Calcineurin and Erk1/2-signaling pathways are involved in the antiapoptotic effect of cyclosporin A on astrocytes exposed to simulated ischemia in vitro

Abstract

The present study focused on mechanisms involved in the anti-apoptotic effect of cyclosporin A (CsA) towards ischemic injured astrocytes in vitro [under combined oxygen glucose deprivation (OGD)]. We investigated whether this action might be mediated through activation of extracellular signal regulated kinases 1 and 2 (Erk1/2) or attenuation of calcineurin (CaN) by immunosuppressant in ischemic astrocytes. Additionally, the influence of CsA on phosphorylation of Akt kinase was determined. After 21 days of in vitro culture, astrocytes were subjected to OGD (for 8 h) and CsA (0.25-10 microM); 0.25 microM CsA distinctly stimulated the Erk1/2 pathway in astrocytes exposed to OGD. This protective effect of CsA was strongly associated with CaN inhibition, increased expression of anti-apoptotic factors such as Bcl-X(L) and NF-kappaB, as well as suppression of caspase-3 activity. Maximum p-Akt kinase expression was observed following treatment with 1 microM CsA. Finally, we also demonstrated that the beneficial effect of CsA at a concentration of 10 microM is related mainly to strong CaN inhibition. The results obtained suggest that, depending on the concentration used, CsA might act as a protective agent towards ischemia-injured astroglial cells through alternative intracellular pathways associated with increased p-Erk1/2 and p-Akt expression or CaN inactivation.