Diosgenin alleviates alcohol-mediated escalation of social defeat stress and the neurobiological sequalae.

RATIONALE: Emerging evidence indicates that persistent alcohol consumption escalates psychosocial trauma achieved by social defeat stress (SDS)-induced neurobiological changes and behavioral outcomes. Treatment with compounds with neuroprotective functions is believed to reverse ethanol (EtOH)-aggravated SDS-induced behavioral impairments. OBJECTIVES: We investigated the outcomes of diosgenin treatment, a phytosteroidal sapogenin in mice co-exposed to repeated SDS and EtOH administration. METHODS: During a period of 14 days, SDS male mice were repeatedly administered EtOH (20%, 10 mL/kg) orally from days 8-14 (n = 9). Within days 1-14, SDS mice fed with EtOH were simultaneously treated with diosgenin (25 and 50 mg/kg) or fluoxetine (10 mg/kg) by oral gavage. Locomotor, cognitive-, depressive-, and anxiety-like behaviors were assessed. Adrenal weight, serum glucose, and corticosterone levels were assayed. Brain markers of oxido-inflammatory, neurochemical levels, monoamine oxidase-B, and acetylcholinesterase activities were measured in the striatum, prefrontal cortex, and hippocampus. RESULTS: The anxiety-like behavior, depression, low stress resilience, social, and spatial/non-spatial memory decline exhibited by SDS mice exposed to repeated EtOH administration were alleviated by diosgenin (25 and 50 mg/kg) and fluoxetine, illustrated by increased dopamine and serotonin concentrations and reduced monoamine oxidase-B and acetylcholinesterase activities in the prefrontal cortex, hippocampus, and striatum. Diosgenin attenuated SDS + EtOH interaction induced corticosterone release and adrenal hypertrophy, accompanied by reduced TNF-α, IL-6, malondialdehyde, and nitrite levels in the striatum, prefrontal cortex, and hippocampus. Diosgenin increased glutathione, superoxide dismutase, and catalase levels in SDS + EtOH-exposed mice. CONCLUSIONS: Our data suggest that diosgenin reverses SDS + EtOH interaction-induced behavioral changes via normalization of hypothalamic-pituitary-adrenal axis, neurochemical neurotransmissions, and inhibition of oxidative and inflammatory mediators in mice brains.

Possible mechanisms involved in the protective effect of lutein against cyclosporine-induced testicular damage in rats.

Oxidative stress and aberrant inflammatory response have important implications in cyclosporin-induced reproductive functions. Previous studies have shown that agents with antioxidant and anti-inflammatory activities might be beneficial in reversing cyclosporin-induced reproductive impairment. Lutein is a naturally occurring compound with antioxidant and anti-inflammatory properties. However, the effect of lutein against cyclosporin-induced reproductive impairment remains in complete. Hence, we investigated the protective effect of lutein, specifically focusing on the role of nuclear factor erythroid 2 related factor-2 (Nrf2)/heme-oxygenase-1 (HO-1)/connexin-43 (Cx-43) upregulation system against cyclosporine-induced reproductive impairment. Six male Wistar rats were allotted into 5 groups and given daily gavage of cyclosporine (40 mg/kg) and/or lutein (30 mg/kg) for four (4) weeks or in combination, respectively. The testicular antioxidant scaffolds: superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), add to sulfhydryl (T-SH), non-protein sulfhydryl (NP-SH), glutathione reductase (GR), glutathione-S -transferase (GST), glutathione peroxidase (GSH-Px), thiobarbituric acid reactive substances (TBARS), myeloperoxidase (MPO), testicular proinflammatory cytokines, apoptotic related protein, nucleic acids, sialic acid, testicular proton pump ATPase, stress responsive protein, BTB-related protein and total protein levels in the testes were assayed thereafter. Cyclosporin significantly increased NOX-1, TNF-α, IL-1ß, MPO, caspase-3 and -9 levels, which were reversed by lutein. Lutein reversed cyclosporin-induced decreases in Nrf2, HO-1, BCL-2, cytochrome C, with corresponding increase in CAT, SOD, GSH, T-SH, NP-SH, GST, GR, GSH-Px, and Cx-43 levels compared to cyclosporin groups. Lutein also abates cyclosporin-induced alterations Na + -K + -ATPase activities. Our findings showed that lutein's protective effect against cyclosporin-induced reproductive impairment might be associated with mechanisms linked to its antioxidant, anti-apoptotic, and anti-inflammatory properties, notably through up-regulation of Nrf2/HO-1/Cx-43 signaling and down-regulation of NOX-1 signaling.

Prenatal double-hit with aluminium and cadmium mediate testicular atrophy and hypothalamic hypoplasia: the role of oxido-nitrergic stress and endocrine perturbations.

