6 Kallikrein Protects Against Ischimic Stroke by Inhibiting Apoptosis.pdf

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6 Kallikrein Protects Against Ischimic Stroke by Inhibiting Apoptosis.pdf

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6 Kallikrein Protects Against Ischimic Stroke by Inhibiting Apoptosis

HUMAN GENE THERAPY 17:206–219 (February 2006) ? Mary Ann Liebert, Inc. Kallikrein Protects Against Ischemic Stroke by Inhibiting Apoptosis and Inflammation and Promoting Angiogenesis and Neurogenesis CHUN-FANG XIA,1 HANG YIN,1 YU-YU YAO,1 CESAR V. BORLONGAN,2 LEE CHAO,1 and JULIE CHAO1 ABSTRACT Stroke-induced neurological deficits and mortality are often associated with timing of treatment after the on- set of stroke. We showed that local delivery of the human tissue kallikrein gene into rat brain immediately after middle cerebral artery occlusion (MCAO) exerts neuroprotection. In this study, we investigated the ef- fect of systemic delivery of the kallikrein gene 8 hr after MCAO. Expression of recombinant human tissue kallikrein after gene transfer was identified in the ischemic brain region and blood vessels. Intravenous in- jection of adenovirus encoding the kallikrein gene significantly reduced neurological deficit scores 2 and 7 days after gene transfer. Kallikrein gene transfer also reduced ischemia–reperfusion (I/R)-induced cerebral infarction and promoted the survival and migration of glial cells from penumbra to the ischemic core from 3 to 14 days after gene delivery. Kallikrein reduced I/R-induced apoptosis of neuronal cells and inhibited in- flammatory cell accumulation in the ischemic brain. These effects were blocked by the kinin B2 receptor an- tagonist icatibant. In addition, kallikrein enhanced angiogenesis and promoted neurogenesis after I/R and the stimulatory effect of kinin on neuronal cell proliferation was confirmed in primary cultured neuronal cells. The protective effects of kallikrein, through the kinin B2 receptor, were accompanied by increased cerebral nitric oxide and Bcl-2 levels, Akt phosphorylation, and reduced NAD(P)H oxidase activity, superoxide pro- duction, Bax levels, and caspase-3 activity. These results indicate that delayed systemic administration of the kallikrein gene after onset of stroke protects against ischemic brain inj