Journal
TRANSLATIONAL STROKE RESEARCH
Volume 3, Issue 1, Pages 114-121Publisher
SPRINGER
DOI: 10.1007/s12975-011-0105-1
Keywords
Cerebral circulation; Newborn; Plasminogen activators; Signal transduction; Ischemia
Categories
Funding
- National Institutes of Health [NS53410, HD57355, HL76406, CA83121, HL76206, HL07971, HL81864, HL77760, HL82545, HL66442, HL090697]
- University of Pennsylvania Research Foundation
- University of Pennsylvania Institute for Translational Medicine and Therapeutics
- Israeli Science Foundation
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The sole Food and Drug Administration-approved treatment for acute stroke is tissue-type plasminogen activator (tPA), but tPA aggravates impairment of cerebrovasodilation during hypotension in a newborn pig photothrombotic model of stroke. Coupling to carrier red blood cells (RBC) enhances thrombolytic effects of tPA, while reducing its side effects. ATP- and Ca-sensitive K channels (Katp and Kca) are important regulators of cerebrovascular tone and mediate cerebrovasodilation during hypotension. Mitogen-activated protein kinase, a family of at least three kinases, ERK, p38, and c-Jun-N-terminal kinase (JNK), is upregulated after photothrombosis. This study examined the effect of photothrombosis on Katp- and Kca-induced cerebrovasodilation and the roles of tPA and JNK during/after injury. Photothrombosis blunted vasodilation induced by the Katp agonists cromakalim, calcitonin gene-related peptide, and the Kca agonist NS 1619, which was aggravated by injection of tPA. In contrast, both pre- or post-injury thrombosis injection of RBC-tPA and JNK antagonist SP 600125 prevented impairment of Katp- and Kca-induced vasodilation. Therefore, JNK activation in thrombosis impairs K channel-mediated cerebrovasodilation. Standard thrombolytic therapy of central nervous system ischemic disorders using free tPA poses the danger of further dysregulation of cerebrohemodynamics by impairing cation-mediated control of cerebrovascular tone, whereas RBC-coupled tPA both restores reperfusion and normalizes cerebral hemodynamics.
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