title: The contribution of L-arginine to the neurotoxicity of recombinant tissue plasminogen activator following cerebral ischemia: a review of rtPA neurotoxicity.
abstract: 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.
authors.affiliation: Nuffield Department of Clinical Medicine, Acute Stroke Programme, University of Oxford, Oxford, UK.
authors.forename: George W J
authors.initials: GW
authors.lastname: Harston
authors.forename: Brad A
authors.initials: BA
authors.lastname: Sutherland
authors.forename: James
authors.initials: J
authors.lastname: Kennedy
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Buchan
mesh_terms: D000818:Animals; D001120:Arginine / Q000009:adverse effects* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004347:Drug Interactions; D004355:Drug Stability; D005343:Fibrinolytic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D009498:Neurotoxins / Q000378:metabolism; D009569:Nitric Oxide / Q000138:chemical synthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011994:Recombinant Proteins / Q000009:adverse effects; D012720:Severity of Illness Index; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000187:drug effects / Q000627:therapeutic use
chemical_list: D005343:Fibrinolytic Agents; D007527:Isoenzymes; D009498:Neurotoxins; D011973:Receptors, LDL; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D010959:Tissue Plasminogen Activator