| The contribution of L-arginine to the neurotoxicity of recombinant tissue plasminogen activator following cerebral ischemia: a review of rtPA neurotoxicity. | |
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MedLine Citation:
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PMID: 20736961 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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George W J Harston; Brad A Sutherland; James Kennedy; Alastair M Buchan |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Review Date: 2010-08-25 |
Journal Detail:
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Title: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Volume: 30 ISSN: 1559-7016 ISO Abbreviation: J. Cereb. Blood Flow Metab. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-02 Completed Date: 2010-11-29 Revised Date: 2011-11-01 |
Medline Journal Info:
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Nlm Unique ID: 8112566 Medline TA: J Cereb Blood Flow Metab Country: United States |
Other Details:
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Languages: eng Pagination: 1804-16 Citation Subset: IM |
Affiliation:
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Nuffield Department of Clinical Medicine, Acute Stroke Programme, University of Oxford, Oxford, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arginine / adverse effects*, pharmacology Brain / metabolism Brain Ischemia / drug therapy*, etiology, pathology, physiopathology Cerebrovascular Circulation / drug effects Drug Interactions Drug Stability Fibrinolytic Agents / adverse effects*, therapeutic use Humans Isoenzymes / metabolism Neurotoxicity Syndromes / etiology* Neurotoxins / metabolism Nitric Oxide / chemical synthesis Nitric Oxide Synthase / metabolism Receptors, LDL / metabolism Receptors, N-Methyl-D-Aspartate / metabolism Recombinant Proteins / adverse effects Severity of Illness Index Tissue Plasminogen Activator / adverse effects*, drug effects, therapeutic use |
| Grant Support | |
ID/Acronym/Agency:
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//Medical Research Council |
| Chemical | |
Reg. No./Substance:
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0/Fibrinolytic Agents; 0/Isoenzymes; 0/Neurotoxins; 0/Receptors, LDL; 0/Receptors, N-Methyl-D-Aspartate; 0/Recombinant Proteins; 10102-43-9/Nitric Oxide; 74-79-3/Arginine; EC 1.14.13.39/Nitric Oxide Synthase; EC 3.4.21.68/Tissue Plasminogen Activator |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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