There is limited experimental evidence on the biochemical consequences of aluminium (Al) and cadmium (Cd) co-exposures during pregnancy and postnatal life.This study investigated the impacts of perinatal Al chloride (AlCl3) and Cd chloride (CdCl2) co-exposures on neuroendocrine functions in mice offspring during postnatal life. The study comprised of four pregnant experimental groups. Group 1 received AlCl3 (10 mg/kg), group 2 were administered CdCl2 (1.5 mg/kg), while group 3 received both AlCl3 (10 mg/kg) and CdCl2 (1.5 mg/kg) (AlCl3+CdCl2), and group 4 received saline (10 mL/kg) only and served as control group. All experimental animals were chemically exposed once daily from gestation days 7-20. Upon delivery, male pups were regrouped based on maternal chemical exposure on postnatal day 21 (PND 21) and allowed to grow to adulthood until PND 78, after which they were sacrificed for assessment of neuroendocrine markers and histological investigations. There was no statistical significance (p > 0.05) on follicle stimulating hormone, testosterone, estrogen and progesterone, thyroid stimulating hormone, thyroxine (T4) in all treatment groups relative to controls|. However, AlCl3 and AlCl3-CdCl2 significantly (p < 0.05) reduced triiodothyronine (T3) levels, with a profound increase in T3:T4 ratio by AlCl3, and AlCl3+CdCl2 compared to control. Furthermore, pups from pregnant mice treated with CdCl2 and AlCl3+CdCl2 demonstrated increased testicular malondialdehyde concentration with increased catalase activity relative to controls, suggesting oxidative imbalance. In addition, AlCl3, CdCl2, and AlCl3+CdCl2 exposures induced testicular and hypothalamic architectural disruption compared to controls, with marked architectural derangement in the AlCl3+CdCl2 group. Our findings suggest that prenatal co-exposures to Alcl3 and CdCl2 induce testicular and hypothalamic alterations in offspring via a testicular oxidative stress and thyrotoxicosis-dependent mechanisms.

Antipsychotic effect of diosgenin in ketamine-induced murine model of schizophrenia: Involvement of oxidative stress and cholinergic transmission.

A decrease in the levels of antioxidant arsenals exacerbate generation of reactive oxygen/nitrogen species, leading to neurochemical dysfunction, with significant impact on the pathogenesis of psychotic disorders such as schizophrenia. This study examined the preventive and reversal effects of diosgenin, a phyto-steroidal saponin with antioxidant functions in mice treated with ketamine which closely replicates schizophrenia-like symptoms in human and laboratory animals. In the preventive phase, adult mice cohorts were clustered into 5 groups (n = 9). Groups 1 and 2 received saline (10 mL/kg, i.p.), groups 3 and 4 were pretreated with diosgenin (25 and 50 mg/kg), and group 5 received risperidone (0.5 mg/kg) orally for 14 days. Mice in groups 2-5 additionally received a daily dose of ketamine (20 mg/kg, i.p.) or saline (10 mL/kg/day, i.p.). In the reversal phase, mice received intraperitoneal injection of ketamine or saline for 14 consecutive days prior to diosgenin (25 and 50 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) treatment from days 8-14. Mice were assessed for behavioral changes. Oxidative, nitrergic markers, and cholinergic (acetylcholinesterase activity) transmission were examined in the striatum, prefrontal-cortex and hippocampus. Diosgenin prevented and reversed hyperlocomotion, cognitive and social deficits in mice treated with ketamine relative to ketamine groups. The increased acetylcholinesterase, malondialdehyde and nitrite levels produced by ketamine were reduced by diosgenin in the striatum, prefrontal-cortex and hippocampus, but did not reverse striatal nitrite level. Diosgenin increased glutathione, and catalase levels, except for hippocampal catalase activity when compared with ketamine controls. Conclusively, these biochemical changes might be related to the behavioral deficits in ketamine-treated mice, which were prevented and reversed by diosgenin.

D-ribose-L-cysteine exhibits restorative neurobehavioral functions through modulation of neurochemical activities and inhibition oxido-inflammatory perturbations in rats exposed to polychlorinated biphenyl.

