1. The paradox of tPA in ischemic stroke: tPA knockdown following recanalization improves functional and histological outcomes.
- Author
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Challa SR, Nalamolu KR, Fornal CA, Baker IM, Mohandass A, Mada SR, Wang BC, Pinson DM, Lahoti S, Klopfenstein JD, and Veeravalli KK
- Subjects
- Humans, Rats, Male, Female, Animals, Infant, Tissue Plasminogen Activator, RNA, Small Interfering genetics, RNA, Small Interfering therapeutic use, Fibrinolytic Agents therapeutic use, Fibrinolytic Agents pharmacology, Disease Models, Animal, Ischemic Stroke drug therapy, Brain Ischemia metabolism, Stroke drug therapy, Stroke pathology
- Abstract
Previous studies have demonstrated that endogenous tissue-type plasminogen activator (tPA) is upregulated in the brain after an acute ischemic stroke (AIS). While mixed results were observed in genetic models, the pharmacological inhibition of endogenous tPA showed beneficial effects. Treatment with exogenous recombinant tPA exacerbated brain damage in rodent models of stroke. Despite the detrimental effects of tPA in ischemic stroke, recombinant tPA is administered to AIS patients to recanalize the occluded blood vessels because the benefits of its administration outweigh the risks associated with tPA upregulation and increased activity. We hypothesized that tPA knockdown following recanalization would ameliorate sensorimotor deficits and reduce brain injury. Young male and female rats (2-3 months old) were subjected to transient focal cerebral ischemia by occlusion of the right middle cerebral artery. Shortly after reperfusion, rats from appropriate cohorts were administered a nanoparticle formulation containing tPA shRNA or control shRNA plasmids (1 mg/kg) intravenously via the tail vein. Infarct volume during acute and chronic phases, expression of matrix metalloproteinases (MMPs) 1, 3, and 9, enlargement of cerebral ventricle volume, and white matter damage were all reduced by shRNA-mediated gene silencing of tPA following reperfusion. Additionally, recovery of somatosensory and motor functions was improved. In conclusion, our results provide evidence that reducing endogenous tPA following recanalization improves functional outcomes and reduces post-stroke brain damage., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2024
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