Potentiation of aspirin-induced cerebroprotection by minocycline: A therapeutic approach to attenuate exacerbation of transient focal cerebral ischaemia

Abstract

Cerebrovascular disease is a major cause of mortality and disability in adults. Diabetes mellitus increases the risk of cerebral ischaemia and is associated with worse clinical outcome following an event. Upregulation of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes appears to play a role in vascular complications of diabetes. We hypothesised that inhibition of MMP-2 and MMP-9 by minocycline can be potentiated by aspirin through inhibition of cyclooxygenase-2 and tissue plasminogen activator, resulting in amelioration of clinical cerebral ischaemia in diabetes. In the present study, cerebral ischaemia/reperfusion injury was induced in streptozotocin diabetic rats by 1 h middle cerebral artery occlusion and 24 h reperfusion. Infarct volume, cerebral oedema, neurological severity score and blood–brain barrier disruption were significantly increased in diabetic animals compared with the normoglycemic control group. The combination of aspirin and minocycline treatment significantly improved these parameters in diabetic animals. Moreover, this therapy was associated with significantly lower mortality and reduction in MMP-2 and MMP-9 levels. Our data indicate that combination of aspirin and minocycline therapy protects from the consequences of cerebral ischaemia in animal models of diabetes and is associated with inhibition of MMP-2 and MMP-9. Therefore, this combination therapy may represent a novel strategy to reduce the neurological complications of cerebral ischaemia in diabetes.