Cyclosporin A ameliorates early brain injury after subarachnoid hemorrhage through inhibition of a Nur77 dependent apoptosis pathway

Abstract

Nur77 is a potent pro-apoptotic member of the orphan nuclear receptor superfamily. It has been demonstrated that can mediate apoptosis in many system cells in response to extracellular stimuli. Our previous study revealed Nur77-mediated apoptotic also involved in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). CsA, a Nur77 inhibitor, can abolish DNA binding activity of Nur77, further inhibit the Nur77 dependent apoptosis pathway. CsA has the neuroprotective effects and has been demonstrated in ischemic stroke and traumatic brain injury. Hence, in this study was designed to explore the neuroprotective effects of CsA in EBI after SAH. Adult male SD rats were randomly assigned to four groups: (1) control group (n = 24); (2) SAH (n = 24); (3) SAH+DMSO group (n = 24); and (4) SAH+CsA (n = 24), 10 mg/kg of CsA or same volume of DMSO was administered by femoral vein injection at 15 min before SAH. CsA markedly decreased expressions of Nur77, p-Nur77, Bcl-2 and cyto C, and inhibited apoptosis.Improvement of neurological deficit, alleviation of brain edema and amelioration of EBI were obtained after prophylactic use of CsA. TUNEL-positive cells were reduced markedly in brain cortex by CsA. These findings suggest that neuroprotective effects of CsA during early peroid after SAH may be related to its inhibition of Nur77 dependent apoptosis pathway.

Keywords: Apoptosis; Arly brain injury; Cyclosporin A; Nur77; Subarachnoid hemorrhage.