Modulation of GABA by sodium butyrate ameliorates hypothalamic inflammation in experimental model of PCOS.

Polycystic ovarian syndrome (PCOS) is a known endocrine disorder that has affected many women of childbearing age, and is accompanied by various neurodegenerative conditions. Hence, this study investigates the impact of butyrate in reversing hypothalamic-related disorder, possibly through γ aminobutyric acid (GABA) in a rat model of PCOS. Eight-week-old female Wistar rats were allotted into four groups (n = 5), which include control, butyrate, letrozole, and letrozole + butyrate groups. PCOS was induced by administering 1 mg/kg of letrozole (oral gavage) for 21 days. After confirmation of PCOS, 200 mg/kg of butyrate (oral gavage) was administered for 6 weeks. Rats with PCOS were characterized by elevated levels of plasma insulin and testosterone. Increases in plasma and hypothalamic triglyceride levels, inflammatory biomarker (SDF-1), apoptotic marker (caspase-6), and decreased plasma GnRH were observed. Additionally, a decrease in hypothalamic GABA was revealed. Nevertheless, the administration of butyrate attenuated these alterations. The present study suggests that butyrate ameliorates hypothalamic inflammation in an experimental model of PCOS, a beneficial effect that is accompanied by enhanced GABA production.

Prolonged ketamine therapy differentially rescues psychobehavioural deficits via modulation of nitro-oxidative stress and oxytocin receptors in the gut-brain-axis of chronically-stressed mice.

Ketamine is an anaesthetic known to have short but rapid-acting anti-depressant effects; however, the neurobehavioural effects of its prolonged use and its role on the oxytocin system in the gut-brain axis are largely undetermined. Female BALB/c mice were either exposed to the chronic unpredictable mild stress (CUMS) paradigm for 21 days and then treated with ketamine in four doses for 14 days or exposed to CUMS and treated simultaneously in four doses of ketamine during the last two weeks of CUMS exposure. After each dose, the forced swim test was conducted to assess depressive-like behaviour. Before sacrifice, all the mice were subjected to behavioural tests to assess anxiety, memory, and social interaction. Prolonged treatment of depression with ketamine did not rescue depressive-like behaviour. It did, however, improve depression-associated anxiety-like behaviours, short-term memory and social interaction deficits when compared to the stressed untreated mice. Furthermore, ketamine treatment enhanced plasma oxytocin levels, expression of oxytocin receptors; as well as abrogated nitro-oxidative stress biomarkers in the intestinal and hippocampal tissues. Taken together, our findings indicate that while short-term use of ketamine has anti-depressant benefits, its prolonged therapeutic use does not seem to adequately resolve depressive-like behaviour in mice.

Flavonoid glycoside fraction of Ginkgo biloba extract modulates antioxidants imbalance in vanadium-induced brain damage.

Human and animal diseases have always been reported to be treated by medicinal herbs owing to their constituents. Excess sodium metavanadate is a potential environmental toxin when consumed and could induce oxidative damage leading to various neurological disorders and Parkinsons-like diseases. This study is designed to investigate the impact of the flavonoid Glycoside Fraction of Ginkgo Biloba Extract (GBE) (at 30 mg/kg body weight) on vanadium-treated rats. Animals were divided randomly into four groups: Control (Ctrl, normal saline), Ginkgo Biloba (GIBI, 30mg/kg BWT), Vanadium (VANA, 10 mg/kg BWT) and Vanadium + Ginkgo biloba (VANA + GIBI). Markers of oxidative stress (Glutathione Peroxidase and Catalase) were assessed and found to be statistically increased with GIBI when compared with CTRL and treatment groups. Results from routine staining revealed that the control and GIBI group had a normal distribution of cells and a pronounced increase in cell count respectively compared to the VANA group. When compared to the VANA group, the NeuN photomicrographs revealed that the levels of GIBI were within the normal range (***p < 0.001; ** p < 001). The treatment with GIBI showed a better response by increasing the neuronal cells in the VANA+GIBI when compared with the VANA group. The NLRP3 Inflammasome photomicrographs denoted that there was a decrease in NLRP3-positive cells in the control and GIBI groups. The treatment group shows fewer cells compared to that of the VANA group. The treatment group shows fewer cells compared to that of the VANA group. The findings of the study confirmed that ginkgo biloba extract via its flavonoid glycoside fraction has favorable impacts in modulating vanadium-induced brain damage with the potential ability to lower antioxidant levels and reduce neuroinflammation.