Polychlorinated biphenyl (PCB) is potentially harmful environmental toxicant causing cognitive decline with depressive features. PCB-induced behavioral deficits are associated with neurochemical dysfunctions, immune changes, and oxidative stress. This study investigated the neuroprotective effects of D-ribose-L-cysteine (DRLC), a neuroprotective precursor element of glutathione on PCB-induced neurobehavioral impairments. Following the initial 15 days of PCB (2 mg/kg) exposure to rats, DRLC (50 mg/kg) was given orally for an additional 15 days, from days 16 to 30. Animals were assessed for behavioral effect such as changes in locomotion, cognition, and depression. Oxidative/nitrergic stress markers; antioxidant regulatory proteins paraoxonase-1 (PON-1), heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nfr2), NADPH oxidase-1 (NOX-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and neuroinflammation (NF-kß, and TNF-α); and neurochemical metabolizing enzymes (acetylcholinesterase (AChE), monoamine oxidase-A and -B (MAO-A, MAO-B)) were carried out. The PCB-induced decline in locomotion, cognitive performance, and depressive-like features were reversed by DRLC. More specifically, PCB-induced oxidative and nitrergic stress, typified by reduced levels GSH, CAT, and SOD, accompanied by elevated MDA and nitrite were attenuated by DRLC. Additionally, DRLC restored the neuroinflammatory milieu indicated by decreased NF-kß and TNF-α levels toward normal. Hyperactivities of AChE, MAO-A, MAO-B, PON-1, and NOX-1 levels as well as Nfr2, NQO1, and PON-1 due to PCB exposure were mitigated by DLRC. Our results suggest DRLC as a prospective neurotherapeutic agent against PCB-induced neurobehavioral impairments such as cognitive deficit and depressive-like feature through antioxidative and anti-nitrergic stress, anti-neuroinflammation, inhibition of brain metabolizing enzymes, and normalization of neurochemical homeostasis.

Epigallocatechin-gallate attenuates rapamycin exacerbated high fat diet-induced autophagy, hormonal dysregulation, testicular and brain oxidative stress, and neurochemical changes in rats.

This study investigated whether epigallocatechin-gallate (EGCG) could counteract the detrimental effects of high-fat diet (HFD)-induced obesity in rats exposed to rapamycin-induced reproductive and neuronal changes. Six rats per treatment group (n = 6) were utilized, in which groups 1 and 2 had dimethylsulfoxide (DMSO) (0.1%) and EGCG (80 mg/kg) respectively. Group 3 received HFD + 0.1% DMSO daily for 56 days. Group 4 received HFD + rapamycin (1 mg/kg) orally for 56 days. Rats in group 5 received HFD for 56 days and EGCG (80 mg/kg, p.o.) from days 29-56. Group 6 received the combination of HFD + rapamycin (56 days) with EGCG (80 mg/kg) from days 29-56. Cognitive loss was assessed using Y-maze-test (YMT). Afterwards, serum sex hormones, insulin-glucose balance, serotonin concentration, acetylcholinesterase activity, sperm features, antioxidants, and the markers of oxido-nitrergic, autophagy and apoptotic mediators were assessed. EGCG reversed rapamycin exacerbated HFD-induced alterations in spermatogenesis, insulin-glucose balance, reproductive hormones, oxido-nitrergic stress, and altered serotonin, acetylcholinesterase levels, and autophagic and apoptotic activities in rats' testes and brains respectively. EGCG significantly attenuated HFD-induced cognitive loss. The study showed that EGCG attenuated rapamycin-mediated HFD-induced spermatogenesis deficiency and cognitive impairment via normalization of reproductive hormones, testicular and brain oxidative stress, apoptotic, autophagic activities, with serotonin and cholinergic levels in rats.

Geraniol attenuates behavioral and neurochemical impairments by inhibitions of HPA-axis and oxido-inflammatory perturbations in mice exposed to post-traumatic stress disorder.

Geraniol is an acyclic isoprenoid monoterpenoid analogue that has been shown to elicit neuroprotective functions, primarily through its ability to stimulate antioxidant and anti-inflammatory systems. An increase in inflammatory cytokines and oxidative stress exacerbate activation hypothalamic-pituitary-adrenal axis (HPA), leading to neurochemical dysfunction, which has important roles in the pathogenesis of post-traumatic disorder (PTSD), a mental health disorder characterized of post-trauma-induced intense fear. The aim of this study was to evaluate the anti-PTSD-like effects and underlying mechanisms of geraniol against single-prolonged-stress (SPS)-induced PTSD in mice. Following concomitant exposure to SPS (triple-paradigm traumatic events) and isolation for 7 days, mice (n = 9) were treated with geraniol (50 and 100 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.) from days 8-21. Mice were assessed for behavioral changes. Neurochemical changes, inflammatory, oxido-nitrergic markers, adrenal weight, serum glucose and corticosterone concentrations were assayed. Geraniol inhibits SPS-induced anxiety- and depressive-like features as well as behavioral despair in the depression paradigms. SPS-induced locomotor and memory impairments were also abated by geraniol treatment similarly to fluoxetine. SPS-induced adrenal hypertrophy and increased blood glucose and corticosterone concentrations, were attenuated by the geraniol treatment. Elevated levels of TNF-α and IL-6, and malondialdehyde, nitrite, acetylcholinesterase enzyme were reduced by geraniol. Geraniol also increased glutathione, superoxide-dismutase, and catalase levels as well as dopamine, serotonin concentrations and GABAergic glutamic acid decarboxylase enzyme activity in the striatum, prefrontal cortex and hippocampus in the PTSD-mice relative to SPS control. In conclusion, geraniol attenuates behavioral impairments and neurochemical dysregulations by inhibitions of HPA-axis and oxido-inflammatory perturbations in mice exposed to PTSD.

