TELMISARTAN ALLEVIATES NITROSATIVE STRESS IN TURN DOPAMINERGIC DEGENERATION IN MICE MPTP MODEL OF PARKINSONISM–BIOCHEMICAL AND HISTOPATHOLOGICAL EVIDENCES

Objective: Telmisartan (TEL), an angiotensin type 1 receptor blocker, exerts neuroprotection in MPTP induced Parkinson's disease. The present study was aimed to investigate its effects on oxidative stress markers–inducible nitric oxide synthase (iNOS), nitric oxide (NO) and reduced glutathione (GSH) content in C57BL/6J mice brain.Methods: Young healthy male C57BL/6J mice were injected intraperitoneally with MPTP at 80 mg/kg in two divided doses (2 x 40 mg/kg at 16h interval). TEL was administered one hour prior to first MPTP intoxication and thereafter once in two consecutive days. The animals were sacrificed 48 h after first MPTP injection and brains were collected for further analysis.Results: TEL administration increased GSH content and decreased iNOS expression and NO level in MPTP intoxicated mice brains. Histopathological evaluation revealed that TEL decreased the cytoplasmic vacuolation and nuclear pigmentation in striatal and substantial nigral regions of MPTP intoxicated mice brain. The neuroprotective effect of TEL was further evidenced with increased neuronal nuclei (NeuN) immune fluorescence in MPTP mice brains.Conclusion: The present study showed that TEL exerts neuroprotection by suppressing nitric oxide induced oxidative stress and the dopaminergic degeneration. The above findings suggests that TEL may act as a potential target in the management of PD.Â

IN VITRO AND IN VIVO PROTECTIVE EFFECTS OF AMBREX, A POLYHERBAL FORMULATION, AGAINST METHOTREXATE INDUCED DAMAGES IN HEPATIC CELLS

Objective: To evaluate the hepatoprotective effect of Ambrex, a poly herbal formulation against methotrexate (MTX) induced hepatotoxicity in Swiss albino mice as well as in Chang liver cell lines.Methods: Ambrex was exposed to MTX intoxicated chang liver cells and cells were harvested for studying the gene expressions of Dihydrofolate reductase (DHFR), B-cell lymphoma 2 (BCL2) and Bcl-2-associated X protein (BAX). In in vivo study, Ambrex was administered orally for a period of 7 days at two dose levels (250 and 500 mg/kg b. wt) and MTX (20 mg/kg b. wt, i. p) was injected one hour after the last test drug administration. Protective effect of Ambrex was evaluated by measuring aspartate transaminase (SGOT), alanine transaminase (SGPT), alkaline phosphatase (ALP), γ–glutamyl transferase (γGT) and total bilirubin. Its effect on superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and lipid peroxide (LPO) was also determined.Results: Data revealed that Ambrex was able to restore the levels of antioxidants such as SOD, Catalase, and Glutathione to near normal and reduced the elevated plasma levels of SGOT, SGPT, ALP, γ–GT and total bilirubin. It also inhibited the formation of hepatic malondialdehyde induced by MTX. In vitro studies revealed that Ambrex protected MTX induced hepatotoxicity at the dose of 50 and 500ng/ml. Further, mRNA expression also illustrated that Ambrex inhibited the over expression of BAX and suppressed BCL2 and DHRF expressions.Conclusion: Results suggest that Ambrex has potent hepatoprotective effect which was evident from both in vivo and in vitro results.Â

3-AMINOBENZAMIDE, A POLY (ADP-RIBOSE) POLYMERASE INHIBITOR, RESTORES BIOENERGETICS BUT FAILS TO ALLEVIATE EXCITOTOXICITY AND MOTOR FUNCTIONS IN 3-NITROPROPIONIC ACID INTOXICATED MICE

Objective: The present study was undertaken to investigate the effects of 3-aminobenzamide (3-AB), a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor, on motor functions along with brain excito toxicity and bioenergetics alterations in 3-nitropropionic acid (3-NPA) intoxicated mice model of Huntington's disease (HD).Methods: Young healthy male C57BL/6J mice were pre-treated with vehicle/3-AB for a period of five days and intoxicated with two doses of 3-NPA (15 mg/kg, i. p) at 24 h interval on day 4 and 5. Animals were observed for motor functions 5 days after 3-NPA injection. They were sacrificed at the end of motor tests and brains were collected for neurochemical, bioenergetics, glial cells and cytokines analysis.Results: 3-AB treatment significantly increased the bioenergetics (ATP and NAD) and succinate dehydrogenase activity in 3-NPA intoxicated mice brains. But, it failed to decrease glutamate content, cytokines-TNFα and IL-1β and glial markers–glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (IBA1) expressions. Further, 3-AB administered produced only a non-significant restoration of motor functions in 3-NPA intoxicated mice.Conclusion: The present study revealed that excito toxicity and inflammatory pathways are major perpetrators in 3-NPA induced neuro degeneration and motor dysfunction. Therapeutic approach with 3-AB alone may not be sufficient to manage the multi-cascade pathogenetic mechanisms in HD neither symptomatic management too.Â

Protective effects of fecal microbiota transplantation against ischemic stroke and other neurological disorders: an update

