title: Protection of neuronal cells from excitotoxicity by disrupting nNOS-PSD95 interaction with a small molecule SCR-4026.
abstract: Stroke is a major public health problem leading to high rates of death and disability in adults. Coupling of postsynaptic density protein-95 (PSD-95) and neuronal nitric oxide synthase (nNOS) plays an important part in neuronal damage caused by stroke. Recent studies suggest the possibility of alleviating post ischemia neuron damage by blocking ischemia-induced nNOS-PSD-95 association. Here, we report a small-molecular inhibitor of nNOS-PSD-95 interaction, SCR-4026, which exhibits neuroprotective activities in NMDA-induced or Oxygen and glucose deprivation (OGD)-induced neuronal damage in primary cortical neurons cultures, and ameliorated focal cerebral ischemic damage in rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion. Furthermore, we found that SCR-4026 was also able to promote neural stem cells to differentiate into neurons-like cells, which is potentially of great significance for neural protection. Taken together, SCR-4026 is identified as a novel small molecule that shows great potential in treating stroke.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu 210023, PR China; MtC BioPharma Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China; Simcere Pharmaceutical Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China.
authors.forename: Shi-Fu
authors.initials: SF
authors.lastname: Mo
authors.affiliation: MtC BioPharma Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China; Simcere Pharmaceutical Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China.
authors.forename: Gao-Yong
authors.initials: GY
authors.lastname: Liao
authors.affiliation: MtC BioPharma Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China; Simcere Pharmaceutical Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: MtC BioPharma Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China; Simcere Pharmaceutical Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China.
authors.forename: Meng-Yu
authors.initials: MY
authors.lastname: Wang
authors.affiliation: MtC BioPharma Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China; Simcere Pharmaceutical Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: MtC BioPharma Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China; Simcere Pharmaceutical Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China.
authors.forename: Guo-Ning
authors.initials: GN
authors.lastname: Lian
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu 210023, PR China. Electronic address: kongld@nju.edu.cn.
authors.forename: Ling-Dong
authors.initials: LD
authors.lastname: Kong
authors.affiliation: MtC BioPharma Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China; Simcere Pharmaceutical Co., Ltd, 699-18 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China. Electronic address: zhaoyong@mtcbiopharma.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage* / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D000814:Aniline Compounds; D001549:Benzamides; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; C000621366:SCR-4026; D052248:Nitric Oxide Synthase Type I; D005947:Glucose; D010100:Oxygen
keywords: Cerebral ischemia; PSD95; nNOS