A review of the auditory-gut-brain axis.

Hearing loss places a substantial burden on medical resources across the world and impacts quality of life for those affected. Further, it can occur peripherally and/or centrally. With many possible causes of hearing loss, there is scope for investigating the underlying mechanisms involved. Various signaling pathways connecting gut microbes and the brain (the gut-brain axis) have been identified and well established in a variety of diseases and disorders. However, the role of these pathways in providing links to other parts of the body has not been explored in much depth. Therefore, the aim of this review is to explore potential underlying mechanisms that connect the auditory system to the gut-brain axis. Using select keywords in PubMed, and additional hand-searching in google scholar, relevant studies were identified. In this review we summarize the key players in the auditory-gut-brain axis under four subheadings: anatomical, extracellular, immune and dietary. Firstly, we identify important anatomical structures in the auditory-gut-brain axis, particularly highlighting a direct connection provided by the vagus nerve. Leading on from this we discuss several extracellular signaling pathways which might connect the ear, gut and brain. A link is established between inflammatory responses in the ear and gut microbiome-altering interventions, highlighting a contribution of the immune system. Finally, we discuss the contribution of diet to the auditory-gut-brain axis. Based on the reviewed literature, we propose numerous possible key players connecting the auditory system to the gut-brain axis. In the future, a more thorough investigation of these key players in animal models and human research may provide insight and assist in developing effective interventions for treating hearing loss.

Jobelyn® improves motor dysfunctions induced by haloperidol in mice via neuroprotective mechanisms relating to modulation of cAMP response-element binding protein and mitogen-activated protein kinase.

The clinical efficacy of haloperidol in the treatment of psychosis has been limited by its tendency to cause parkinsonian-like motor disturbances such as bradykinesia, muscle rigidity and postural instability. Oxidative stress-evoked neuroinflammation has been implicated as the key neuropathological mechanism by which haloperidol induces loss of dopaminergic neurons and motor dysfunctions. This study was therefore designed to evaluate the effect of Jobelyn® (JB), an antioxidant supplement, on haloperidol-induced motor dysfunctions and underlying molecular mechanisms in male Swiss mice. The animals were distributed into 5 groups (n = 8), and treated orally with distilled water (control), haloperidol (1 mg/kg) alone or in combination with each dose of JB (10, 20 and 40 mg/kg), daily for 14 days. Thereafter, changes in motor functions were evaluated on day 14. Brain biomarkers of oxidative stress, proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), cAMP response-element binding protein (CREB), mitogen-activated protein kinase (MAPK) and histomorphological changes were also investigated. Haloperidol induces postural instability, catalepsy and impaired locomotor activity, which were ameliorated by JB. Jobelyn® attenuated haloperidol-induced elevated brain levels of MDA, nitrite, proinflammatory cytokines and also boosted neuronal antioxidant profiles (GSH and catalase) of mice. It also restored the deregulated brain activities of CREB and MAPK, and reduced the histomorphological distortions as well as loss of viable neuronal cells in the striatum and prefrontal cortex of haloperidol-treated mice. These findings suggest possible benefits of JB as adjunctive remedy in mitigating parkinsonian-like adverse effects of haloperidol through modulation of CREB/MAPK activities and oxidative/inflammatory pathways.

Involvement of oxidative stress and pro-inflammatory cytokines in copper sulfate-induced depression-like disorders and abnormal neuronal morphology in mice.

Epidemiological studies have implicated copper as one of the key environmental risk factors for the pathogenesis of depression. However, the precise mechanism by which copper contribute to the genesis of depression particularly the involvement of oxidative stress-driven neuroinflammation is yet to be fully investigated. Thus, this study was designed to evaluate the effects of copper sulfate (CuSO4) on depression-like behaviors and the role of oxidative stress and pro-inflammatory cytokines in mice. Forty male Swiss mice were distributed into control and three test groups (n = 10), and were treated orally with distilled water (10 mL/kg) or CuSO4 (25, 50 and 100 mg/kg) daily for 28 days. Afterwards, the tail suspension, forced swim, and sucrose splash tests were used for the detection of depression-like effects. The animals were then euthanized and the brains were processed for the estimation of biomarkers of oxidative stress and pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6). The histomorphological features and neuronal viability of the prefrontal cortex, hippocampus and striatum were also determined. Mice exposed to CuSO4 displayed depression-like features when compared with controls. The brain concentrations of malondialdehyde, nitrite and pro-inflammatory cytokines were elevated in CuSO4-treated mice. Mice exposed to CuSO4 also had reduced brain antioxidant status (glutathione, glutathione-s-transferase, total thiols, superoxide-dismutase and catalase), as well as altered histomorphological features, and decreased population of viable neuronal cells. These findings suggest that CuSO4 increases oxidative stress and pro-inflammatory cytokines to elicit depression-like effects in mice.

