Abstract
Excessive presynaptic glutamate release after cerebral ischaemia leads to neuronal death mainly through excessive calcium entry of N-methyl-D-aspartate receptors (NMDARs). Our recent study reported that cerebroside can open large-conductance Ca²⁺-activated K⁺ (BKCa) channels. The present study evaluated the effects of cerebroside-A (CS-A), a single molecule isolated from an edible mushroom, on brain injury after focal or global ischaemia in adult male mice and rats. We herein report that treatment with CS-A after 60-min middle cerebral artery occlusion dose-dependently reduced the cerebral infarction with at least a 6-h efficacious time-window, which was partially blocked by the BKCa channel blocker charybdotoxin (CTX). Treatment with CS-A after 20 min global cerebral ischaemia (four-vessel occlusion) significantly attenuated the death of pyramidal cells in hippocampal CA1 area, which was also sensitive to CTX. CS-A, by opening the BKCa channel, could prevent excessive glutamate release after oxygen-glucose deprivation (OGD). In addition, CS-A could inhibit NMDAR Ca²⁺ influx, which did not require the activation of the BKCa channel. Furthermore, CS-A blocked the OGD-induced NMDAR-dependent long-term potentiation in hippocampal CA1 region. These findings indicate that treatment with CS-A after stroke exerts potent neuroprotection through prevention of excessive glutamate release and reduction of Ca²⁺ influx through NMDARs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
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Analysis of Variance
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Animals
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Brain Ischemia / prevention & control
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Calcium / metabolism*
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Cerebral Infarction / etiology
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Cerebral Infarction / prevention & control*
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Cerebrosides / chemistry
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Cerebrosides / therapeutic use*
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Charybdotoxin / pharmacology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Interactions
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Electric Stimulation
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Glucose / deficiency
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Glutamic Acid / metabolism*
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Hippocampus / drug effects
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Hippocampus / physiology
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Hypoxia / prevention & control
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In Vitro Techniques
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Infarction, Middle Cerebral Artery / complications
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Infarction, Middle Cerebral Artery / drug therapy
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Long-Term Potentiation / drug effects
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Long-Term Potentiation / physiology
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Male
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Mice
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Mice, Inbred C57BL
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N-Methylaspartate / pharmacology
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / therapeutic use*
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Neurotoxins / pharmacology
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Patch-Clamp Techniques
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Rats
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Rats, Sprague-Dawley
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Receptors, N-Methyl-D-Aspartate / physiology*
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Tetrazolium Salts
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Valine / analogs & derivatives
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Valine / pharmacology
Substances
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Cerebrosides
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Excitatory Amino Acid Antagonists
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Neuroprotective Agents
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Neurotoxins
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Receptors, N-Methyl-D-Aspartate
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Tetrazolium Salts
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cerebroside A
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Charybdotoxin
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Glutamic Acid
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N-Methylaspartate
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6-Cyano-7-nitroquinoxaline-2,3-dione
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2-amino-5-phosphopentanoic acid
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triphenyltetrazolium
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Valine
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Glucose
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Calcium