Modification of alprazolam-induced liver injury by bone marrow-derived mesenchymal stem cells and the role of miRNA-192

Abstract

The group of drugs known as Benzodiazepines (BDZs) are among the most widely prescribed CNS-depressant drugs. Alprazolam (Alp) is a member of the BDZs family, commonly prescribed as an antipsychotic and anxiolytic agent. Induction of oxidative stress, impairment of cognitive functions and psychomotor skills, conformational alterations in hemoglobin structure and elevation of liver enzymes are among the side effects reported on the use of alprazolam. Several studies have found that alprazolam could favor hepatotoxicity, whereas other studies contradicted those findings. Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been studied as a novel approach for treatment of liver diseases. The current study was designed to assess the biochemical, histopathological and molecular liver alterations in response to oral administration of alprazolam at a dose of 0.3 mg/kg/day for 4 weeks in adult male albino rats and to evaluate the therapeutic effect of BM-MSCs on the alprazolam- induced alterations. Forty adult male albino rats (Sprague Dawley strain; 170-200 g mean body weight) were used. Liver enzymes were measured, isolation and preparation of BM- MSCs were done, and immunohistochemical staining for alpha smooth muscle actin and FGF2 were assessed. Moreover, histological and ultrastructural liver tissue examination and PCR detection of SOD, TNF-α and mirNA-192 were investigated. Animals exposed to alprazolam developed liver injury characterized by significant increase in TNF-α and significant decrease in SOD and miRNA- 192 expression. Histological findings provided supportive evidence for the biochemical and molecular analyses. Treatment with stem cells caused a significant alleviation of the alprazolam- induced findings. In conclusion, alprazolam was found to induce liver injury and oxidative stress, which were ameliorated by BM-MSCs administration.