Abstract WP285: tPA Variant tPA-A296-299 Prevents Impairment of Cerebral Autoregulation and Hippocampal Neuronal Necrosis After Stroke Through Inhibition of ET-1 Upregulation

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Abstract

Introduction: The sole FDA approved treatment for acute stroke is tissue type plasminogen activator (tPA). However, its brief therapeutic window and post-treatment complications markedly constrain its use. The limited efficacy of tPA may be explained in part by our finding that it potentiates impairment of cerebral autoregulation after stroke in pigs. Upregulation of JNK MAPK after thrombotic stroke contributes to tPA mediated impairment of autoregulation. However, the role of ET-1, and its relationship to JNK, in impairment of autoregulation is unknown. Impairment of autoregulation is linked to Glasgow Coma Scale after brain injury, but unknown if autoregulation correlates with hippocampal histopathology after stroke.

Hypothesis: Wild type (wt) tPA can bind to either the lipoprotein-related receptor (LRP), which mediates vasodilation, or NMDA-Rs. We propose that wt tPA given after stroke primarily binds to NMDA-Rs, upregulates ET-1 in a JNK dependent manner, which impairs autoregulation, causing histopathology. tPA-A296-299, a variant that is fibrinolytic but cannot bind to NMDA-Rs, preferentially binds LRP, which blocks ET-1 and JNK upregulation and limits impairment of autoregulation and histopathology after stroke.

Methods: Anesthetized pigs equipped with a closed cranial window were used. Stroke was induced by photothrombosis, CBF determined by radiolabeled microspheres, CSF ET-1 and JNK determined by ELISA and histopathology determined with H + E stain.

Results: CBF was unchanged during hypotension (mean arterial pressure decreased by 45%) in sham animals. CBF was reduced in brain tissue surrounding the infarct and was reduced further during hypotension, indicating impairment of autoregulation. CA1 and CA3 neuronal cell necrosis and autoregulation were further impaired by wt tPA which was prevented by BQ 123 and tPA-A296-299. Cerebral ET-1 was increased by stroke, potentiated by wt tPA, but returned to sham baseline value by tPA-A296-299 and the JNK antagonist SP600125.

Conclusions: JNK contributes to ET-1 release after stroke. tPA-A296-299 prevents impairment of cerebral autoregulation and histopathology after stroke through inhibition of ET-1 upregulation.

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