Levomilnacipran alleviates cyclophosphamide-induced hepatic dysfunction in male Wistar albino rats; emerging role of α-Klotho/TLR4/p38-MAPK/NF-κB p65 and caspase-3-driven apoptosis trajectories.

Objective: This study aims to investigate the potential protective effect of levomilnacipran (LVM) against cyclophosphamide (CPA)-induced hepatotoxicity by targeting α-Klotho/TLR4/p38-MAPK/NF-κB p65 and Caspase-3-dependent apoptosis signaling pathways.

Methods: The toxicity of CPA was assessed using biochemical analysis of the serum hepatotoxicity parameters (AST, ALT, and direct bilirubin) and histopathological examination. Hepatic MDA and SOD were evaluated. The ELISA procedure was employed to evaluate the levels of hepatic TNF-α, IL-1β, and IL-18, hepatic caspase-3, and serum α-Klotho. The expression of hepatic TLR4 and NF-κB p65 was examined using an immunohistochemical technique. A western blot assay was used to determine the expression of MYD88, and p38-MAPK.

Results: LVM abrogated CPA-induced hepatotoxicity by reducing the elevated hepatoxicity markers and mitigating the histopathological aberrations. It also lowered MDA content and increased SOD activity. Furthermore, it reduced TNF-α, IL-1β, and IL-18 contents, as well as caspase-3 activity. Additionally, LVM diminished TLR4, MYD88, NF-κB p65, and p38 MAPK expression and boosted the levels of α-Klotho.

Conclusions: LVM alleviated hepatic injury generated by CPA via downregulating TLR4/p38 MAPK/NF-κB p65 signaling cascade through the participation of α-Klotho, as well as inhibiting caspase-3-driven apoptosis.