Low-dose spironolactone combats dyslipidemia and hepatic inflammation by modulating PCSK9 in rat model of polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder among women and it is associated with overt metabolic derangement. Circulating lipids are regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9) which blocks low density lipoprotein (LDL) receptors especially in the liver. The liver is highly vulnerable in dyslipidemia as lipid accumulation leads to progression of non-alcoholic fatty liver disease (NAFLD). An array of scientific endeavours hold that low-dose spironolactone (LDS) is beneficial as intervention for PCOS traits, but this claim is yet to be fully elucidated. The aim of this study was to investigate the effect of LDS on dyslipidemia and hepatic inflammation in rats with letrozole (LET)-induced PCOS and to assess the possible involvement of PCSK9 in these effects. Eighteen female Wistar rats were randomly assigned into 3 groups. The control group received vehicle (distilled water; p.o.), LET-treated group received letrozole (1 mg/kg; p.o.), LET+LDS-treated group received LET plus LDS (0.25 mg/kg, p.o.) for 21 days. Exposure to LET increased body and hepatic weights, plasma and hepatic total cholesterol (TC), TC/HDL, LDL, interleukin-6, MDA, PCSK9, ovarian degenerated follicles and hepatic NLRP3 intensity, reduced GSH and normal ovarian follicles. Interestingly, LDS averted dyslipidemia, NLRP3-dependent hepatic inflammation and ovarian PCOS traits. It is evident herein that LDS ameliorates PCOS traits and combats dyslipidemia and hepatic inflammation in PCOS by a PCSK9-dependent mechanism.

Quercetin abrogates lipopolysaccharide-induced depressive-like symptoms by inhibiting neuroinflammation via microglial NLRP3/NFκB/iNOS signaling pathway.

BACKGROUND: Major depressive disorder is a serious psychiatric illness having serious damaging effect on the quality of life of suffers. Quercetin is a plant flavonoid, mostly used as a constituent in dietary products. This study evaluated antidepressant effect of quercetin on lipopolysaccharide (LPS)-induced depression in rats. MATERIALS AND METHODS: Twenty-one male rats were randomly assigned into three groups (n = 7): group 1 (vehicle only), group 2 (quercetin), group 3 (LPS). Rats were treated with vehicle (10 mL/kg, p.o.) or quercetin (50 mg/kg, p.o.) for seven days. Sixty minutes after treatment on day seven, all animals were injected with LPS (0.83 mg/kg, i.p.) except group 1 (vehicle only). Twenty-four hours after LPS injection, animals were assessed for depressive symptoms using forced swim, sucrose splash and open field tests. Animals were sacrificed; brain samples collected for bioassay of pro-inflammatory mediators, TNF-α, IL-6 and IL-17 were measured using enzyme-linked immunosorbent assay (ELISA) while expressions of NF-κB, inflammasomes, microglia and iNOS were quantified by immunohistochemistry. RESULTS: The LPS significantly (p < 0.05) decreased mobility of rats in FST and decreased sucrose preference, which is indicative of depressive-like behaviours. These behaviours were significantly (p < 0.05) attenuated by quercetin compared to control (vehicle only). Following LPS exposure, the expressions of inflammasomes, NF-κB, iNOS, proinflammatory cytokines and microglia positive cells in the hippocampus and prefrontal cortex were significantly (p < 0.05) elevated. All these were attenuated by pretreating animals with quercetin. CONCLUSION: Quercetin exhibit antidepressant-like property, which may be related to inhibition of neuroinflammatory signaling pathways.

Combined Exposure to Chronic Sleep Deprivation and Caffeine Potentiates Behavioural Deficits by Altering Neurochemical Profile and Synaptophysin Expression in Long-Evans Rats.

