Authors: Armstead WM Ph D, Bohman LE, Riley J, Yarovoi SV, Higazi AA, Cines DB.
Traumatic brain injury (TBI) is associated with loss of cerebrovascular autoregulation, which leads to cerebral hypoperfusion. Mitogen activated protein kinase (MAPK) isoforms ERK, p38, and JNK and endothelin-1 (ET-1) are mediators of impaired cerebral hemodynamics after TBI. Excessive tPA released after TBI may cause loss of cerebrovascular autoregulation either by over-activating N-methyl-D-aspartate receptors (NMDA-Rs) or by predisposing to intracranial hemorrhage. Our recent work shows that a catalytically inactive tPA variant (tPA-S481A) that competes with endogenous wild type (wt) tPA for binding to NMDA-R through its receptor docking site but that cannot activate it, prevents activation of ERK by wt tPA and impairment of autoregulation when administered 30 min after FPI. We investigated the ability of variants that lack proteolytic activity but bind/block activation of NMDA-Rs by wt tPA (tPA-S481A), don't bind/block activation of NMDA-Rs but are proteolytic (tPA-A296-299), or neither bind/block NMDA-Rs nor are proteolytic (tPA-A296-299S481A) to prevent impairment of autoregulation after TBI and the role of MAPK and ET-1 in such effects. Results show that tPA-S481A given 3h post TBI, but not tPA-A296-299 or tPA-A29-299S481A prevents impaired autoregulation by upregulating p38 and inhibiting ET-1, suggesting that tPA-S481A has a realistic therapeutic window and focuses intervention on NMDA-Rs to improve outcome.
Full text and source: Mary Ann Liebert publ.
J Neurotrauma. 2013 Jun 3.