Neuroprotective Effects of Poly(ADP-ribose)polymerase Inhibitor Olaparib in Transient Cerebral Ischemia

Abstract

Olaparib was the first poly(ADP-ribose)polymerase inhibitor approved by Food and Drug Administration for oncology treatment. However, its neuroprotective effects have not been elucidated. This study aimed to evaluate the effects of olaparib in transient cerebral ischemia. A mouse model of transient middle cerebral artery occlusion was used. Reperfusion was performed at 2 h after ischemia. Different doses of olaparib (1, 3, 5, 10 and 25 mg/kg) were administered intraperitoneally immediately after reperfusion. Twenty-four hours after ischemia, the neurological score was assessed, and grip and string tests were performed to evaluate the behavioral deficits in the mice. Cresyl violet staining was used to assess cerebral edema and the lesion volume. Immunohistochemistry was performed to evaluate the expression of blood-brain barrier proteins collagen IV and claudin-5, as well as extravasation of IgG. Ischemia induced a neurological deficit, which was significantly ameliorated by olaparib at 3 and 5 mg/kg. However, this neuroprotective effect was not observed in mice treated with either low-dose or high-dose olaparib. Both 3 and 5 mg/kg olaparib markedly reduced cerebral infarction volume, but not cerebral edema. The expression of collagen IV decreased after cerebral ischemia, which was improved by olaparib at 3 and 5 mg/kg. These results were confirmed by the reduction of IgG extravasation with olaparib. Olaparib showed clear neuroprotective effects in transient ischemic mice mainly through the reduction of cerebral infarction and blood-brain barrier damage.

Keywords: Blood–brain barrier; Ischemic stroke; Olaparib; Poly(ADP-ribose)polymerase.