Ginkgo biloba supplement abates lead-induced endothelial and testicular dysfunction in Wistar rats via up-regulation of Bcl-2 protein expression, pituitary-testicular hormones and down-regulation of oxido-inflammatory reactions.

BACKGROUND: Apoptotic and oxido-inflammatory pathways have been found to be up-regulated in lead acetate poisoning which has been associated to endothelial and testicular dysfunctions. It is yet uncertain, nevertheless, if treatment with Ginkgo biloba supplements (GBS), a flavonoid-rich natural product can lessen the adverse effects of lead on endothelial and testicular functions. This study investigated the impact of Ginkgo biloba supplementation on lead-induced endothelial and testicular dysfunctions. METHODS: The animals were treated with GBS (50 mg/kg and 100 mg/kg orally) for 14 days following oral exposure to lead acetate (25 mg/kg) for 14 days. After euthanasia, blood samples, epididymal sperm, testes, and aorta were collected. The quantities of the hormones (testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH), as well as the anti-apoptotic, oxidative, nitrergic, inflammatory markers, were then determined using immunohistochemistry, ELISA, and conventional biochemical methods. RESULTS: GBS reduced lead-induced oxidative stress by increasing the levels of the antioxidant enzymes catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD), while lowering malondialdehyde (MDA) in endothelium and testicular cells. Normal testicular weight was restored by GBS which also decreased endothelial endothelin-I and increased nitrite levels. TNF-α and IL-6 were decreased while Bcl-2 protein expression was enhanced. Lead-induced alterations in reproductive hormones (FSH, LH, and testosterone) were also restored to normal. CONCLUSION: According to our result, using Ginkgo biloba supplement prevented lead from causing endothelial and testicular dysfunction by raising pituitary-testicular hormone levels, boosting Bcl-2 protein expression and lowering oxidative and inflammatory stress in the endothelium and testes.

Underlying biochemical effects of intermittent fasting, exercise and honey on streptozotocin-induced liver damage in rats.

Purpose: Derangements of liver transcriptional factors and enzymes have important implications in diabetes-induced related complications. Hence, this study which consists of two experimental phases was aimed at evaluating the possible underlying molecular mechanisms of intermittent fasting (IF), exercise starvation and honey in streptozotocin (STZ)-mediated liver damage in diabetic rats. Methods: The diabetic rats were treated orally with distilled water (0.5 ml/kg), IF, starvation and honey at 1 g/kg body weight in the non-diabetic phase for four (4) weeks. After STZ injections, four (4) weeks of IF, exercise, starvation, and honey therapy were used as interventions prior to a biochemical evaluation of the liver. Results: IF and exercise greatly decreased liver transcription factor (resistin, SREBP-1c), inflammatory cytokines/enzyme (TNF-α, IL-6, IL-1ß, MPO) as well as oxidative and nitrergic stress with correspondence increased liver PPAR-γ, IL-10, SOD, CAT and GSH in diabetic rats unlike starvation and honey regimen relative to diabetic controls. Furthermore, IF and exercise significantly improved hepatic glycogen synthase and decreased glycogen phosphorylase in diabetic rats compared to the diabetic control group, but starvation and honey therapy had no such influence. IF and exercise strategically reduces STZ-induced liver metabolic disorder via through modulation of liver transcriptional factors and inhibition of pro-inflammatory cytokines, oxido-nitrergic and adipokine signaling pathway.

Emerging epigenetic dynamics in gut-microglia brain axis: experimental and clinical implications for accelerated brain aging in schizophrenia.

Brain aging, which involves a progressive loss of neuronal functions, has been reported to be premature in probands affected by schizophrenia (SCZ). Evidence shows that SCZ and accelerated aging are linked to changes in epigenetic clocks. Recent cross-sectional magnetic resonance imaging analyses have uncovered reduced brain reserves and connectivity in patients with SCZ compared to typically aging individuals. These data may indicate early abnormalities of neuronal function following cyto-architectural alterations in SCZ. The current mechanistic knowledge on brain aging, epigenetic changes, and their neuropsychiatric disease association remains incomplete. With this review, we explore and summarize evidence that the dynamics of gut-resident bacteria can modulate molecular brain function and contribute to age-related neurodegenerative disorders. It is known that environmental factors such as mode of birth, dietary habits, stress, pollution, and infections can modulate the microbiota system to regulate intrinsic neuronal activity and brain reserves through the vagus nerve and enteric nervous system. Microbiota-derived molecules can trigger continuous activation of the microglial sensome, groups of receptors and proteins that permit microglia to remodel the brain neurochemistry based on complex environmental activities. This remodeling causes aberrant brain plasticity as early as fetal developmental stages, and after the onset of first-episode psychosis. In the central nervous system, microglia, the resident immune surveillance cells, are involved in neurogenesis, phagocytosis of synapses and neurological dysfunction. Here, we review recent emerging experimental and clinical evidence regarding the gut-brain microglia axis involvement in SCZ pathology and etiology, the hypothesis of brain reserve and accelerated aging induced by dietary habits, stress, pollution, infections, and other factors. We also include in our review the possibilities and consequences of gut dysbiosis activities on microglial function and dysfunction, together with the effects of antipsychotics on the gut microbiome: therapeutic and adverse effects, role of fecal microbiota transplant and psychobiotics on microglial sensomes, brain reserves and SCZ-derived accelerated aging. We end the review with suggestions that may be applicable to the clinical setting. For example, we propose that psychobiotics might contribute to antipsychotic-induced therapeutic benefits or adverse effects, as well as reduce the aging process through the gut-brain microglia axis. Overall, we hope that this review will help increase the understanding of SCZ pathogenesis as related to chronobiology and the gut microbiome, as well as reveal new concepts that will serve as novel treatment targets for SCZ.

