title: Neuroprotection of Cilostazol against ischemia/reperfusion-induced cognitive deficits through inhibiting JNK3/caspase-3 by enhancing Akt1.
abstract: Cilostazol(CTL) is a phosphodiesterase inhibitor, which has been widely used as anti-platelet agent. It also has preventive effects on various central nervous system (CNS) diseases, including ischemic stroke, Parkinson's disease and Alzheimer disease. However, the molecular mechanism underlying the protective effects of CTL is still unclear, and whether CTL can prevent I/R induced cognitive deficit has not been reported. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The open field tasks and Morris water maze were used to assess the effect of CTL on anxiety-like behavioral and cognitive impairment after I/R. Western blotting were performed to examine the expression of related proteins, and HE-staining was used to detect the percentage of neuronal death in the hippocampal CA1 region. Here we found that CTL significantly improved cognitive deficits and the behavior of rats in Morris water maze and open field tasks (P<0.05). HE staining results showed that CTL could significantly protect CA1 neurons against cerebral I/R (P<0.05). Additionally, Akt1 phosphorylation levels were evidently up-regulated (P<0.05), while the activation of JNK3, which is an important contributor to I/R-induced neuron apoptosis, was reduced by CTL after I/R (P<0.05), and caspase-3 levels were also decreased by CTL treatment. Furthermore, all of CTL's protective effects were reversed by LY294002, which is a PI3K/Akt1 inhibitor. Taken together, our results suggest that CTL could protect hippocampal neurons and ameliorate the impairment of learning/memory abilities and locomotor/ exploratory activities in ischemic stroke via a PI3K-Akt1/JNK3/caspase-3 dependent mechanism.
authors: Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, People's Republic of China; Department of Genetics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, People's Republic of China. Electronic address: qidashi@126.com.
authors: Da-Shi
authors: DS
authors: Qi
authors: Pediatric Emergency and Critical Care Center, Children' Hospital of Fudan University, Shanghai, People's Republic of China.
authors: Jin-Hao
authors: JH
authors: Tao
authors: Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, People's Republic of China; Department of Genetics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, People's Republic of China.
authors: Lian-Qin
authors: LQ
authors: Zhang
authors: Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, People's Republic of China; Department of Genetics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, People's Republic of China.
authors: Man
authors: M
authors: Li
authors: Department of Genetics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, People's Republic of China.
authors: Mei
authors: M
authors: Wang
authors: Xuzhou Medical College affiliated Hospital, Xuzhou, Jiangsu 221004, People's Republic of China.
authors: Rui
authors: R
authors: Qu
authors: Xuzhou Mine Hosptial, Xuzhou, Jiangsu, People's Republic of China.
authors: Shi-Chun
authors: SC
authors: Zhang
authors: Department of Genetics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, People's Republic of China.
authors: Pei
authors: P
authors: Liu
authors: Department of Genetics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, People's Republic of China.
authors: Fuming
authors: F
authors: Liu
authors: Sino-British SIPPR/B&K Lab Animal Ltd., People's Republic of China.
authors: Jian-Cheng
authors: JC
authors: Miu
authors: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors: Jing-Yi
authors: JY
authors: Ma
authors: Interdisciplinary Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China.
authors: Xin-Yu
authors: XY
authors: Mei
authors: Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University, Shanghai, People's Republic of China. Electronic address: hsfayongzhang@163.com.
authors: Fayong
authors: F
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D000077407:Cilostazol; D003072:Cognition Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D013777:Tetrazoles; D048057:Mitogen-Activated Protein Kinase 10; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; C505410:Casp3 protein, rat; D053148:Caspase 3; D000077407:Cilostazol
keywords: Akt1; Cilostazol; Cognitive deficits; Global cerebral ischemia; JNK3; Rat