Serotonin protects C6 glioma cells from glutamate toxicity.
It was recently shown that addition of L-glutamate in millimolar amounts to a culture of C6 glioma cells induced cell death within 24 h. The mechanism for glutamate toxicity in the C6 glioma cells is linked to the inhibition of cystine uptake, leading to glutathione depletion through the cystine/glutamate antiporter (Xc) system. In the present study, neurotransmitters, whose receptors were localized on the glioma (glial) cells, were evaluated for their ability to protect C6 cells from glutamate toxicity through this amino acid antiporter. Among them, only 100 microM serotonin suppressed cell death by glutamate in a constant co-existence culture. The suppressive dose of serotonin was relatively low and the half-effective dose was about 35 microM. 8-Hydroxy-2-(DL-n-propylamino)tetralin, a specific serotonin1A agonist, showed a comparable suppression to glutamate damage, while 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, a specific serotonin2 agonist, and quipazine, a non-selective serotonin1B agonist, did not suppress it. Furthermore, propranolol and pindolol significantly blocked the serotonin effect, but spiperone, mianserin and ketanserin did not block it. These results strongly indicate that this protective action of serotonin to glutamate toxicity was receptor (serotonin1A) mediated. Serotonin did not protect the C6 cells from glutathione depletion by glutamate. The cellular level of glutathione was depleted even under the co-existence of serotonin and glutamate. Serotonin induced a significant inhibition of lipid peroxide accumulation in the C6 glioma cells to glutamate exposure and the low rate of lipid peroxide accumulation was controlled.(ABSTRACT TRUNCATED AT 250 WORDS)
Shinagawa
S
S
Department of Neurobiology, University of Kanazawa School of Medicine, Ishikawa, Japan.
D000818:Animals; D017920:Antiporters / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D003553:Cystine / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists; D005910:Glioma / Q000473:pathology; D005912:Gliotoxin / Q000494:pharmacology / Q000633:toxicity; D005971:Glutamates / Q000633:toxicity; D018698:Glutamic Acid; D005978:Glutathione / Q000096:biosynthesis*; D015227:Lipid Peroxidation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D017920:Antiporters; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D012701:Serotonin; D018698:Glutamic Acid; D003553:Cystine; D005912:Gliotoxin; D016318:Quisqualic Acid; D005978:Glutathione