Hepatoprotective potential of gabapentin in cecal ligation and puncture-induced sepsis; targeting oxidative stress, apoptosis, and NF-kB/MAPK signaling pathways

Aims: Sepsis is a severe inflammatory response to infection with an incidence rate exceeding 48 million cases and 11 million sepsis-related deaths yearly. Furthermore, sepsis remains the fifth most common cause of death worldwide. The present study aimed to examine, for the first time, the potential hepatoprotective activity of gabapentin on cecal ligation and puncture (CLP)-induced sepsis in rats at the molecular level.Main methods: CLP was used as a model of sepsis in male Wistar rats. Histological examination and liver functions were evaluated. Levels of MDA, GSH, SOD, IL-6, IL-1(i, and TNF-alpha were investigated using ELISA. mRNA levels of Bax, Bcl-2, and NF-kB were assessed by qRT-PCR. Western blotting investigated the expression of ERK1/2, JNK1/ 2, and cleaved caspase 3 proteins.Key findings: CLP resulted in liver damage, elevated serum levels of ALT, AST, ALP, MDA, TNF-alpha, IL-6, and IL-1(i, increased expression of ERK1/2, JNK1/2, and cleaved caspase 3 proteins, and upregulated Bax and NF-kappa B genes expression while it down-regulated Bcl-2 gene expression. However, gabapentin treatment significantly reduced the severity of CLP-induced biochemical, molecular, and histopathological changes. Gabapentin attenuated the levels of the proinflammatory mediators, decreased the expression of JNK1/2, ERK1/2, and cleaved caspase 3 proteins, suppressed Bax and NF-kappa B genes expression and increased the expression of the Bcl-2 gene.Significance: Consequently, Gabapentin reduced hepatic injury resulting from CLP-induced sepsis by reducing proinflammatory mediators, attenuating apoptosis, and inhibiting the intracellular MAPK (ERK1/2, JNK1/2)-NF-kB signaling pathway.

Automated summary

This study examined the potential hepatoprotective activity of gabapentin on cecal ligation and puncture-induced sepsis in rats. The results showed that gabapentin could alleviate liver damage, reduce inflammation, inhibit apoptosis, and regulate intracellular signaling pathways and gene expression.