RNA interference-mediated downregulation of Beclin1 attenuates cerebral ischemic injury in rats.

AIM

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.

CONCLUSION

RNAi-mediated downregulation of Beclin1 improves outcomes after transient MCAO.Acta Pharmacologica Sinica (2009) 30: 919-927; doi: 10.1038/aps.2009.79.