasma corticosterone level and loss of adrenal gland weight indicating modulation of HPA axis. Shilajit prevented CFS-induced mitochondrial dysfunction by stabilizing the complex enzyme activities and the loss of MMP. Shilajit reversed CFS-induced mitochondrial oxidative stress in terms of NO concentration and, LPO, SOD and catalase activities. Conclusion: The results indicate that shilajit mitigates the effects of CFS in this model possibly through the modulation of HPA axis and preservation of mitochondrial function and integrity. The reversal of CFS-induced behavioral symptoms and mitochondrial bioenergetics by shilajit indicates mitochondria as a potential target for treatment of CFS. [Copyright &y& Elsevier]

Abstract: Bergenin, a major constituent of Caesalpinia digyna Rottler (Leguminosae) was isolated from its roots and was characterized by comparing its melting point and spectroscopic data (IR, 1H, 13C, Mass Spectra) with standard bergenin. Isolated bergenin was then evaluated for antidiabetic (Type 2) activity in streptozotocin (STZ)-nicotinamide induced diabetic rats. Bergenin was administered at doses of 2.5, 5, and 10mg/kg; p.o. to normal rats which were subjected to oral glucose tolerance test (OGTT). Bergenin at same dose level was given to diabetic rats and fasting blood glucose level was estimated on 0th, 7th and 14th day of treatment while plasma lipids, antioxidant enzymes and liver glycogen level in diabetic rats were estimated on 14th day of treatment followed by histopathological studies of pancreas. Bergenin at 10mg/kg; p.o. was found to reduce blood glucose level significantly in OGTT (P<0.01) while it showed a significant reduction in fasting blood glucose level in diabetic rats at same dose level only on 14th day of treatment. Bergenin in all dose levels reversed plasma lipid (reduced elevated TC, LDL-C and increased HDL-C level) profile to normal values except TG. However, bergenin showed no significant effect on liver glycogen at all dose level. The decrease in lipid peroxides and increase in superoxide dismutase (SOD) and catalase (CAT) in liver illustrated the antioxidant potential of bergenin. Histopathological studies demonstrated the regenerative effect of bergenin on pancreatic β cells. Hence, bergenin isolated from C. digyna possesses significant antidiabetic, hypolipidemic and antioxidant activity in Type 2 diabetic rats. [Copyright &y& Elsevier]