The bidirectional communication between the gut and brain or gut-brain axis is regulated by several gut microbes and microbial derived metabolites, such as short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides. The Gut microbiota (GM) produce neuroactives, specifically neurotransmitters that modulates local and central neuronal brain functions. An imbalance between intestinal commensals and pathobionts leads to a disruption in the gut microbiota or dysbiosis, which affects intestinal barrier integrity and gut-immune and neuroimmune systems. Currently, fecal microbiota transplantation (FMT) is recommended for the treatment of recurrent Clostridioides difficile infection. FMT elicits its action by ameliorating inflammatory responses through the restoration of microbial composition and functionality. Thus, FMT may be a potential therapeutic option in suppressing neuroinflammation in post-stroke conditions and other neurological disorders involving the neuroimmune axis. Specifically, FMT protects against ischemic injury by decreasing IL-17, IFN-γ, Bax, and increasing Bcl-2 expression. Interestingly, FMT improves cognitive function by lowering amyloid-β accumulation and upregulating synaptic marker (PSD-95, synapsin-1) expression in Alzheimer’s disease. In Parkinson’s disease, FMT was shown to inhibit the expression of TLR4 and NF-κB. In this review article, we have summarized the potential sources and methods of administration of FMT and its impact on neuroimmune and cognitive functions. We also provide a comprehensive update on the beneficial effects of FMT in various neurological disorders by undertaking a detailed interrogation of the preclinical and clinical published literature

Gut microbiome-based dietary intervention in Parkinson disease subject: A case report

A 54-year-old woman was seeking medical treatment for Parkinson disease (PD) in the neurology outpatient department in JSS Hospital, Mysore, India. She was challenged in terms of reduced mobility and had sought several treatment options to control her PD symptoms without successful outcome. After examination and confirmation of diagnosis, the decision was taken to design a precision nutritional intervention using a gut microbiome-based diet combined with medical treatment. After 2 months of a superfood dietary intervention, the patient showed signs of clinical improvement as evidenced by improved mobility and a change in the Hoehn and Yahr clinical severity scale from stages 3 to 2. In conclusion, it is possible to modulate the gut microbiome to reverse the established gut dysbiosis associated with the neurodegenerative process in PD, which can lead to clinical benefit by reducing functional disability

Sleep Deprivation and Neurological Disorders

Sleep plays an important role in maintaining neuronal circuitry, signalling and helps maintain overall health and wellbeing. Sleep deprivation (SD) disturbs the circadian physiology and exerts a negative impact on brain and behavioural functions. SD impairs the cellular clearance of misfolded neurotoxin proteins like α-synuclein, amyloid-β, and tau which are involved in major neurodegenerative diseases like Alzheimer\u27s disease and Parkinson\u27s disease. In addition, SD is also shown to affect the glymphatic system, a glial-dependent metabolic waste clearance pathway, causing accumulation of misfolded faulty proteins in synaptic compartments resulting in cognitive decline. Also, SD affects the immunological and redox system resulting in neuroinflammation and oxidative stress. Hence, it is important to understand the molecular and biochemical alterations that are the causative factors leading to these pathophysiological effects on the neuronal system. This review is an attempt in this direction. It provides up-to-date information on the alterations in the key processes, pathways, and proteins that are negatively affected by SD and become reasons for neurological disorders over a prolonged period of time, if left unattended

Protective effects of fecal microbiota transplantation against ischemic stroke and other neurological disorders: an update

The bidirectional communication between the gut and brain or gut-brain axis is regulated by several gut microbes and microbial derived metabolites, such as short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides. The Gut microbiota (GM) produce neuroactives, specifically neurotransmitters that modulates local and central neuronal brain functions. An imbalance between intestinal commensals and pathobionts leads to a disruption in the gut microbiota or dysbiosis, which affects intestinal barrier integrity and gut-immune and neuroimmune systems. Currently, fecal microbiota transplantation (FMT) is recommended for the treatment of recurrent Clostridioides difficile infection. FMT elicits its action by ameliorating inflammatory responses through the restoration of microbial composition and functionality. Thus, FMT may be a potential therapeutic option in suppressing neuroinflammation in post-stroke conditions and other neurological disorders involving the neuroimmune axis. Specifically, FMT protects against ischemic injury by decreasing IL-17, IFN-γ, Bax, and increasing Bcl-2 expression. Interestingly, FMT improves cognitive function by lowering amyloid-β accumulation and upregulating synaptic marker (PSD-95, synapsin-1) expression in Alzheimer’s disease. In Parkinson’s disease, FMT was shown to inhibit the expression of TLR4 and NF-κB. In this review article, we have summarized the potential sources and methods of administration of FMT and its impact on neuroimmune and cognitive functions. We also provide a comprehensive update on the beneficial effects of FMT in various neurological disorders by undertaking a detailed interrogation of the preclinical and clinical published literature

Sleep deprivation and neurological disorders

Sleep plays an important role in maintaining neuronal circuitry, signalling and helps maintain overall health and wellbeing. Sleep deprivation (SD) disturbs the circadian physiology and exerts a negative impact on brain and behavioural functions. SD impairs the cellular clearance of misfolded neurotoxin proteins like α-synuclein, amyloid-β, and tau which are involved in major neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. In addition, SD is also shown to affect the glymphatic system, a glial-dependent metabolic waste clearance pathway, causing accumulation of misfolded faulty proteins in synaptic compartments resulting in cognitive decline. Also, SD affects the immunological and redox system resulting in neuroinflammation and oxidative stress. Hence, it is important to understand the molecular and biochemical alterations that are the causative factors leading to these pathophysiological effects on the neuronal system. This review is an attempt in this direction. It provides up-to-date information on the alterations in the key processes, pathways, and proteins that are negatively affected by SD and become reasons for neurological disorders over a prolonged period of time, if left unattended