Remifentanil Mitigates Hepatic Ischemia/Reperfusion-Induced D1-Medium Spiny Neurons Damage via Fibroblast Growth Factor 18 Upregulation.

Abstract

Aims: Hepatic ischemia/reperfusion (I/R) injury induces liver damage and secondary neuronal injury, particularly in D1-medium spiny neurons (D1-MSNs). This study investigates whether remifentanil exerts neuroprotective effect by regulating oxidative stress and inflammation via fibroblast growth factor 18 (FGF18) upregulation. Results: Remifentanil markedly attenuated liver and striatal injury in a murine I/R model, as indicated by decreased serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, along with reduced inflammatory cytokines interleukin 1 beta and interleukin 18. Oxidative stress was mitigated through enhanced activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and reduced reactive oxygen species levels, confirmed by lower dihydroethidium and mitochondrial superoxide indicator red fluorescence. Neuronal injury was alleviated, demonstrated by improved D1-MSN morphology, reduced apoptosis, increased expression of D1-dopamine receptor and Substance P, and fewer c-Fos-positive cells. Transcriptomic and machine learning analyses identified FGF18 as a key mediator of remifentanil's neuroprotective effects. Functional studies further confirmed that FGF18 overexpression reduced neuronal damage, whereas its knockdown abolished the protective effects of remifentanil, highlighting its pivotal role. Innovation: This study is the first to demonstrate that remifentanil exerts neuroprotective effects in hepatic I/R injury by upregulating FGF18, providing new insights into its combined hepatoprotective and neuroprotective mechanisms. Conclusion: Remifentanil mitigates hepatic I/R-induced injury to D1-MSNs by upregulating FGF18, thereby reducing oxidative stress and inflammation while preserving neuronal structure and function. These findings identify FGF18 as a potential therapeutic target for liver I/R-related neurological damage. Antioxid. Redox Signal. 00, 000-000.