Antihypertensive and antihyperglycemic effects of combinations of losartan with metformin and/or glibenclamide in desoxycorticosterone acetate and streptozotocin-induced hypertensive diabetic rats.

BACKGROUND: Hypertension is a medical condition that often comorbidly exist in patients with type II diabetes. Therefore, it is very important to manage both conditions simultaneously to mitigate the complications and mortality connected with this comorbidity. Hence, this study investigated the antihypertensive and antihyperglycemic effects of combinations of losartan (LOS) with metformin (MET) and/or glibenclamide (GLB) in hypertensive diabetic rats. Hypertensive diabetic state was induced with desoxycorticosterone acetate (DOCA) and streptozotocin (STZ) in adult Wistar rats. The rats were divided into 5 groups (n = 5): control group (group 1), hypertensive diabetic (HD) control (group 2), treatment groups receiving LOS + MET (group 3), LOS + GLB (group 4), and LOS + MET + GLB (group 5). Group 1 comprised healthy rats while groups 2-5 were HD rats. The rats were treated orally once daily for 8 weeks. Fasted blood glucose (FBS) level, haemodynamic parameters, and some biochemical indices were thereafter assessed. RESULTS: FBS level and blood pressure measurements were significantly (P < 0.05) increased following induction by DOCA/STZ. The drug treatment combinations, particularly combination of LOS + MET + GLB, significantly (P < 0.05) reduced the induced hyperglycemia and remarkably decreased systolic blood pressure and heart rate. There was significant (P < 0.05) reduction in raised lactate dehydrogenase and creatinine kinase levels by all drug treatment combinations except LOS + GLB. CONCLUSIONS: Our findings suggest that LOS combinations with MET and/or GLB exhibited significant antidiabetic and antihypertensive effects against DOCA/STZ-induced hypertensive diabetic state in rats.

Co-administration of metformin and/or glibenclamide with losartan reverse NG-nitro-l-arginine-methyl ester-streptozotocin-induced hypertensive diabetes and haemodynamic sequelae in rats.

Over the years, there have been opinions on whether to reduced blood pressure (BP) to a different levels in patients with diabetes mellitus. Hence, this study investigated the efficacy of the co-administration of losartan (angiotensin receptor blocking antihypertensive agent) with metformin and/or glibenclamide (antidiabetic agents) on hypertensive-diabetic experimental rats induced by NG-nitro-l-arginine-methyl-ester hydrochloride (l-NAME), and streptozotocin (STZ). STZ (45 mg/kg, i.p.)-induced diabetic rats combined with l-NAME (40 mg/kg, p.o.)-induced hypertension were allotted into different groups. Group 1 received distilled water (10 mL/kg) and served as normal control, group 2 comprised hypertensive diabetic rats with distilled water, groups 3-5 were hypertensive-diabetic rats but received combination treatments of losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide daily for 8 weeks, respectively. Our finding revealed no changes in the body weights, but there was a significant increase in fasting blood sugar levels in l-NAME - STZ-induced hypertensive-diabetes, which were lowered by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide treatments. Moreover, the increased systolic-BP, mean arterial pressure but not diastolic-BP and heart rate by l-NAME + STZ were attenuated more significantly by losartan + metformin + glibenclamide between weeks 2-8 relative to hypertensive-diabetic control. l-NAME + STZ-induced elevated levels of lactate dehydrogenase and creatinine kinase, were differentially reversed by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide. However, l-NAME + STZ-induced decreased nitrite level was significantly restored by all treatments, suggesting increased nitrergic transmission. Additionally, l-NAME + STZ-induced degeneration of pancreatic islet and myocardial cells were dramatically alleviated by losartan + metformin + glibenclamide treatments. Our findings suggest hyperglycemia with raised systolic-BP should be managed with losartan combined with both metformin and glibenclamide than single combination of losartan with antidiabetics.