Using the Unpredictable Chronic Sleep Deprivation (UCSD) paradigm we developed, the combined effects of chronic sleep deprivation and high caffeine intake on prefrontal cortical synaptophysin expression, neurochemical profiles, and behavioural outcomes in Long-Evans rats were evaluated. The combination of chronic sleep deprivation and high-dose caffeine treatment produced varying degrees of behavioural impairments, depletion of antioxidants, serotonin, and an upregulation of acetylcholinesterase (AChE) activity in the prefrontal cortex. An immunohistochemical assessment revealed a reduction in synaptophysin protein expression in the prefrontal cortex following exposure to high-dose caffeine and chronic sleep deprivation. Overall, our findings support the advocacy for adequate sleep for optimal mental performance as a high intake of caffeine to attenuate the effects of sleep deprivation that may alter the neurochemical profile and synaptic plasticity in the prefrontal cortex, significantly increasing the risk of neuropsychiatric/degenerative disorders.

Acetate-mediated-obestatin modulation attenuates adipose-hepatic dysmetabolism in high fat diet-induced obese rat model.

PURPOSE: Approximately 650 million of world adult population is affected by obesity, which is characterized by adipose and hepatic metabolic dysfunction. Short chain fatty acids (SCFAs) have been linked to improved metabolic profile. However, the effect of SCFAs, particularly acetate on adipose-hepatic dysfunction is unclear. Therefore, the present study investigated the role of acetate on adipose-hepatic metabolic dysfunction and the possible involvement of obestatin in high fat diet-induced obese Wistar rats. METHODS: Adult male Wistar rats (160-190 g) were allotted into groups (n = 6/group): Control, acetate-treated, obese and obese + acetate-treated groups received vehicle (distilled water), sodium acetate (200 mg/kg), 40% HFD and 40% HFD plus sodium acetate respectively. The administration lasted for 12 weeks. RESULTS: HFD caused increased body weight gain and visceral adiposity, insulin resistance, hyperinsulinemia and increased pancreatic-ß cell function and plasma/hepatic triglyceride and total cholesterol as well as decreased adipose triglyceride and total cholesterol, increased plasma, adipose, and hepatic malondialdehyde, TNF-α, uric acid, lactate production and plasma/adipose but not gamma-glutamyl transferase and decreased plasma, adipose, and hepatic nitric oxide, glucose-6-phosphate dehydrogenase (G6PD), glutathione (GSH) and obestatin concentration compared to the control group. Notwithstanding, treatment with acetate attenuated the alterations. CONCLUSIONS: The results demonstrate that high fat diet-induced obesity is characterized with adipose and hepatic lipid dysmetabolism, which is associated with obestatin suppression. Findings also suggest that acetate provide protection against adipose and hepatic metabolic perturbations by restoring obestatin as well as G6PD/GSH-dependent antioxidant system.

Quercetin mitigates memory deficits in scopolamine mice model via protection against neuroinflammation and neurodegeneration.

AIMS: Neurodegenerative disorders like Alzheimer's disease (AD) are outcomes of neuroinflammatory processes that result in memory impairment. Quercetin (QT), a plant based flavonoid, has demonstrated notable effects against neurodegeneration and inflammation in models of dementia. However, the underlying mechanisms have not been well elucidated. This study evaluated the possible effects of QT against neuroinflammation and neurodegeneration in scopolamine (SC) induced memory impairment. MAIN METHODS: SC was used to induce memory loss in mice after which novel object recognition test (NORT) was used to assess memory function. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the brain tissues of the animals. Brain histology was carried out on the hippocampus (cornus ammonis 1, cornus ammonis 3 and dentate gyrus), and the prefrontal cortex. The population of healthy neuronal cells was counted, using ImageJ software. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was employed for the identification of cells undergoing apoptosis. KEY FINDINGS: QT reversed memory impairment in the NORT. Increases in TNF-α and IL-6 were attenuated by QT, and histology revealed that QT attenuated SC-induced cell degeneration and death in the hippocampal sub-regions and prefrontal cortex. QT diminished the population of dead cells in SC-treated mice, and also reversed the process of apoptosis induced by SC. SIGNIFICANCE: Findings from the study suggest that QT mitigates pro-inflammatory mediators and reverses neurodegeneration to restore memory function.

