tPA contributes to impaired NMDA cerebrovasodilation after traumatic brain injury through activation of JNK MAPK

Abstract

Objective 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. Methods 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. Results 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. Discussion 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.

tPA-S481A Prevents Impairment of Cerebrovascular Autoregulation by Endogenous tPA after Traumatic Brain Injury by Upregulating p38 MAPK and Inhibiting ET-1

“…18,21 As upregulation of p38 MAPK by wt tPA appears to limit impairment of NMDA-Rmediated pial artery dilation after FPI, 18 we speculated that increasing p38 might serve as a mechanism for vasoprotection by tPA-S 481 A. In partial support of this hypothesis, the increase in CSF p38 MAPK post-FPI was mildly augmented by wt tPA but more so by tPA-S 481 A.…”

“…NMDA-R-mediated pial artery dilation after FPI, 18 we speculated that a change in the MAPK isoform profile toward further increasing p38, concomitant with diminished ERK might serve as the mechanism underlying the vasoprotective effect of tPA-S 481 A after TBI. Indeed, the increase in CSF p38 MAPK post-FPI was augmented mildly by wt tPA but was elevated more robustly by tPA-S 481 A (Fig.…”

“…11 Release of endogenous tPA in the setting of FPI aggravates NMDA-R-mediated vasoconstriction. 11,18 The PAI-1 derived hexapeptide EEIIMD blocked reversal of NMDA-R induced dilation to vasoconstriction as well as reductions in baseline pial artery diameter after FPI, 11 indicating that the interaction between tPA and NMDA-Rs is altered in the setting of TBI. Because the NMDA-R antagonist MK801 prevents impairment of pial artery dilation during hypotension after FPI, 20 these data indicate that reversal of NMDA-R-mediated dilation to vasoconstriction and its aggravation by tPA likely contributes to cerebral dysregulation in the setting of TBI.…”

“…Similarly, upregulation of endogenous wild type (wt) tissue plasminogen activator (tPA) after TBI not only enhances excitotoxic neuronal cell death through excessive activation of NMDA-Rs, 12,13 but also contributes to impaired NMDA-R-mediated vasodilation, loss of autoregulation during hypotension, and histopathology [14][15][16][17] via mitogen activated protein kinase (MAPK), 18 a family of three kinases (ERK, p38, and JNK) critically important in hemodynamics after TBI. 14 We found that activation of ERK and JNK contributed to impaired NMDA-R cerebrovasodilation after FPI, while p38 was protective.…”

“…14 We found that activation of ERK and JNK contributed to impaired NMDA-R cerebrovasodilation after FPI, while p38 was protective. 18 Endothelin-1 (ET-1) is also upregulated and antagonizes NMDA-R-mediated vasodilation after FPI. 19 The link between activation of NMDA-Rs and autoregulation is supported by several interventions at the receptor level.…”