Lipopolysaccharide Exacerbates Ketamine-Induced Psychotic-Like Behavior, Oxidative Stress, and Neuroinflammation in Mice: Ameliorative Effect of Diosmin.

Schizophrenia, a neuropsychiatric disorder has been associated with aberrant neurotransmission affecting behaviors, social preference, and cognition. Limitations in understanding its pathogenesis via the dopamine hypothesis have engendered other hypotheses such as the glutamate hypothesis. That antagonism of the N-methyl-D-aspartate receptor (NMDAR) elicits schizophrenia-like behaviors indistinguishable from the disorder in animal and human models. There are growing concerns that redox imbalance and neuro-immuno dysfunction may play role in aggravating the symptomologies of this disorder. This 14-day treatment study was designed to investigate the effect of diosmin on lipopolysaccharide (LPS) plus ketamine (NMDAR antagonist). Mice were divided into 4 groups (n = 6). Group 1 was administered 5% DMSO (10 mL/kg, i.p) while group 2-4 received LPS (0.1 mg/kg, i.p) daily for 14 days. Diosmin (50 mg/kg, i.p) and risperidone (0.5 mg/kg, i.p) were given to groups 3 and 4 respectively. Groups 2-4 were given KET (20 mg/kg, i.p.) daily from days 8-14. Behavioral tests were done 30 min after the last dose, and oxidative stress and neuroinflammatory maker were assayed. LPS plus ketamine-induced hyperlocomotion, stereotypy, decreased social preference, and memory impairment. Furthermore, LPS plus-ketamine-induced oxidative stress (reduced GSH, CAT, SOD, and increased MDA and nitrite levels) and marked pro-inflammatory cytokines TNF-α and IL-6 suggesting neuroinflammation. However, diosmin attenuated behavioral deficits and improved memory. Additionally, diosmin potentiated antioxidant level via increased GSH, CAT, and SOD while reducing MDA and nitrite levels. Finally, diosmin reduced TNF-α and IL-6 suggesting anti-neuro-immuno activity. Conclusively, diosmin attenuated LPS plus ketamine-induced behavioral deficits, oxidative stress, neuroinflammation, and improved memory.

Aggressive-like behaviour and neurocognitive impairment in alcohol herbal mixture-fed mice are associated with increased neuroinflammation and neuronal apoptosis in the prefrontal cortex.

Alcohol-induced aggression and related violence is a serious and common social problem globally. Alcohol use is increasingly found in the form of alcoholic herbal mixtures (AHM) with indiscriminate and unregulated alcohol content. This study investigated the effects of AHM on aggressive-like, neurocognitive impairment and brain biochemical alteration in mice. Thirty-two male resident mice were paired housed with female mice for 21 days in four groups (n = 8). Resident mice were treated orally with normal saline, AHM, ethanol and AHM + ethanol daily for 14 days. Aggressive-like behaviour was scored based on the latency and frequency of attacks by the resident mouse on the intruder. Neurocognitive impairment was determined using the Y-maze test (YMT) and novel object recognition test (NORT). Acetylcholinesterase, glutamic acid decarboxylase (GAD), pro-inflammatory and oxidative stress parameters were determined in the prefrontal cortex (PFC). Neuronal morphology, cytochrome c (Cyt-c) and nuclear factor-kappa B (NF-ĸB) expressions were determined. AHM and in combination with ethanol showed an increased index of aggression typified by frequency of attack and reduced latency to attack when compared to normal saline-treated animals. Co-administration of AHM and ethanol significantly reduced cognitive correct alternation (%) and discrimination index in the YMT and NORT, respectively. AHM and ethanol increased acetylcholinesterase, Pro-inflammatory cytokines and oxidative stress parameters while they reduced GAD. There were significantly reduced neuronal counts and increased expression of Cyt-c and NF-ĸB, respectively Alcoholic herbal mixture increased aggressiveness and caused neurocognitive impairment via increased oxido-inflammatory stress in the prefrontal cortex.

Mechanisms underpinning Carpolobia lutea G. Don ethanol extract's neurorestorative and antipsychotic-like activities in an NMDA receptor antagonist model of schizophrenia.

