The sole FDA-approved treatment for
acute stroke is recombinant
tissue-type plasminogen activator (rtPA). However, rtPA aggravates the impairment of cerebrovasodilation induced by global
hypoxia/
ischemia; this impairment is attenuated by the preinjury treatment with the
plasminogen activator inhibitor derivative EEIIMD. MAPK (a family of
kinases, p38, and JNK) is upregulated after
cerebral ischemia. In this study, we determined whether the novel
plasminogen activator inhibitor-derived
peptide,
Ac-RMAPEEIIMDRPFLYVVR-amide, (PAI-1-DP) given 30 min before or 2 h after, focal central nervous system injury induced by photothrombosis would preserve responses to cerebrovasodilators and the role of p38 and JNK MAPK in such effects. Cerebrospinal fluid JNK and p38 levels were elevated by photothrombotic injury, an effect potentiated by rtPA. Cerebrovasodilation was blunted by photothrombosis and reversed to vasoconstriction by rtPA but restored to dilation by
PAI-1-DP pre- and posttreatment.
PAI-1-DP blocked JNK, but preserved
p38 MAPK upregulation after photothrombosis. The JNK MAPK antagonist
SP600125 prevented, and the p38 antagonist
SB203580 potentiated, impaired cerebrovasodilation after photothrombosis. These data indicate that rtPA impairs cerebrovasodilation after injury by activating JNK, while
p38 MAPK is protective, and that the novel
peptide PAI-1-DP protects by inhibiting activation of JNK by rtPA. JNK MAPK inhibitors, including
PAI-1-DP, may offer a novel approach to increase the benefit-to-risk ratio of
thrombolytic therapy and enable its use in central nervous system ischemic disorders.