Fermented maize slurry (Ogi) and its supernatant (Omidun) mitigate elevated intraocular pressure by modulating BDNF expression and glial plasticity in the retina-gut axis of glaucomatous rats.

OBJECTIVES: Growing interest has been reported on the health benefits of fermented foods, which includes cognition enhancement and inflammation attenuation. BDNF is a known protectant against retinal degeneration, however, therapies that target this neurotrophic factor has been limited. Therefore, we assessed the reaction of BDNF and glial cells in glaucomatous rats and their response to treatment with fermented maize products. METHODS: Thirty male adult rats were either injected via the episcleral vein with hypertonic saline to elevate intraocular pressure (IOP) or treated with fermented maize slurry (Ogi) or its supernatant (Omidun). Following sacrifice, the retina and duodenum were studied by immunohistochemical analysis using antibodies directed against GFAP, AIF-1 and BDNF. RESULTS: Hypertonic saline injection produced hypertrophy of the Müller cells and increased GFAP and AIF-1 expression in the retina and gut when compared to the control. Treatment with Ogi and Omidun produced varying degrees of reduction of gliosis, protection against hypertonic saline-induced retinal ganglion cell loss, and reduced intraocular pressure. BDNF expression was downregulated following the hypertonic saline assault, while Omidun and Ogi treatment abrogated its reduction following the hypertonic saline assault. CONCLUSIONS: Collectively, our findings suggest that acute elevation of IOP alters crosstalk between gut and retina with consequent aberrant activation of glial cells; and that probiotic bacteria like the lactic acid bacteria rich in fermented foods including Ogi and Omidun may offer neuroprotection to the ganglionic cells by attenuating the retinal glial reaction and improving BDNF activity.

Ketamine abrogates sensorimotor deficits and cytokine dysregulation in a chronic unpredictable mild stress model of depression.

Major depressive disorder (MDD) is a serious mental disorder with influence across the functional systems of the body. The pathogenesis of MDD has been known to involve the alteration of normal body functions responsible for the normal inflammation processes within the CNS; this along with other effects results in the depreciation of the sensorimotor performance of the body. Ketamine hydrochloride, a novel antidepressant agent, has been used as a therapeutic agent to treat MDD with its efficacy stretching as far as enhancing sensorimotor performance and restoring normal cytokine levels of the CNS. While these therapeutic actions of ketamine may or may not be related, this study made use of chronic unpredictable mild stress (CUMS) to generate the mouse model of depression. The efficacy of ketamine as an antidepressant following sequential exposure and co-administrative treatment protocols of administration was evaluated using behavioural tests for sensorimotor performance and depressive-like behaviours. Its effect in managing CNS inflammation was assessed via the biochemical analysis of inflammatory cytokine levels in the cerebrum, spinal cord and cerebellum; and immunohistochemical demonstration of microglial activity in the corpus striatum and cerebellum. The sensorimotor performance which had been diminished by CUMS showed greater improvement under the sequential exposure regimen of ketamine. Ketamine was also efficacious in decreasing the level of inflammation with an evident reduction in microglial activation and pro-inflammatory cytokines in the studied regions, following CUMS exposure. Taken together, our study indicates that ketamine therapy can improve sensorimotor deficits co-morbid with a depressive disorder in parallel with modulation of the inflammatory system.

Naringin ameliorates motor dysfunction and exerts neuroprotective role against vanadium-induced neurotoxicity.

Exposure to vanadium has been known to lead to a progressive neurodegenerative disorder like Parkinson's disease. Naringin is a known flavonoid glycoside that is mostly seen in the flesh of grapefruit and orange and is believed to have protective effects for the treatment of neurodegenerative disorders. This study sought to investigate the role of Naringin in the treatment of vanadium-induced neurotoxicity. Vanadium (10 mg/kg BW) was injected intraperitoneally to induce motor dysfunction, followed by treatment with Naringin (30 mg/kg BW) intraperitoneally for 14 days. Oxidative stress imbalance was monitored by checking Glutathione Peroxidase (GPX) and Catalase levels. Histological and immunohistochemical alterations were observed using RBFOX3 polyclonal antibody to determine neuronal cell distribution and NLRP3 inflammasome antibody as a marker of inflammation. Exposure to vanadium induces neurotoxicity by significantly increasing the Catalase and Glutathione Peroxidase (GPX) levels. Vanadium administration also led to increased inflammatory cells and a significant reduction of the viable neuronal cells in the SNc and CPu. Treatment with Naringin showed a neuroprotective role by dependently restoring the Catalase and Glutathione Peroxidase (GPX) levels, inflammasome activation, and neuronal damage in the SNc and CPu. Naringin demonstrated anti-oxidative, and anti-inflammatory responses by inhibiting oxidative stress, and inflammation and exerts neuroprotective effects by inhibiting apoptosis following vanadium-induced neurotoxicity in adult Wistar rats.

