Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 30, Issue 11, Pages 1804-1816Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2010.149
Keywords
cerebral ischemia; L-arginine; neurotoxicity; stroke; tissue plasminogen activator
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Funding
- Oxford University Clinical Academic Graduate School
- Fondation Leducq
- Medical Research Council UK
- National Institute for Health Research Biomedical Research Centre
- Medical Research Council [G0500495] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10213] Funding Source: researchfish
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Alteplase is the only drug licensed for acute ischemic stroke, and in this formulation, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) is stabilized in a solution of L-arginine. Improved functional outcomes after alteplase administration have been shown in clinical trials, along with improved histological and behavioral measures in experimental models of embolic stroke. However, in animal models of mechanically induced ischemia, alteplase can exacerbate ischemic damage. We have systematically reviewed the literature of both rtPA and L-arginine administration in mechanical focal ischemia. The rtPA worsens ischemic damage under certain conditions, whereas L-arginine can have both beneficial and deleterious effects dependent on the time of administration. The interaction between rtPA and L-arginine may be leading to the production of nitric oxide, which can cause direct neurotoxicity, altered cerebral blood flow, and disruption of the neurovascular unit. We suggest that alternative formulations of rtPA, in the absence of L-arginine, would provide new insight into rtPA neurotoxicity, and have the potential to offer more efficacious thrombolytic therapy for ischemic stroke patients. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1804-1816; doi:10.1038/jcbfm.2010.149; published online 25 August 2010
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