Affiliation:
1. Department of Pharmacy Children's Hospital of Soochow University Suzhou China
2. Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Disorders, Department of Pharmacology, College of Pharmaceutical Sciences Soochow University Suzhou Jiangsu China
Abstract
AbstractAimsAstrocytic senescence is inextricably linked to aging and neurodegenerative disorders, including Parkinson's disease (PD). P7C3 is a small, neuroprotective aminopropyl carbazole compound that exhibits anti‐inflammatory properties. However, the effects of P7C3 on astrocytic senescence in PD remain to be elucidated.MethodsAn in vitro, long culture‐induced, replicative senescence cell model and a 1‐methyl‐4‐phenylpyridinium (MPP+)/rotenone‐induced premature senescence cell model were used to investigate the effects of P7C3 on astrocytic senescence. An in vivo, 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse PD model was used to study the role of P7C3 in astrocytic senescence. Immunoblotting, real‐time quantitative RT‐PCR (qPCR), immunofluorescence, subcellular fractionation assays, and immunohistochemistry were utilized to confirm the effects of P7C3 on astrocytic senescence and elucidate its underlying mechanisms.ResultsThis study determined that P7C3 suppressed the senescence‐associated secretory phenotype (SASP) in both cell models, as demonstrated by the reduction in the critical senescence marker p16 and proinflammatory factors (IL‐6, IL‐1β, CXCL10, and MMP9) and increased laminB1 levels, implying that P7C3 inhibited replicative astrocytic senescence and MPP+/rotenone‐induced premature astrocytic senescence, Most importantly, we demonstrated that P7C3 prevented the death of dopamine (DA) neurons and reduced the behavioral deficits in the MPTP‐induced mouse model of PD, which is accompanied by a decrease in senescent astrocytes in the substantia nigra compacta (SNc). Mechanistically, P7C3 promoted Nrf2/Sirt3‐mediated mitophagy and reduced mitochondrial reactive oxygen species (mitoROS) generation, which contributed to the suppression of astrocytic senescence. Furthermore, Sirt3 deficiency obviously abolished the inhibitory effects of P7C3 on astrocytic senescence.ConclusionThis study revealed that P7C3 inhibited astrocytic senescence via increased Nrf2/Sirt3‐mediated mitophagy and suppression of mitoROS, which further protected against DA neuronal loss. These observations provide a prospective theoretical basis for P7C3 in the treatment of age‐associated neurodegenerative diseases, such as PD.
Funder
National Natural Science Foundation of China