Cilostazol attenuates ischemic brain injury and enhances neurogenesis in the subventricular zone of adult mice after transient focal cerebral ischemia.

Abstract

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.

• Authors: Y Tanaka, R Tanaka, M Liu, N Hattori, T Urabe
• Journal: Neuroscience (Neuroscience) Vol. 171 Issue 4 Pg. 1367-76 (Dec 29 2010) ISSN: 1873-7544 [Electronic] United States
• PMID: 20933581 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Dcx protein, mouse
• Doublecortin Protein
• Nerve Tissue Proteins
• Neuroprotective Agents
• Proto-Oncogene Proteins c-bcl-2
• Tetrazoles
• CREB-Binding Protein
• Bromodeoxyuridine
• Cilostazol

Topics

• Animals
• Brain Infarction (drug therapy, etiology)
• Bromodeoxyuridine (metabolism)
• CREB-Binding Protein (metabolism)
• Cell Count (methods)
• Cerebral Ventricles (drug effects, physiopathology)
• Cilostazol
• Disease Models, Animal
• Doublecortin Protein
• In Situ Nick-End Labeling (methods)
• Ischemic Attack, Transient (complications, drug therapy, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Nerve Tissue Proteins (metabolism)
• Neurogenesis (drug effects, physiology)
• Neurologic Examination (methods)
• Neuroprotective Agents (therapeutic use)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Regional Blood Flow (drug effects)
• Tetrazoles (therapeutic use)