NMDA induced pial artery dilation (PAD) is reversed to vasoconstriction after fluid percussion brain injury (FPI). Tissue type plasminogen activator (tPA) is upregulated and the tPA antagonist, EEIIMD, prevents impaired NMDA PAD after FPI. Mitogen activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is also upregulated after TBI. We hypothesize that tPA impairs NMDA induced cerebrovasodilation after FPI in a MAPK isoform dependent mechanism.
Lateral FPI was induced in newborn pigs. The closed cranial window technique was used to measure pial artery diameter and to collect CSF. ERK, p38, and JNK MAPK concentrations in CSF were quantified by ELISA.
CSF JNK MAPK was increased by FPI, increased further by tPA, but blocked by JNK antagonists SP600125 and D-JNKI1. FPI modestly increased p38 and ERK isoforms of MAPK. NMDA induced PAD was reversed to vasoconstriction after FPI, whereas dilator responses to papaverine were unchanged. tPA, in post FPI CSF concentration, potentiated NMDA induced vasoconstriction while papaverine dilation was unchanged. SP 600125 and D-JNKI1, blocked NMDA induced vasoconstriction and fully restored PAD. The ERK antagonist U 0126 partially restored NMDA-induced PAD, while the p38 inhibitor SB203580 aggravated NMDA-induced vasoconstriction observed in the presence of tPA after FPI.
These data indicate that tPA contributes to impairment of NMDA mediated cerebrovasodilation after FPI through JNK, while p38 may be protective. These data suggest that inhibition of the endogenous plasminogen activator system and JNK may improve cerebral hemodynamic outcome post TBI.