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2-Hydroxy-4-Methylbenzoic Anhydride Inhibits Neuroinflammation in Cellular and Experimental Animal Models of Parkinson's Disease.

ABSTRACT: Microglia-mediated neuroinflammation is one of the key mechanisms involved in acute brain injury and chronic neurodegeneration. This study investigated the inhibitory effects of 2-hydroxy-4-methylbenzoic anhydride (HMA), a novel synthetic derivative of HTB (3-hydroxy-4-trifluoromethylbenzoic acid) on neuroinflammation and underlying mechanisms in activated microglia in vitro and an in vivo mouse model of Parkinson's disease (PD). In vitro studies revealed that HMA significantly inhibited lipopolysaccharide (LPS)-stimulated excessive release of nitric oxide (NO) in a concentration dependent manner. In addition, HMA significantly suppressed both inducible NO synthase and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in LPS-stimulated BV-2 microglia cells. Moreover, HMA significantly inhibited the proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in LPS-stimulated BV-2 microglial cells. Furthermore, mechanistic studies ensured that the potent anti-neuroinflammatory effects of HMA (0.1, 1.0, and 10 ?M) were mediated by phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (I?B?) in LPS-stimulated BV-2 cells. In vivo evaluations revealed that intraperitoneal administration of potent neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg, four times a 1 day) in mice resulted in activation of microglia in the brain in association with severe behavioral deficits as assessed using a pole test. However, prevention of microglial activation and attenuation of Parkinson's disease (PD)-like behavioral changes was obtained by oral administration of HMA (30 mg/kg) for 14 days. Considering the overall results, our study showed that HMA exhibited strong anti-neuroinflammatory effects at lower concentrations than its parent compound. Further work is warranted in other animal and genetic models of PD for evaluating the efficacy of HMA to develop a potential therapeutic agent in the treatment of microglia-mediated neuroinflammatory disorders, including PD.

SUBMITTER: Song SY

PROVIDER: S-EPMC7662568 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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2-Hydroxy-4-Methylbenzoic Anhydride Inhibits Neuroinflammation in Cellular and Experimental Animal Models of Parkinson's Disease.

Song Soo-Yeol SY Kim In-Su IS Koppula Sushruta S Park Ju-Young JY Kim Byung-Wook BW Yoon Sung-Hwa SH Choi Dong-Kug DK

International journal of molecular sciences 20201102 21

Microglia-mediated neuroinflammation is one of the key mechanisms involved in acute brain injury and chronic neurodegeneration. This study investigated the inhibitory effects of 2-hydroxy-4-methylbenzoic anhydride (HMA), a novel synthetic derivative of HTB (3-hydroxy-4-trifluoromethylbenzoic acid) on neuroinflammation and underlying mechanisms in activated microglia in vitro and an in vivo mouse model of Parkinson's disease (PD). In vitro studies revealed that HMA significantly inhibited lipopol ...[more]

PMID: 33147699

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Project description:Parkinson's disease (PD) is a chronic, progressive movement disorder of adults and the second most common neurodegenerative disease after Alzheimer's disease. Neuropathologic diagnosis of PD requires moderate-to-marked neuronal loss in the ventrolateral substantia nigra pars compacta and ?-synuclein (?S) Lewy body pathology. Nigrostriatal dopaminergic neurodegeneration correlates with the Parkinsonian motor features, but involvement of other peripheral and central nervous system regions leads to a wide range of non-motor features. Nigrostriatal dopaminergic neurodegeneration is shared with other parkinsonian disorders, including some genetic forms of parkinsonism, but many of these disorders do not have Lewy bodies. An ideal animal model for PD, therefore, should exhibit age-dependent and progressive dopaminergic neurodegeneration, motor dysfunction, and abnormal ?S pathology. Rodent models of PD using genetic or toxin based strategies have been widely used in the past several decades to investigate the pathogenesis and therapeutics of PD, but few recapitulate all the major clinical and pathologic features of PD. It is likely that new strategies or better understanding of fundamental disease processes may facilitate development of better animal models. In this review, we highlight progress in generating rodent models of PD based on impairments of four major cellular functions: mitochondrial oxidative phosphorylation, autophagy-lysosomal metabolism, ubiquitin-proteasome protein degradation, and endoplasmic reticulum stress/unfolded protein response. We attempt to evaluate how impairment of these major cellular systems contribute to PD and how they can be exploited in rodent models. In addition, we review recent cell biological studies suggesting a link between ?S aggregation and impairment of nuclear membrane integrity, as observed during cellular models of apoptosis. We also briefly discuss the role of incompetent phagocytic clearance and how this may be a factor to consider in developing new rodent models of PD.

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.

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2-Hydroxy-4-Methylbenzoic Anhydride Inhibits Neuroinflammation in Cellular and Experimental Animal Models of Parkinson's Disease.

Publications

2-Hydroxy-4-Methylbenzoic Anhydride Inhibits Neuroinflammation in Cellular and Experimental Animal Models of Parkinson's Disease.

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