title: Cerebroside-A provides potent neuroprotection after cerebral ischaemia through reducing glutamate release and Ca²⁺ influx of NMDA receptors.
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.
authors.affiliation: Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Yang
authors.forename: Kaiyue
authors.initials: K
authors.lastname: Sun
authors.forename: Yinyang
authors.initials: Y
authors.lastname: Bai
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Libin
authors.initials: L
authors.lastname: Zhou
authors.forename: Zhi
authors.initials: Z
authors.lastname: Qi
authors.forename: Jianhua
authors.initials: J
authors.lastname: Qi
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism*; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control*; D002554:Cerebrosides / Q000737:chemistry / Q000627:therapeutic use*; D018999:Charybdotoxin / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D000860:Hypoxia / Q000517:prevention & control; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D009498:Neurotoxins / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013778:Tetrazolium Salts; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002554:Cerebrosides; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D013778:Tetrazolium Salts; C116024:cerebroside A; D018999:Charybdotoxin; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; C009591:triphenyltetrazolium; D014633:Valine; D005947:Glucose; D002118:Calcium