Acute neurotoxicity of L-glutamate induced by impairment of the glutamate uptake system.
We examined the effect of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) on the neurotoxicity of L-glutamate in organotypic cultures of rat spinal cord. Eighteen-day-old cultures were incubated with 500 microM L-glutamate, 1 mM PDC, or both. After 72 hours, the tissues were stained for acetylcholinesterase (AChE), and the ventral horn AChE-positive neurons (VHANs) analyzed using morphometry. Neither L-glutamate nor PDC affected AChE staining, but in combination they produced markedly reduced AChE staining in the dorsal horn and a significant decrease in the number of VHANs (especially the smaller VHANs) as compared with the control. Moreover, treatment with 200 microM PDC for 2 weeks preferentially affected the smaller VHANs. The neurotoxicity of L-glutamate plus PDC was blocked by the N-methyl-D-aspartate (NMDA) antagonist 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). Results suggest that glutamate uptake system has an important protective function in the aggravation of acute neuronal damage.
Okazaki
S
S
First Department of Internal Medicine, School of Medicine, University of Tokushima, Japan.
Nishida
Y
Y
Kawai
H
H
Saito
S
S
D000110:Acetylcholinesterase / Q000032:analysis; D000818:Animals; D003470:Culture Media; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D003470:Culture Media; D003998:Dicarboxylic Acids; D009498:Neurotoxins; D014179:Neurotransmitter Uptake Inhibitors; D011759:Pyrrolidines; D018698:Glutamic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid; D000110:Acetylcholinesterase