Hippocampus and Prefrontal Cortex Following the Use of Anti-Retroviral Therapy in Adult Wistar Rats: Therapeutic Role of Epigallocatechin Gallate.

The contribution of prefrontal-hippocampal interactions to brain function of people infected with HIV may be aggravated by toxicities due to long-term use of antiretroviral agents. This study was designed to investigate the curative potential of Epigallotatechin gallate (EGCG) in the treatment of neurodegenerative disorders as a possible consequence of antiretroviral toxicity. Twenty-four adult male Wistar rats, weighing 80~100g, were divided into four groups and treated as follows: control A (distilled water), B (HAART), C (EGCG 2.5mg/kg), D (EGCG 2.5mg/kg) + HAART) Brain histology, immunohistochemistry, and oxidative stress markers such as superoxide dismutase (SOD), glutathione (GSH),catalase (CAT)  and malondialdehyde (MDA) were examined. The use of highly active antiretroviral therapy (HAART) showed extensive architectural deformation with pyknotic neuronal cells and obliterated neurons in the hippocampus and prefrontal cortex. Expression of inflammasome cells was also evident in this group. MDA levels increased significantly with a significant reduction in the levels of GSH, as well as antioxidant enzyme (SOD and CAT) activities compared to other treatment groups. Treatment with EGCG resulted in partial neuronal restoration of histopathological alterations, and modulation of NLRP3 inflammasome in the hippocampus and prefrontal cortex. EGCG also showed significant improvements in terms of increased antioxidant levels of SOD, GSH, CAT and a reduced MDA level and well-preserved brain architecture. Epigallocatechin gallate improves brain morphology and function with a reversal of HAART-induced alterations.

Acetate supplementation restores testicular function by modulating Nrf2/PPAR-γ in high fat diet-induced obesity in Wistar rats.

PURPOSE: Several studies have established impaired testicular function in obese male population, including the young males with childhood obesity, contributing to increased male infertility, which is a universal trend in the last few decades. Short chain fatty acids (SCFAs) have been recently demonstrated to inhibit progression to metabolic comorbidities. The present study therefore hypothesized that SCFAs, acetate attenuates testicular dysfunction in high fat diet (HFD)-induced obese rat model, possibly by modulating Nrf2/PPAR-γ. METHODS: Adult male Wistar rats weighing 160-190 g were randomly allotted into three groups (n = 6/group): The groups received vehicle (distilled water), 40% HFD and sodium acetate (200 mg/kg) plus 40% HFD respectively. The administration lasted for 12 weeks. RESULTS: HFD caused obesity, which is characterized with increased body weight and visceral adiposity and insulin resistance/hyperinsulinemia. In addition, it increased testicular lipid deposition, malondialdehyde, pro-inflammatory mediators, lactate/pyruvate ratio, γ-Glutamyl transferase, and circulating leptin as well as decreased testicular glutathione, nitric oxide, Nrf2, PPAR-γ and circulating follicle stimulating hormone and testosterone without a significant change in testicular lactate dehydrogenase, blood glucose and luteinizing hormone when compared to the control group. Nevertheless, administration of acetate reversed the HFD-induced alterations. CONCLUSION: The present results demonstrates that HFD causes obesity-driven testicular dysfunction, associated with testicular lipid deposition, oxidative stress, and inflammation. The study in addition suggests the restoration of testicular function in obese animals by acetate, an effect that is accompanied by elevated Nrf2/PPAR-γ.

