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Mucuna pruriens Protects against MPTP Intoxicated Neuroinflammation in Parkinson's Disease through NF-?B/pAKT Signaling Pathways.

ABSTRACT: Till date, drugs that have been used to manage Parkinson's disease (PD) have only shown symptomatic relief with several adverse effects besides their inability to prevent neurodegeneration. Neuroinflammation plays an important role in the advancement of PD and can be targeted for its effective treatment. Researchers have suggested that herbal plants exhibiting the anti-inflammatory and anti-oxidant properties are therefore beneficial to human health. Conventionally, Mucuna pruriens (Mp) seeds are used for maintaining male virility in India. Reportedly, Mp is used as a rejuvenator drug having neuroprotective property. Our study aimed to investigate effects of aqueous extract of Mp (100 mg/kgbwt) on neuroinflammation, orally administered to mice intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as the molecular mechanism involved in the progression of PD. In this study, we have observed significant behavioral abnormalities beside decreased antioxidant defense in MPTP intoxicated mice. We have also observed significant increase in inflammatory parameters like Glial Fibrillary Acidic Protein, Inducible Nitric Oxide Synthase, Intercellular Cell Adhesion Molecule, and Tumor Necrosis Factor alpha in substantia nigra pars compacta (SNpc) of parkinsonian mice, while Mp treatment has notably reduced these inflammatory parameters. Mp also inhibited the MPTP induced activation of NF-?B and promoted pAkt1 activity which further prevented the apoptosis of the dopaminergic neurons. Moreover, Mp exhibited significant antioxidant defense by inhibiting the lipid peroxidation and nitrite level, and by improving catalase activity and enhancing GSH level in nigrostriatal region of mouse brain. Mp also recovered the behavioral abnormalities in MPTP treated mice. Additionally, Mp treatment considerably increased the immunoreactivity of Tyrosine Hydroxylase and Dopamine Transporter in SNpc of parkinsonian mice. Our high performance liquid chromatography analysis of the Mp seed extract have shown L-DOPA, gallic acid, phytic acid, quercetin, and catechin equivalents as the major components which might cause neuroprotection in PD mice. Our result suggested that Mp extract treatment containing L-DOPA and a mixture of rich novel phytochemicals significantly alleviates the MPTP induced neurotoxicity by NF-?B and pAkt pathway. The findings observed thereby indicate that Mp extract have suggestively ameliorated MPTP induced neuroinflammation, restored the biochemical and behavioral abnormalities in PD mouse and thus provided a scientific basis for its traditional claim.

SUBMITTER: Rai SN

PROVIDER: S-EPMC5742110 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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<i>Mucuna pruriens</i> Protects against MPTP Intoxicated Neuroinflammation in Parkinson's Disease through NF-κB/pAKT Signaling Pathways.

Rai Sachchida N SN Birla Hareram H Singh Saumitra S SS Zahra Walia W Patil Ravishankar R RR Jadhav Jyoti P JP Gedda Mallikarjuna R MR Singh Surya P SP

Frontiers in aging neuroscience 20171219

Till date, drugs that have been used to manage Parkinson's disease (PD) have only shown symptomatic relief with several adverse effects besides their inability to prevent neurodegeneration. Neuroinflammation plays an important role in the advancement of PD and can be targeted for its effective treatment. Researchers have suggested that herbal plants exhibiting the anti-inflammatory and anti-oxidant properties are therefore beneficial to human health. Conventionally, <i>Mucuna pruriens</i> (Mp) s ...[more]

