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: Lin Li, Rong Yang, Kaiyue Sun, Yinyang Bai, Zhuo Zhang, Libin Zhou, Zhi Qi, Jianhua Qi, Ling Chen
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 15 Issue 4 Pg. 497-507 (May 2012) ISSN: 1469-5111 [Electronic] England
• PMID: 21557879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cerebrosides
• Excitatory Amino Acid Antagonists
• Neuroprotective Agents
• Neurotoxins
• Receptors, N-Methyl-D-Aspartate
• Tetrazolium Salts
• cerebroside A
• Charybdotoxin
• Glutamic Acid
• N-Methylaspartate
• 6-Cyano-7-nitroquinoxaline-2,3-dione
• 2-amino-5-phosphopentanoic acid
• triphenyltetrazolium
• Valine
• Glucose
• Calcium

Topics

• 6-Cyano-7-nitroquinoxaline-2,3-dione (pharmacology)
• Analysis of Variance
• Animals
• Brain Ischemia (prevention & control)
• Calcium (metabolism)
• Cerebral Infarction (etiology, prevention & control)
• Cerebrosides (chemistry, therapeutic use)
• Charybdotoxin (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Interactions
• Electric Stimulation
• Excitatory Amino Acid Antagonists (pharmacology)
• Excitatory Postsynaptic Potentials (drug effects)
• Glucose (deficiency)
• Glutamic Acid (metabolism)
• Hippocampus (drug effects, physiology)
• Hypoxia (prevention & control)
• In Vitro Techniques
• Infarction, Middle Cerebral Artery (complications, drug therapy)
• Long-Term Potentiation (drug effects, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• N-Methylaspartate (pharmacology)
• Neuroprotective Agents (chemistry, therapeutic use)
• Neurotoxins (pharmacology)
• Patch-Clamp Techniques
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (physiology)
• Tetrazolium Salts
• Valine (analogs & derivatives, pharmacology)