Virgin coconut oil abrogates depression-associated cognitive deficits by modulating hippocampal antioxidant balance, GABAergic and glutamatergic receptors in mice.

OBJECTIVES: GABA and glutamate neurotransmission play critical roles in both the neurobiology of depression and cognition; and Virgin coconut oil (VCO) is reported to support brain health. The present study investigated the effect of VCO on depression-associated cognitive deficits in mice. METHODS: Thirty male mice divided into five groups were either exposed to chronic unpredicted mild stress (CUMS) protocol for 28 days or pre-treated with 3 mL/kg b. wt. of VCO for 21 days or post-treated with 3 mL/kg b. wt. of VCO for 21 days following 28 days of CUMS exposure. Mice were subjected to behavioural assessments for depressive-like behaviours and short-term memory, and thereafter euthanised. Hippocampal tissue was dissected from the harvested whole brain for biochemical and immunohistochemical evaluations. RESULTS: Our results showed that CUMS exposure produced depressive-like behaviours, cognitive deficits and altered hippocampal redox balance. However, treatment with VCO abrogated depression-associated cognitive impairment, and enhanced hippocampal antioxidant concentration. Furthermore, immunohistochemical evaluation revealed significant improvement in GABAA and mGluR1a immunoreactivity following treatment with VCO in the depressed mice. CONCLUSIONS: Therefore, findings from this study support the dietary application of VCO to enhance neural resilience in patients with depression and related disorders.

Caffeine abrogates oxidative stress imbalance: Its implication on lateral geniculate nucleus and visual cortex following hyaluronic acid exposure.

This study assessed the role of caffeine (adenosine receptor antagonist) in the Lateral geniculate body as well as the primary visual cortex of hyaluronic acid model of glaucomatous rats. Twenty (20) male Long evans rats were randomly divided into four groups with five animals each. This research confirmed that hyaluronic acid (HA) significantly induces elevated intraocular pressure from 18 to 35 mmHg and caffeine had no effect on its reduction to palliate visual impairment; There were a significant increase in the lipid peroxidation and conversely decrease in superoxide level with HA which were attenuated by caffeine. Although, caffeine showed a capability of ameliorating the histopathological changes induced by HA in terms of maintenance of a viable neuronal cell count and significant reduction of tumour necrosis factor-α immune positive cells in the LGB and visual cortex. These findings suggest that caffeine was unable to lower the intraocular pressure after hyaluronic acid exposure but has the ability to restore the antioxidant imbalance via mitigating pro-oxidant mediators and abrogate neurodegeneration.

Ficus exasperata Vahl leaves extract attenuates motor deficit in vanadium-induced parkinsonism mice.

Medicinal herbs have played significant roles in the treatment of various diseases in humans and animals. Sodium metavanadate is a potentially toxic environmental pollutant that induces oxidative damage, neurological disorder, Parkinsonism and Parkinson-like disease upon excessive exposure. This study is designed to investigate the impact of saponin fraction of Ficus exasperata Vahl leaf extract (at 50 and 100 mg/kg body weight for 14 days at different animal groupings) on vanadium treated mice. Animals were randomly grouped into five groups. Control (normal saline), NaVO3 (10 mg/kg for 7 days), withdrawal group, NaVO3+Vahl (low dose) and NaVO3+Vahl (high dose). The animals were screened for motor coordination using rotarod and PBTs and a post mortem study was conducted by quantitatively assessing the markers of oxidative stress such as lipid peroxidation, catalase, glutathione activities, and also through immunohistochemistry via glia fibrillary acidic protein, tyrosine hydroxylase and dopamine transporter to study the integrity of astrocytes and dopaminergic neurons of the substantia nigra (SNc). Vanadium-exposed group showed a decreased motor activity on the neurobehavioural tests as well as an increase in markers of oxidative stress. Saponin fraction of F. exasperata Vahl leaves extract produced a statistically significant motor improvement which may be due to high antioxidant activities of saponin, thereby providing an ameliorative effect on the histoarchitecture of the SNc. It can be inferred that the saponin fraction of F. exasperata Vahl leaves extract to possesses ameliorative, motor-enhancing and neurorestorative benefit on motor deficit in vanadium-induced parkinsonism mice.