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Remifentanil Mitigates Hepatic Ischemia/Reperfusion-Induced D1-Medium Spiny Neurons Damage via Fibroblast Growth
Yujuan You1, Xianliang Xing1, Binquan Tang1
1Department of Anesthesiology, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People's Republic of China.
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. 43, 709-726.
Insights
Remifentanil protects brain cells from liver injury by increasing fibroblast growth factor 18 (FGF18). This reduces oxidative stress and inflammation, preserving neuronal function after hepatic ischemia/reperfusion (I/R) injury.
Area of Science:
- Neuroscience
- Hepatology
- Pharmacology
Background:
- Hepatic ischemia/reperfusion (I/R) injury causes significant liver damage and secondary neurological deficits, particularly affecting D1-medium spiny neurons (D1-MSNs) in the striatum.
- Understanding the mechanisms underlying neuroprotection in hepatic I/R injury is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the neuroprotective potential of remifentanil against hepatic I/R-induced neuronal injury, focusing on its effects on oxidative stress, inflammation, and the role of fibroblast growth factor 18 (FGF18).
Main Methods:
- A murine model of hepatic I/R injury was established to assess the effects of remifentanil.
- Biochemical assays measured liver injury markers and inflammatory cytokines.
- Oxidative stress markers, including reactive oxygen species and antioxidant enzyme activities, were evaluated.
- Neuronal integrity, apoptosis, and specific protein expressions (D1-dopamine receptor, Substance P, c-Fos) in D1-MSNs were analyzed.
- Transcriptomic analysis and machine learning identified key molecular mediators.
- Functional studies involved FGF18 overexpression and knockdown to confirm its role.
Main Results:
- Remifentanil significantly reduced liver and striatal injury markers and inflammatory cytokines (IL-1β, IL-18).
- It mitigated oxidative stress by enhancing antioxidant enzyme activity and reducing reactive oxygen species.
- Neuronal damage was alleviated, evidenced by improved D1-MSN morphology, reduced apoptosis, and normalized expression of key neuronal markers.
- FGF18 was identified as a critical mediator, with its upregulation by remifentanil conferring neuroprotection, while its knockdown abolished these effects.
Conclusions:
- Remifentanil demonstrates significant neuroprotective effects against hepatic I/R injury by upregulating FGF18, thereby reducing oxidative stress and inflammation in D1-MSNs.
- This study highlights FGF18 as a potential therapeutic target for mitigating neurological damage associated with liver I/R injury.
