RNA interference-mediated downregulation of Beclin1 attenuates cerebral ischemic injury in rats.
OBJECTIVE
To test the role of the Beclin 1-dependent autophagy pathway in brain damage during cerebral ischemia.


METHODS
Focal cerebral ischemia was established in rats using a middle cerebral artery occlusion (MCAO) model. A lentiviral vector-associated RNA interference (RNAi) system was stereotaxically injected into the ipsilateral lateral ventricle to reduce Beclin1 expression. We measured the ipsilateral infarct volume, autophagosome formation, neurogenesis and apoptosis, all of which could be modulated by Beclin1 RNAi.


RESULTS
On the 14th day after MCAO, Beclin1 downregulation by RNAi increased the population of neural progenitor cells (BrdU(+)-DCX(+)), newborn immature cells (BrdU(+)-Tuj-1(+)) and mature neurons (BrdU(+)-MAP-2(+)), and reduced the apoptosis of immature neurons (caspase-3(+)-DCX(+) and caspase-3(+)-Tuj-1(+)) surrounding the ischemic core of the ipsilateral hemisphere. Furthermore, RNAi-mediated downregulation of Beclin1 decreased infarct volume and inhibited histological injury and neurological deficits.


CONCLUSIONS
RNAi-mediated downregulation of Beclin1 improves outcomes after transient MCAO.Acta Pharmacologica Sinica (2009) 30: 919-927; doi: 10.1038/aps.2009.79.
Zheng
Yong-Qiu
YQ
Research Center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China.
Liu
Jian-Xun
JX
Li
Xin-Zhi
XZ
Xu
Li
L
Xu
Yong-Gang
YG
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000071186:Beclin-1; D001522:Behavior, Animal / Q000502:physiology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D000089662:Doublecortin Protein; D015536:Down-Regulation; D020244:Infarction, Middle Cerebral Artery; D020547:Lateral Ventricles / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein