Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
4339209 | Neuroscience | 2010 | 10 Pages |
Evidence suggests that neurogenesis occurs in the adult mammalian brain, and that various stimuli, for example, ischemia/hypoxia, enhance the generation of neural progenitor cells in the subventricular zone (SVZ) and their migration into the olfactory bulb. In a mouse stroke model, focal ischemia results in activation of neural progenitor cells followed by their migration into the ischemic lesion. The present study assessed the in vivo effects of cilostazol, a type 3 phosphodiesterase inhibitor known to activate the cAMP-responsive element binding protein (CREB) signaling, on neurogenesis in the ipsilateral SVZ and peri-infarct area in a mouse model of transient middle cerebral artery occlusion. Mice were divided into sham operated (n=12), vehicle- (n=18) and cilostazol-treated (n=18) groups. Sections stained for 5-bromodeoxyuridine (BrdU) and several neuronal and a glial markers were analyzed at post-ischemia days 1, 3 and 7. Cilostazol reduced brain ischemic volume (P<0.05) and induced earlier recovery of neurologic deficit (P<0.05). Cilostazol significantly increased the density of BrdU-positive newly-formed cells in the SVZ compared with the vehicle group without ischemia. Increased density of doublecortin (DCX)-positive and BrdU/DCX-double positive neural progenitor cells was noted in the ipsilateral SVZ and peri-infarct area at 3 and 7 days after focal ischemia compared with the vehicle group (P<0.05). Cilostazol increased DCX-positive phosphorylated CREB (pCREB)-expressing neural progenitor cells, and increased brain derived neurotrophic factor (BDNF)-expressing astrocytes in the ipsilateral SVZ and peri-infarct area. The results indicated that cilostazol enhanced neural progenitor cell generation in both ipsilateral SVZ and peri-infarct area through CREB-mediated signaling pathway after focal ischemia.
Research Highlights▶Cilostazol, type III phosphodiesterase inhibitor, significantly attenuated the infarct volume of mice brain compared to vehicle group after transient middle cerebral artery occlusion. ▶Treatment with cilostazol also significantly increased the DCX positive neural progenitor cells both in the ipsilateral SVZ and peri-infarct area compared to vehicle group after cerebral ischemia. ▶Treatment with cilostazol increased the pCREB expressing DCX positive neural progenitor cells and GFAP positive glial cells in the ipsilateral SVZ and peri-infarct area. ▶Treatment with cilostazol significantly increased the number of BDNF expressing glial cells both in the ipsilateral SVZ and peri-infarct area.