PMID: 29311905

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Project description:BackgroundNeuroinflammation has been widely accepted as a cause of the degenerative process. Increasing interest has been devoted to developing intervening therapeutics for preventing neuroinflammation in Parkinson's disease (PD). It is well known that virus infections, including DNA viruses, are associated with an increased risk of PD. In addition, damaged or dying dopaminergic neurons can release dsDNA during PD progression. However, the role of cGAS, a cytosolic dsDNA sensor, in PD progression remains unclear.MethodsAdult male wild-type mice and age-matched male cGAS knockout (cGas-/- ) mice were treated with MPTP to induce neurotoxic PD model, and then behavioral tests, immunohistochemistry, and ELISA were conducted to compare disease phenotype. Chimeric mice were reconstituted to explore the effects of cGAS deficiency in peripheral immune cells or CNS resident cells on MPTP-induced toxicity. RNA sequencing was used to dissect the mechanistic role of microglial cGAS in MPTP-induced toxicity. cGAS inhibitor administration was conducted to study whether GAS may serve as a therapeutic target.ResultsWe observed that the cGAS-STING pathway was activated during neuroinflammation in MPTP mouse models of PD. cGAS deficiency in microglia, but not peripheral immune cells, controlled neuroinflammation and neurotoxicity induced by MPTP. Mechanistically, microglial cGAS ablation alleviated the neuronal dysfunction and inflammatory response in astrocytes and microglia by inhibiting antiviral inflammatory signaling. Additionally, the administration of cGAS inhibitors conferred the mice neuroprotection during MPTP exposure.ConclusionsCollectively, these findings demonstrate microglial cGAS promote neuroinflammation and neurodegeneration during the progression of MPTP-induced PD mouse models and suggest cGAS may serve as a therapeutic target for PD patients.Limitations of the studyAlthough we demonstrated that cGAS promotes the progression of MPTP-induced PD, this study has limitations. We identified that cGAS in microglia accelerate disease progression of PD by using bone marrow chimeric experiments and analyzing cGAS expression in CNS cells, but evidence would be more straightforward if conditional knockout mice were used. This study contributed to the knowledge of the role of the cGAS pathway in PD pathogenesis; nevertheless, trying more PD animal models in the future will help us to understand the disease progression deeper and explore possible treatments.

Project description:BackgroundSepsis is a high-mortality disease without effective therapeutic options. The hyperactivation of the monocyte-macrophage system, especially M1 macrophages, triggers the onset of septic shock. Gentiopicroside (GENT), the main active component in the traditional Chinese medicinal herb Radix Gentianae, has been shown to have anti-inflammatory properties. Nevertheless, this anti-inflammatory effect has not been fully elucidated.MethodsIn vitro, we stimulated primary bone marrow-derived macrophages (BMMs) or peritoneal elucidated macrophages (PEMs) by lipopolysaccharide (LPS) and interferon (IFN)-γ and pre-treated with GENT and we tested the cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF) α production by enzyme linked immunosorbent assay (ELISA) or real-time quantitative PCR (qPCR). Further, we determined the NF-κB-mediated inflammatory pathway such as IKKα/β and p65 phosphorylation by Western blot. Then we detected the p65 nuclear localization by immunofluorescent staining. Moreover, NF-κB inhibitor and p65-targeted siRNAs were further used to validate the anti-inflammatory mechanism of GENT. In vivo, GENT (50 mg/kg) was administered intragastrically before and after LPS (40 mg/kg) injection. The death time were recorded and the serum levels of IL-1β, IL-6 and TNFα were tested by ELISA, and the IL-1β, IL-6 and TNFα mRNA expression in the lung were test by qPCR and the M1 infiltration in the lung were determined by F4/80 and INOS immunofluorescent staining.ResultsIn vitro, we observed that GENT reduced the inflammatory cytokine production of BMMs stimulated by (LPS)/IFN-γ and ameliorated the phosphorylation of IKKα/β and p65, the degradation of IκBα, and the translocation of p65 into the nucleus. We did not find GENT has any effect on MAPK signaling under LPS/IFN-γ stimulation. NF-κB inhibitor and p65 siRNAs eliminated the inhibition effect of GENT. In vivo, we observed GENT prevented mice from dying in the LPS-induced shock model and decreased the serum levels of IL-1β and IL-6, the mRNA expression of IL-1β, IL-6 and TNFα in lung tissue, and the amount of M1 macrophage infiltration in the lung.ConclusionsGENT prevented LPS/IFN-γ-induced inflammatory cytokine production by macrophages through the NF-κB signaling pathway in vitro and protected against the endotoxin shock induced by LPS in vivo.

Dataset Information

Mucuna pruriens Protects against MPTP Intoxicated Neuroinflammation in Parkinson's Disease through NF-?B/pAKT Signaling Pathways.

Publications

<i>Mucuna pruriens</i> Protects against MPTP Intoxicated Neuroinflammation in Parkinson's Disease through NF-κB/pAKT Signaling Pathways.

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