ETHNOPHARMACOLOGICAL RELEVANCE: Persistent ketamine insults to the central nervous system block NMDA receptors and disrupt putative neurotransmission, oxido-nitrosative, and inflammatory pathways, resulting in schizophrenia-like symptoms in animals. Previously, the ethnomedicinal benefits of Carpolobia lutea against insomnia, migraine headache, and insanity has been documented, but the mechanisms of action remain incomplete. AIM OF THE STUDY: Presently, we explored the neuro-therapeutic role of Carpolobia lutea ethanol extract (C. lutea) in ketamine-induced schizophrenia-like symptoms in mice. MATERIALS AND METHODS: Sixty-four male Swiss (22 ± 2 g) mice were randomly assigned into eight groups (n = 8/group) and exposed to a reversal ketamine model of schizophrenia. For 14 days, either distilled water (10 mL/kg; p.o.) or ketamine (20 mg/kg; i.p.) was administered, following possible reversal treatments with C. lutea (100, 200, 400, and 800 mg/kg; p.o.), haloperidol (1 mg/kg, p.o.), or clozapine (5 mg/kg; p.o.) beginning on days 8-14. During the experiment, a battery of behavioral characterizations defining schizophrenia-like symptoms were obtained using ANY-maze software, followed by neurochemical, oxido-inflammatory and histological assessments in the mice brains. RESULTS: A 7-day reversal treatment with C. lutea reversed predictors of positive, negative and cognitive symptoms of schizophrenia. C. lutea also mitigated ketamine-induced neurochemical derangements as evidenced by modulations of dopamine, glutamate, norepinephrine and serotonin neurotransmission. Also, the increased acetylcholinesterase activity, malondialdehyde nitrite, interleukin-6 and tumor necrosis-factor-α concentrations were reversed by C. lutea accompanied with elevated levels of catalase, superoxide dismutase and reduced glutathione. Furthermore, C. lutea reversed ketamine-induced neuronal alterations in the prefrontal cortex, hippocampus and cerebellum sections of the brain. CONCLUSION: These findings suggest that C. lutea reverses the cardinal symptoms of ketamine-induced schizophrenia in a dose-dependent fashion by modulating the oxido-inflammatory and neurotransmitter-related mechanisms.

Psychobiotic interventions attenuate chronic alcohol use-mediated exacerbation of posttraumatic stress disorder in rats: the role of gut-liver axis response.

OBJECTIVES: The incidence of co-occurring alcohol-use disorder (AUD) and post-traumatic stress disorder (PTSD) is high, and the presence of one disorder aggravates the severity of the other. Emerging evidence shows the neuroprotective and anti-inflammation functions of psychobiotics. Hence, the study explored the effects of probiotics and synbiotic inulin on the gut- and liver-oxidative and inflammatory biomarkers in chronic alcohol exacerbation of PTSD symptoms in rats. METHODS: Young adult rats were administered 10% ethanol in a two-bottle choice test for six weeks and were subjected to single prolonged stress. Probiotics and synbiotic intervention followed this. Markers of oxido-inflammatory stress, liver functions, intestinal (faecal) metabolites, occludin expression, and histopathology of the ileum and liver were evaluated. RESULTS: Chronic alcohol drinking and PTSD increased oxido-inflammatory stress, markers of hepatic damage, and reduced faecal metabolites, which were attenuated by probiotic and synbiotic interventions. Furthermore, reduced immunoexpression of gut and liver occludin, with loss of barrier integrity, viable hepatocytes, congestive portal area, and shortened villi and crypt depth, were observed. Probiotic and synbiotic interventions mitigated these effects. CONCLUSIONS: The study demonstrates that psychobiotics mitigate the detrimental effects of co-occurring chronic alcohol intake in the context of PTSD.

Chemical characterization, anti-nociceptive and anti-inflammatory activities of Plukenetia conophora seed oil in experimental rodent models.

ETHNOPHARMACOLOGICAL RELEVANCE: The seed of the African walnut, Plukenetia conophora Mull.-Arg is well-known for its nutritional and medicinal values. The seed oil is widely used in massages to relieve pain, as nerve tonic and to enhance sexual performance. OBJECTIVE: The study aimed at investigating the chemical profile, antinociceptive and anti-inflammatory activities of P. conophora oil (PCO). METHODS: Seed oil of P. conophora was characterized using Gas-Liquid Chromatographic method (GC-MS) and oral acute toxicity evaluated at 2000 mg/kg. Antinociceptive effects were evaluated in hot plate, acetic acid and formalin-induced paw licking tests. The anti-inflammatory effects were investigated in egg albumin and carrageenan-, formalin and complete Freund adjuvant (CFA)-induced paw oedema models. The levels of pro-inflammatory cytokines in the fluid exudates were also evaluated in carrageenan air pouch model. RESULTS: PCO exhibited high content of alpha linolenic acid (ALA). No toxicity was observed at 2000 mg/kg of PCO. PCO (50-200 mg/kg) demonstrated significant anti-nociceptive activity in pain models. PCO exhibited anti-inflammatory activity against oedema formation by phlogistic agents. The increased inflammatory oedema and oxidative stress in CFA-treated rats were also attenuated by PCO. The PCO (100 and 200 mg/kg) significantly reduced the levels of TNF-α (59.3% and 85.2%) and IL-6 (27.5% and 72.5%) in carrageenan-induced air pouch model. CONCLUSION: The results of this study suggest that ALA-rich seed oil of Plukenetia conophora demonstrated anti-nociceptive and anti-inflammatory activities via inhibition of pro-inflammatory cytokines and oxidative stress, lending supportive evidences for its use in painful inflammatory conditions.