N-acetylserotonin derivative ameliorates hypoxic-ischemic brain damage by promoting PINK1/Parkin-dependent mitophagy to inhibit NLRP3 inflammasome-induced pyroptosis

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-18 DOI:10.1016/j.intimp.2025.114469

Fang Fang , Jiaxin Tang , Jiaqing Geng , Chengzhi Fang , Binghong Zhang

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引用次数: 0

Abstract

Neonatal hypoxic-ischemic brain damage is the main cause of hypoxic-ischemic encephalopathy and cerebral palsy, whose clinical treatment is still limited to therapeutic hypothermia with limited efficacy. N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC), a derivative of N-acetylserotonin, has shown neuroprotective properties. This study was conducted to evaluate the neuroprotective and molecular mechanisms of HIOC. We established an in vitro model using Oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 cells, alongside an in vivo model via the modified Rice-Vannucci method. The results showed that HIOC reduced OGD/R-induced HT22 cell pyroptosis and inhibited NOD-like receptor pyrin domain- containing protein 3 (NLRP3) inflammasome activation. With the addition of the mitophagy inhibitor 3-MA, we demonstrated that HIOC promoted PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy to reduce HT22 cell pyroptosis. Mechanistically, HIOC stimulated mitophagy to remove damaged mitochondria. The clearance of injured mitochondria reduced reactive oxygen species generation, which consequently inhibited NLRP3 inflammasome expression. In vivo, HIOC remarkably lessened cerebral blood flow, infarct volume, neuronal injury by activating mitophagy. HIOC activated mitophagy to produce antipyroptosis effects. Together, our finding demonstrated that HIOC improves brain injury by promoting PINK1/Parkin-dependent mitophagy to inhibit NLRP3 inflammasome activation and pyroptosis, suggesting its potential for hypoxic-ischemic brain damage treatment.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.