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

• Published in: Neuroscience Vol. 171; no. 4; pp. 1367 - 1376
• Main Authors: Tanaka, Y, Tanaka, R, Liu, M, Hattori, N, Urabe, T
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 29.12.2010; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain Infarction - drug therapy; Brain Infarction - etiology; Bromodeoxyuridine - metabolism; cAMP-responsive element binding protein; Cell Count - methods; Cerebral Ventricles - drug effects; Cerebral Ventricles - physiopathology; CREB-Binding Protein - metabolism; Disease Models, Animal; focal cerebral ischemia; forebrain neurogenesis; Fundamental and applied biological sciences. Psychology; In Situ Nick-End Labeling - methods; Ischemic Attack, Transient - complications; Ischemic Attack, Transient - drug therapy; Ischemic Attack, Transient - pathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins - metabolism; Neurogenesis - drug effects; Neurogenesis - physiology; Neurologic Examination - methods; Neurology; Neuroprotective Agents - therapeutic use; Phosphorylation - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; Regional Blood Flow - drug effects; SVZ; Tetrazoles - therapeutic use; type 3 phosphodiesterase inhibitor; Vascular diseases and vascular malformations of the nervous system; Vertebrates: nervous system and sense organs; Bcl-2; brain derived neurotrophic factor; extracellular signal-regulated kinase; doublecortin; CBF; SGZ; insulin-like growth factor-1; phosphate-buffered saline; terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling; phosphodiesterase 3; CREB; OB; TUNEL; B-cell leukemia/lymphoma 2 protein; SVZ; 5-bromodeoxyuridine; CMC; carboxymethyl cellulose sodium salt; type 3 phosphodiesterase inhibitor; phosphorylated cyclic AMP-responsive element binding protein; forebrain neurogenesis; cAMP-responsive element binding protein; MCAO; PBS; cyclic AMP-responsive element binding protein; subventricular zone; olfactory bulb; PDE 3; BDNF; subgranular zone; IGF-1; neuron-specific nuclear protein; GFAP; NSS; NeuN; pCREB; DCX; cerebral blood flow; focal cerebral ischemia; glial fibrillary acidic protein; BrdU; middle cerebral artery occlusion; neurologic severity score; ERK; Central nervous system; Cardiovascular disease; Neurogenesis; Encephalon; Vascular disease; Binding protein; Cerebrovascular disease; Nervous system diseases; Rodentia; Cyclic AMP; Cilostazol; Cerebral disorder; Prosencephalon; Phosphodiesterase inhibitor; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Brain ischemia; Lesion
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2010.10.008

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.