title: Mdivi-1 Protects Against Ischemic Brain Injury via Elevating Extracellular Adenosine in a cAMP/CREB-CD39-Dependent Manner.
abstract: This study aimed to examine whether the neuroprotective effects of Mdivi-1 are attributable to extracellular ATP and adenosine. Mdivi-1 was administered prior to or post middle cerebral artery occlusion (MCAO). The extracellular adenosine was measured by in vivo microdialysis and high-pressure liquid chromatography (HPLC) in MCAO mouse model. Western blot was done to determine the influence of Mdivi-1 on the expression of CD39 and CREB phosphorylation both in vivo and in the cultured astrocytes. Intracellular cAMP and protein kinase A (PKA) activity were detected in primary astrocytes. Results showed that Mdivi-1 significantly reduced infarct volume and neurological scores when administered either prior to or post MCAO. Interestingly, pretreatment with Mdivi-1 resulted in marked increase of extracellular adenosine and concomitant decrease in ATP. The expression of CD39, but not CD73, was upregulated by Mdivi-1, which was associated with the elevated phosphorylated cAMP response element-binding protein (CREB), a transcription factor potentially regulating CD39 expression. In primary astrocytes, Mdivi-1 treatment induced increases in intracellular cAMP, PKA activity and CREB phosphorylation, and PKA-specific inhibitor completely reversed Mdivi-1-induced CD39 expression. Our results demonstrate that Mdivi-1 protects against ischemic brain injury through increasing extracellular adenosine, a process involving elevated CD39 expression that is likely modulated by cAMP/PKA/CREB cascade. Figure Potential mechanisms by which Mdivi-1 mediates the neuroprotection on cerebral ischemic stroke. Results from the present study indicate that Mdivi-1 protects against ischemic brain injury through increasing extracellular adenosine, a process involving elevated CD39 expression that is likely modulated by the cAMP/PKA/CREB cascades.
authors.affiliation: Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, No. 12 Middle Wulumuqi Road, Shanghai, 200040, China. cuimei@fudan.edu.cn.
authors.forename: Mei
authors.initials: M
authors.lastname: Cui
authors.affiliation: Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, No. 12 Middle Wulumuqi Road, Shanghai, 200040, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, No. 12 Middle Wulumuqi Road, Shanghai, 200040, China.
authors.forename: Fangzhe
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Neurology, The 10th People's Hospital, Tongji University, Shanghai, China.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, No. 12 Middle Wulumuqi Road, Shanghai, 200040, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, No. 12 Middle Wulumuqi Road, Shanghai, 200040, China. dong_qiang@fudan.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Dong
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D006868:Hydrolysis; D008297:Male; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology; D052999:Quinazolinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D015703:Antigens, CD; D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D052999:Quinazolinones; D043682:Receptor, Adenosine A1; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D001081:Apyrase; C067869:CD39 antigen; C486391:Dnm1l protein, mouse; D034281:Dynamins; D000241:Adenosine
keywords: Adenosine; CD39; Cerebral ischemia; Mdivi-1; Regional cerebral blood flow; cAMP response element-binding protein