Cepharanthine, an anti-inflammatory drug, suppresses mitochondrial membrane permeability transition

Cepharanthine (CEP), a biscocrourine alkaloid, has been widely used in Japan for the treatment of several disorders. Furthermore, accumulated evidence shows that CEP protects against some cell death systems but not others. Recently, it was found that mitochondria play an important role in a mechanism of apoptosis involving membrane permeability transition (MPT). Although CEP stabilizes the mitochondrial membrane structure and protects some functions of mitochondria from damage, the mechanism of action of CEP on MPT remains obscure. In this study, therefore, we examined the effect of CEP on Ca²⁺- and Fe²⁺/ADP-induced MPT of isolated mitochondria. CEP inhibited Ca ²⁺-induced swelling, depolarization, Cyt.c release, and the release of Ca²⁺ in a concentration dependent manner. CEP also inhibited Ca²⁺-induced generation of reactive oxygen species and Fe/ADP-induced swelling and lipid peroxidation. Furthermore, CEP suppressed Ca ²⁺-induced thiol modification of adenine nucleotide transloase (ANT). These results suggested that CEP suppressed MPT by a decrease in affinity of cyclophilin D for ANT. From these results it was concluded that the suppression of MPT by CEP might be due to its inhibitory action on Ca²⁺ release and antioxidant activity and that CEP might suppress the mechanism of apoptotic cell death when directly interacted with mitochondria in cells.