IMR Press / FBL / Volume 11 / Issue 2 / DOI: 10.2741/1886

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article
Experimental therapy with tissue kallikrein against cerebral ischemia
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1 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA

Academic Editor: Cesario Borlongan

Front. Biosci. (Landmark Ed) 2006, 11(2), 1323–1327; https://doi.org/10.2741/1886
Published: 1 May 2006
(This article belongs to the Special Issue Gene therapy for stroke)
Abstract

Tissue kallikrein is a serine proteinase capable of cleaving kininogen substrate to produce the potent vasodilator kinin peptide. Kinin mediates a complex set of physiological actions through its receptor signaling. Systemic delivery of the kallikrein gene in an adenoviral vector significantly reduced stroke-induced mortality rate, blood pressure elevation, and aortic hypertrophy in hypertensive Dahl-salt sensitive rats fed a high salt diet. Using a focal cerebral ischemic rat model induced by middle cerebral artery occlusion, intravenous or intracerebroventricular kallikrein gene delivery significantly reduced ischemia/repefusion (I/R)-induced neurological deficits, cerebral infarction, neuronal and glial cell apoptosis, and inflammatory cell infiltration, while promoting angiogenesis and neurogenesis in the ischemic brain. A continuous infusion of a sub-depressor dose of tissue kallikrein protein through implanted minipump decreased I/R-induced neurological dysfunction and cerebral infarction, inflammation and oxidative stress independent of kallikrein's blood pressure-lowering effect. Moreover, kallikrein offered neuroprotection even when delivered at one day after the onset of stroke. Kallikrein's protective effects were blocked by the kinin B2 receptor antagonist icatibant. The role of the kinin B2 receptor in mediating the protective effect against ischemic brain injury was further confirmed by increases in mortality rate and post-ischemic brain injury in kinin B2 receptor-deficient mice. Taken together, these results suggest a novel function of kallikrein as an anti-inflammatory and anti-oxidative agent in protecting the brain against ischemic stroke-induced injuries. These findings also raise the possibility that tissue kallikrein may have value in the treatment of acute ischemic stroke.

Keywords
Nervous system
Neuron
Tissue Kallikrein
Kinin
Gene Therapy
Protein Infusion
Oxidative Stress
Inflammation
Apoptosis
Angiogenesis
Neurogenesis
Review
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