In vivo protective effect of betulinic acid on dexamethasone induced thymocyte apoptosis by reducing oxidative stress

Abstract

Background: Dexamethasone (Dex), a synthetic glucocorticoid, is strictly controlled for use due to its serious side effects, including immune suppression. Betulinic acid (BA), an antioxidant prepared from the white birch, exhibits immunomodulation properties. To assess the implications and investigate the mechanisms of BA-elicited immunomodulation, we hypothesized that Dex induced thymocyte apoptosis via oxidative stress could be lessened by BA.

Methods: Mice were given oral doses of BA (0.25, 0.5, and 1.0mg/kg) daily for 14 days, and induced oxidative stress by giving a single dose of Dex intraperitoneal at the dosage of 25mg/kg body weight 8h after the last administration of BA.

Results: Dex administration alone significantly decreased antioxidant enzyme activities, while significantly increased reactive oxygen species (ROS) production, lipid peroxidation, mitochondrial dysfunctions, caspase-3 activation and cellular apoptosis. However, pretreatment with BA dose-dependently mitigated Dex-induced oxidative damage after 14 days of feeding. In addition to ROS scavenging activity in Dex-induced thymocyte, BA administration decreased lipid peroxidation, up-regulated antioxidant enzymes, restored mitochondrial function, increased Bcl-2 expression but reduced Bax expression, inhibited caspase-3 activation, and improved cell survival.

Conclusions: These findings reveal a protective capability of BA against Dex-induced cell death by reducing oxidative stress via mitochondrial mediated signal pathway which could be the potential mechanism underlying BA-elicited immunomodulation.

Keywords: Apoptosis; Betulinic acid; Dexamethasone; Oxidative stress; Thymocyte.