Exogenous kallikrein enhances neurogenesis and angiogenesis in the subventricular zone and the peri-infarction region and improves neurological function after focal cortical infarction in hypertensive rats.
Kallikrein, a serine proteinase, has been identified as an angiogenic growth factor recently. We investigated whether delayed treatment with exogenous kallikrein enhances neurogenesis and angiogenesis after focal cortical infarction in stroke-prone renovascular hypertensive rats. Human tissue kallikrein (1.6 x 10(-2) PNAU/kg) or vehicle was given through a tail vein daily for 6 consecutive days starting 24 h after distal middle cerebral artery occlusion (MCAO). Cell proliferation was examined by using 5'-bromo-2'-deoxyuridine (BrdU, 50 mg/kg). Rats were sacrificed at 3, 7, 14 or 28 d after MCAO, respectively. Treatment with kallikrein significantly increased the number of BrdU(+) cells in the subventricular zone (SVZ) and the peri-infarction region initiating 3 d after MCAO compared with the vehicle group (all p<0.05). Kallikrein significantly increased the number of BrdU(+)/DCX(+) cells and BrdU(+)/nestin(+) cells in the SVZ as well as vascular density in the peri-infarction region compared with the vehicle group (all p<0.05), which increased at 3 d, peaked at 7-14 d after MCAO, and then gradually decreased. Kallikrein markedly increased the number of BrdU(+)/NeuN(+) cells in the peri-infarction region compared with the vehicle group at 14 d and 28 d after MCAO (all p<0.05). The kallikrein group showed better functional improvement after stroke (all p<0.05). Our study demonstrates that delayed administration of kallikrein at 24 h after cortical infarction promotes the SVZ neuroblasts proliferation, migration, and selective differentiation. Moreover, kallikrein enhanced endogenous neurogenesis is associated with angiogenesis, both attributing to functional improvement after stroke. Therefore, kallikrein may have a potential therapeutic perspective on ischemic stroke.
Ling
Li
L
Department of Neurology and Stroke Center, the First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, PR China.
Hou
Qinghua
Q
Xing
Shihui
S
Yu
Jian
J
Pei
Zhong
Z
Zeng
Jinsheng
J
D042501:Angiogenic Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002540:Cerebral Cortex / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism; D002552:Cerebral Ventricles; D000089662:Doublecortin Protein; D006801:Humans; D006978:Hypertension, Renovascular / Q000150:complications* / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D007610:Kallikreins / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology
D042501:Angiogenic Proteins; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D007610:Kallikreins