Compound IMM-H004, a novel coumarin derivative, protects against CA1 cell loss and spatial learning impairments resulting from transient global ischemia. 2015

Wei Zuo, and Wei Zhang, and Ning Han, and Nai-Hong Chen
State Key Laboratory of Bioactive Substances and Function Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xuanwu District, Beijing, China.

OBJECTIVE Compound IMM-H004 (7-hydroxy-5-methoxy-4-methyl-3-[4-methylpiperazin-1-yl]-2H-chromen-2-one) is a new synthetic derivative of coumarin, and previous studies showed that it exhibited antioxidant and neuroprotective roles in focal cerebral ischemia. However, we know little about the compound's function in transient global ischemia. This study is to investigate whether compound IMM-H004 can protect against transient global ischemic injury. METHODS Four-vessel occlusion (4VO) rat model was induced for a 20-min occlusion and different times of reperfusion to mimic transient global cerebral ischemia. IMM-H004 (3, 6, 9 mg/kg) or Edaravone (6 mg/kg) was administered after 30 min of reperfusion. Morris water maze tests were used to estimate the ability of spatial learning and memory. Nissl staining, TUNEL assay and Immunoblot for Bax/Bcl-2 and activated caspase-3 were used to detect hippocampal neuron injury. Immunoblot for PSD-95 and synapsin 1, and electron microscopy were used to observe synaptic function. RESULTS Compared with vehicle group, IMM-H004 significantly improved the spatial learning performance and exhibited less CA1 neurons loss. The expressions of Bax/Bcl-2 and activated caspase-3 were decreased. IMM-H004 also ameliorated synaptic structure, decreased PSD-95 and increased synapsin 1 expression. CONCLUSIONS These findings suggested that IMM-H004 exerted neuroprotective role in global ischemia by reducing apoptosis and maintaining the integrity of synaptic structure.

UI MeSH Term Description Entries
D007859 Learning Disabilities Conditions characterized by a significant discrepancy between an individual's perceived level of intellect and their ability to acquire new language and other cognitive skills. These may result from organic or psychological conditions. Relatively common subtypes include DYSLEXIA, DYSCALCULIA, and DYSGRAPHIA. Adolescent Learning Disabilities,Adult Learning Disabilities,Child Learning Disabilities,Developmental Academic Disability,Developmental Academic Disorder,Developmental Disabilities of Scholastic Skills,Learning Disabilities, Adolescent,Learning Disabilities, Child,Learning Disorders,Academic Disorder, Developmental,Adult Learning Disorders,Developmental Disorders of Scholastic Skills,Learning Disorders, Adult,Learning Disturbance,Scholastic Skills Development Disorders,Academic Disabilities, Developmental,Academic Disability, Developmental,Academic Disorders, Developmental,Adolescent Learning Disability,Adult Learning Disability,Adult Learning Disorder,Child Learning Disability,Developmental Academic Disabilities,Developmental Academic Disorders,Disabilities, Adolescent Learning,Disabilities, Adult Learning,Disabilities, Child Learning,Disabilities, Developmental Academic,Disabilities, Learning,Disability, Adolescent Learning,Disability, Adult Learning,Disability, Child Learning,Disability, Developmental Academic,Disability, Learning,Disorder, Learning,Disorders, Adult Learning,Disorders, Learning,Disturbance, Learning,Disturbances, Learning,Learning Disabilities, Adult,Learning Disability,Learning Disability, Adolescent,Learning Disability, Adult,Learning Disability, Child,Learning Disorder,Learning Disorder, Adult,Learning Disturbances
D008297 Male Males
D008565 Membrane Proteins Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. Cell Membrane Protein,Cell Membrane Proteins,Cell Surface Protein,Cell Surface Proteins,Integral Membrane Proteins,Membrane-Associated Protein,Surface Protein,Surface Proteins,Integral Membrane Protein,Membrane Protein,Membrane-Associated Proteins,Membrane Associated Protein,Membrane Associated Proteins,Membrane Protein, Cell,Membrane Protein, Integral,Membrane Proteins, Integral,Protein, Cell Membrane,Protein, Cell Surface,Protein, Integral Membrane,Protein, Membrane,Protein, Membrane-Associated,Protein, Surface,Proteins, Cell Membrane,Proteins, Cell Surface,Proteins, Integral Membrane,Proteins, Membrane,Proteins, Membrane-Associated,Proteins, Surface,Surface Protein, Cell
D009474 Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM. Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D011897 Random Allocation A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. Randomization,Allocation, Random
D002545 Brain Ischemia Localized reduction of blood flow to brain tissue due to arterial obstruction or systemic hypoperfusion. This frequently occurs in conjunction with brain hypoxia (HYPOXIA, BRAIN). Prolonged ischemia is associated with BRAIN INFARCTION. Cerebral Ischemia,Ischemic Encephalopathy,Encephalopathy, Ischemic,Ischemia, Cerebral,Brain Ischemias,Cerebral Ischemias,Ischemia, Brain,Ischemias, Cerebral,Ischemic Encephalopathies
D003374 Coumarins Synthetic or naturally occurring substances related to coumarin, the delta-lactone of coumarinic acid. 1,2-Benzopyrone Derivatives,1,2-Benzopyrones,Coumarin Derivative,Coumarine,1,2-Benzo-Pyrones,Benzopyran-2-ones,Coumarin Derivatives,Coumarines,1,2 Benzo Pyrones,1,2 Benzopyrone Derivatives,1,2 Benzopyrones,Benzopyran 2 ones,Derivative, Coumarin,Derivatives, 1,2-Benzopyrone,Derivatives, Coumarin
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D000076122 Disks Large Homolog 4 Protein A neuronal protein consisting of three PDZ DOMAINS, an SH3 DOMAIN, and a C-terminal guanylate kinase-like region (see MAGUK PROTEINS). It localizes to the POST-SYNAPTIC DENSITY and associates with the cytoplasmic tail of NMDA RECEPTORS and SHAKER POTASSIUM CHANNELS, playing a critical role in NMDA receptor-mediated SYNAPTIC PLASTICITY. Discs Large Homolog 4 Protein,PSD-95 Protein,PSD95 Protein,Postsynaptic Density Protein 95,SAP-90 Protein,SAP90 Protein,Synapse-Associated Protein 90,PSD 95 Protein,SAP 90 Protein,Synapse Associated Protein 90

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