• Archives of Pharmacal Research
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• v.20 no.1
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• pp.7-12
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• 1997

Glutamate uptake inhibitor, L-trans-pyrrolidine-2, 4-dicarboxylate (PDC, $20{\mu}M$) elevated basal and N-methyl-D-aspartate (NMDA, $100{\mu}M$)-induced extracellular glutamate accumulation, while it did not augment kainate $100{\mu}M$-induced glutamate accumulation in cultured cerebellar granule neurons. However, pretreatment with PDC for 1 h significantly reduced NMDA-induced glutamate accumulation, but did not affect kainate-induced response. Pretreatment with glutamate $(5{\mu}M)$ for 1 h also reduced NMDA-induced glutamate accumulation, but did not kainate-induced response. Upon a brief application (3-10 min), PDC did neither induce elevation of intracellular calcium concentration $([Ca^{2+}]_i)$ nor modulate NMDA-indLiced $[Ca^{2+}]_1$ elevation. Pretreatment with PDC for 1 h reduced NMDA-induced $[Ca^{2+}]_1$ elevation, but it did not reduce kainate-induced $[Ca^{2+}]_1$ elevation. These results suggest that glutamate concentration in synaptic clefts of neurana cells is increased by prolonged exposure (1 h) of the cells to PDC, and the accumulated glutamate subsequently induces selective desensitization of NMDA receptor.

• International Journal of Oral Biology
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• v.34 no.2
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• pp.97-103
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• 2009

L-trans-pyrrolidine-2,4-dicarboxylate (PDC) is a potent inhibitor of glutamate transporters. In our current study, we investigated whether the neuronal death induced by PDC involves mechanisms other than excitotoxicity in mixed mouse cortical cultures. Cortical cultures at 13-14 days in vitro were used and cell death was assessed by measuring the lactate dehydrogenase efflux into bathing media. Glutamate and PDC both induced neuronal death in a concentration-dependent manner but the neurotoxic effects of glutamate were found to be more potent than those of PDC. Treatment with 10, 100 and 200 ${\mu}$M PDC equally potentiated 50 ${\mu}$M glutamate-induced neuronal death. The neuronal death induced by 75 ${\mu}$M glutamate was almost abolished by treatment with the NMDA antagonists, MK-801 and AP-5, but was unaffected by NBQX (an AMPA antagonist), trolox (antioxidant), BDNF or ZVAD-FMK (a pan-caspase inhibitor). However, the neuronal death induced by 200 ${\mu}$M PDC was partially but significantly attenuated by single treatments with MK-801, AP-5, trolox, BDNF or ZVAD-FMK but not NBQX. Combined treatments with MK-801 plus trolox, MK-801 plus ZVAD-FMK or MK-801 plus BDNF almost abolished neuronal death, whereas combined treatments with trolox plus ZVADFMK, trolox plus BDNF or ZVAD-FMK plus BDNF did not enhance the inhibitory action of any single treatment with these drugs. These results demonstrate that the neuronal death induced by PDC involves not only in the excitotoxicity induced by the accumulation of glutamate but also the oxidative stress induced by free radical generation. This suggests that apoptotic neuronal death plays a role in PDCinduced oxidative neuronal injury.