CILOSTAZOL ATTENUATES ISCHEMIC BRAIN INJURY AND ENHANCES NEUROGENESIS IN THE SUBVENTRICULAR ZONE OF ADULT MICE AFTER TRANSIENT FOCAL CEREBRAL ISCHEMIA

Evidence suggests that neurogenesis occurs in the adult mammalian brain, and that various stimuli, for ex ample, 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 pen 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 pen 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 pen infarct area The results indicated that cilostazol enhanced neural progenitor cell generation in both ipsilateral SVZ and pen infarct area through CREB mediated signaling pathway after focal ischemia (C) 2010 IBRO Published by Elsevier Ltd All rights reserved