Cilostazol protects against brain white matter damage and cognitive impairment in a rat model of chronic cerebral hypoperfusion.
OBJECTIVE
White matter lesions contribute to cognitive impairment in poststroke patients. The present study was designed to assess the neuroprotective mechanisms of cilostazol, a potent inhibitor of type III phosphodiesterase, through signaling pathways that lead to activation of transcription factor cAMP-responsive element binding protein (CREB) phosphorylation using rat chronic cerebral hypoperfusion model.


METHODS
Rats underwent bilateral common carotid artery ligation. They were divided into the cilostazol group (n=80) and the vehicle (control) group (n=80). Performance at the Morris water maze task and immunohistochemistry for 4-hydroxy-2-nonenal (HNE), glutathione-S-transferase-pi (GST-pi), ionized calcium-binding adaptor molecule 1, phosphorylated CREB (p-CREB), Bcl-2, and cyclooxygenase-2 (COX-2) were analyzed at baseline and at 3, 7, 14, 21, and 28 days after hypoperfusion.


RESULTS
Cilostazol significantly improved spatial learning memory (6.8+/-2.3 seconds; P<0.05) at 7 days after hypoperfusion. Cilostazol markedly suppressed accumulation of HNE-modified protein and loss of GST-pi-positive oligodendrocytes in the cerebral white matter during the early period after hypoperfusion (P<0.05). Cilostazol upregulated p-CREB and Bcl-2 (P<0.05), increased COX-2 expression, and reduced microglial activation in the early period of hypoperfusion.


CONCLUSIONS
Our results indicate that cilostazol exerts a brain-protective effect through the CREB phosphorylation pathway leading to upregulation of Bcl-2 and COX-2 expressions and suggest that cilostazol is potentially useful for the treatment of cognitive impairment in poststroke patients.
Watanabe
Terubumi
T
Department of Neurology, Juntendo University School of Medicine, Tokyo 113-0033, Japan.
Zhang
Ning
N
Liu
Meizi
M
Tanaka
Ryota
R
Mizuno
Yoshikuni
Y
Urabe
Takao
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology* / Q000523:psychology; D002908:Chronic Disease; D000077407:Cilostazol; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007858:Learning / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology*
D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D010726:Phosphodiesterase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013777:Tetrazoles; D051546:Cyclooxygenase 2; D000077407:Cilostazol