Tissue-type plasminogen activator (tPA) is neurotoxic and exacerbates uncoupling of cerebral blood flow (CBF) and metabolism after
stroke, yet it remains the sole FDA-approved drug for treatment of
ischemic stroke. Upregulation of c-Jun-terminal
kinase (JNK) after
stroke contributes to tPA-mediated impairment of autoregulation, but the role of
endothelin-1 (ET-1) is unknown. Based on the Glasgow Coma Scale, impaired autoregulation is linked to adverse outcomes after TBI, but correlation with hippocampal histopathology after
stroke has not been established. We propose that given after
stroke, tPA activates
N-Methyl-D-Aspartate receptors (
NMDA-Rs) and upregulates ET-1 in a JNK dependent manner, imparing autoregulation and leading to histopathology. After
stroke, CBF was reduced in the hippocampus and reduced further during
hypotension, which did not occur in hypotensive
sham pigs, indicating impairment of autoregulation. Autoregulation and
necrosis of hippocampal CA1 and CA3 neurons were further impaired by tPA, but were preserved by the ET-1 antagonist
BQ 123 and tPA-A,296-299 a variant that is fibrinolytic but does not bind to
NMDA-Rs. Expression of ET-1 was increased by
stroke and potentiated by tPA but returned to
sham levels by tPA-A296-299 and the JNK antagonist
SP600125. Results show that JNK releases ET-1 after
stroke.
Tissue-type plasminogen activator -A296-299 prevents impairment of cerebral autoregulation and histopathology after
stroke by inhibiting upregulation of ET-1.