Urolithin A promotes mitophagy and suppresses NLRP3 inflammasome activation in lipopolysaccharide-induced BV2 microglial cells and MPTP-induced Parkinson's disease model. (1st April 2022)

• Record Type: Journal Article
• Authors: Qiu, Jingru; Chen, Ye; Zhuo, Jing; Zhang, Li; Liu, Jia; Wang, Baozhu; Sun, Deqing; Yu, Shuyan; Lou, Haiyan
• Is Part Of: Neuropharmacology. Volume 207(2022)
• Publication Date: 2022-04-01
• Subjects: Urolithin A -- Parkinson's disease -- Mitophagy -- Neuroinflammation -- Microglia; AD Alzheimers' disease -- ANOVA analysis of variance -- ATP Adenosine 5′-triphosphate -- BSA Bovine serum albumin -- CNS central nervous system -- DAB diaminobenzidine -- DCFH-DA dichloro-dihydro-fluorescein diacetate -- DMEM Dulbecco's Modified Eagle's Medium -- EA ellagic acid -- ECAR extracellular acidification rate -- ECL enhanced chemiluminescence -- ETs ellagitannins -- FBS fetal bovine serum -- FCCP carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone -- GFAP glial fibrillary acidic protein -- HRP horseradish peroxidase -- IBA1 ionized calcium binding adapter molecule 1 -- IHC immunohistochemistry -- LC3 light chain 3 -- LPS lipopolysaccharide -- MMP mitochondrial membrane potential -- MPP+ 1-methyl-4-phenylpyridinium -- MPTP 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine -- MRC maximal respiratory capacity -- MS multiple sclerosis -- NLRP3 NLR Family Pyrin Domain Containing 3 -- NO nitric oxide -- OCR oxygen consumption rate -- OsO4 osmium tetroxide -- OXPHOS oxidative phosphorylation -- PBS phosphate buffered saline -- PD Parkinson's disease -- PS penicillin and streptomycin -- ROS reactive oxygen species -- SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis -- SN substantia nigra -- TEM Transmission electron microscopy -- TH Tyrosine hydroxylase -- UA Urolithin A -- 2-DG 2-deoxy-d-glucose -- S 3-MA 3-methyladenine; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.108963
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Microglia-mediated neuroinflammation and mitochondrial dysfunction play critical role in the pathogenic process of Parkinson's disease (PD). Mitophagy plays central role in mitochondrial quality control. Hence, regulation of microglial activation through mitophagy could be a valuable strategy in controlling microglia-mediated neurodegeneration and neuroinflammation. Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA). Several preclinical studies have reported the beneficial effects of UA on age-related conditions by increasing mitophagy and blunting excessive inflammatory responses. However, the specific role of UA in pathology of PD remains unknown. In this study, we showed that treatment with UA reduced the loss of dopaminergic neurons, ameliorated behavioral deficits and neuroinflammation in MPTP mouse model of PD. Further study revealed that UA promotes mitophagy, restores mitochondrial function and attenuate proinflammatory response in BV2 microglial cells exposed to LPS. Moreover, UA also reduced NLRP3 inflammasome activation both in vitro and in vivo. Importantly, disruption of microglial mitophagy with pharmacological or genetic approach partly blunted the neuroprotective effects of UA in MPTP mouse model of PD. Collectively, these results provide strong evidence that UA protects against dopaminergic neurodegeneration and neuroinflammation. The mechanism may be related with its inhibition of NLRP3 inflammasome activation via promoting mitophagy in microglia. Graphical abstract: Image 1 Highlights: UA ameliorates motor deficits and dopaminergic neurodegeneration in MPTP-administered mice. UA promotes autophagy and mitigates MPTP-induced neuroinflammation in mice model of PD. UA promotes mitophagy and alleviates mitochondrial dysfunction in LPS-treated BV2 cells. UA attenuates proinflammatory responses and reduced NLRP3 inflammasome activation both in vitro and in vivo. Pharmacological and genetic disruption of mitophagy partly blunted the neuroprotective effects of UA.