The impact of Keap1/Nrf2, PMAPK/NF-κB and Bax/Bcl2/caspase-3 signaling pathways in the protective effects of berberine against methotrexate-induced nephrotoxicity.
Emad H M Hassanein, Abdel-Gawad S Shalkami, Marwa M Khalaf, Wafaa R Mohamed, Ramadan A M Hemeida
Author Information
Emad H M Hassanein: Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524 Egypt.
Abdel-Gawad S Shalkami: Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524 Egypt. Electronic address: abdopharma@gmail.com.
Marwa M Khalaf: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514 Egypt.
Wafaa R Mohamed: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514 Egypt.
Ramadan A M Hemeida: Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524 Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Deraya University, Menia, 61768 Egypt.
berberine (BBR) is a natural compound of plant origin belonging to isoquinoline type of alkaloid. Methotrexate (MTX) is an anti-metabolite used widely for a variety of tumors and autoimmune conditions. Clinical uses of MTX were severely limited by its concomitant renal intoxication. The current study was designed to investigate the efficacy of BBR against MTX-induced nephrotoxicity and for exploring the underlying molecular mechanisms through examining the Keap1/Nrf2, NF-κB/PMAPK and Bax/Bcl2/caspase-3 pathways. Adults male rats were assigned to 4 groups: control, BBR, MTX and MTX + BBR. As compared to MTX-treated group, BBR effectively reduced the serum levels of creatinine, urea, uric acid and kidney/body weight ratio with a remarkable increase in serum level of albumin and the final body weight. Moreover, down-regulation of Keap1, PMAPK and NF-κB genes along with marked up-regulation of Nrf2 gene were observed. In addition, BBR negatively regulated both Bax and caspase-3 proteins expression along with increased expression of the Bcl2 protein. Also, BBR restored GSH content and SOD activity while it decreased both TBARS and NO contents. Biochemical findings confirmed and markedly supported by alleviation of histopathological changes in kidney tissues. Furthermore, MTX cytotoxic activity was markedly enhanced by BBR in vitro using some humancancer cell lines. In conclusion, the current findings indicated that co-administration of BBR with MTX may be a reasonable therapeutic strategy for attenuation of MTX -induced renal damage.
