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The contribution of L-arginine to the neurotoxicity of recombinant tissue plasminogen activator following cerebral ischemia: a review of rtPA neurotoxicity
journal contribution
posted on 2023-05-19, 03:09 authored by Harston, GWJ, Brad SutherlandBrad Sutherland, Kennedy, J, Buchan, AMAlteplase 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.
History
Publication title
Journal of Cerebral Blood Flow and MetabolismVolume
30Issue
11Pagination
1804-1816ISSN
0271-678XDepartment/School
Tasmanian School of MedicinePublisher
Lippincott Williams & WilkinsPlace of publication
United StatesRights statement
Copyright 2010 ISCBFMRepository Status
- Restricted