Tirofiban Prevents Delayed Cerebral Ischemia After Subarachnoid Hemorrhage in Aged Mice

BACKGROUND: Microthrombi formation in the cerebral microvasculature has been demonstrated in animal models of subarachnoid hemorrhage (SAH) as well as autopsy studies of patients with aneurysmal SAH, and microthrombi are thought to contribute to delayed cerebral ischemia and poor neurological outcomes. Our hypothesis was that treatment with tirofiban, an antiplatelet drug that inhibits glycoprotein IIb/IIIa, would reduce microthrombi formation and the subsequent sequalae, delayed cerebral ischemia, in aged mice. METHODS: SAH was induced via endovascular perforation in male mice, and blood injection in female mice, followed by treatment with either tirofiban or saline. Mice underwent daily neurological assessment for 6 days and then were euthanized. Magnetic resonance imaging scans were obtained on days 2, 4, and 6 after SAH to identify infarcted tissue. Magnetic resonance imaging perfusion and laser speckle contrast imaging were performed to evaluate cerebral perfusion. Postmortem microthrombi formation in the cerebral microvascular was quantified. RESULTS: Tirofiban treatment in male mice, compared with saline, led to reduced microthrombi formation, and prevented delayed infarct growth and neurological decline. In female mice, significant neurobehavioral improvements were observed, which corresponded with fewer brain microthrombi. No female mice had infarction, nor was delayed cerebral ischemia detected in any female mouse. CONCLUSIONS: After SAH in mice, treatment with tirofiban reduces both cerebral microthrombi formation and delayed infarct growth leading to a subsequent improvement in neurological outcomes.