Carnosine restores the activation of signaling cascades and the ratio of apoptosis-regulating proteins in the penumbra zone after a permanent focal cerebral ischemia in rats

Abstract

Abstract Introduction. Ischemic stroke is one of the most common and socially significant diseases, and its pathogenesis is associated with oxidative stress. The study of mechanisms of the neuroprotective action of the natural antioxidant carnosine is promising in the context of carnosine-based drug development. Objective. To study the effect of carnosine on the level of apoptosis-regulating proteins of the Bcl-2 family and the level of activation of protein kinase B (Akt) and MAP kinases ERK1/2, p38 and JNK in the rat brain after a 24-hour permanent focal cerebral ischemia. Materials and methods. In the model of permanent focal cerebral ischemia caused by the occlusion of the middle cerebral artery in Wistar rats, we assessed, using Western blotting, the level of expression of Bcl-2 family proteins and the phosphorylation of Akt, ERK1/2, p38 and JNK in the penumbra zone of the cortex in the ischemic hemisphere and in the symmetrical region of the contralateral hemisphere, as well as in similar areas of the brain of intact animals. Carnosine was administered to animals intraperitoneally at doses of 50 mg/kg and 500 mg/kg of body weight in the postischemic period. Results. In permanent focal cerebral ischemia in rats, the amount of Bax and, to a lesser extent, of Bcl-2 increased in the penumbra zone shifting the Bcl-2/Bax ratio towards the pro-apoptotic signal; a decreased Akt activation and an increased ERK1/2 activation was observed. The administration of carnosine rescued the activation of Akt and the Bcl-2/Bax ratio but did not affect an increased activation of ERK1/2. No significant changes in the level of Bak, Bcl-xL and Bcl-w, and no activation of p38 and JNK were observed in the penumbra zone.

Keywords

• carnosine
• permanent focal cerebral ischemia
• ischemic penumbra
• bcl-2 family
• akt
• map kinases