P2 receptor antagonist PPADS confers neuroprotection against glutamate/NMDA toxicity.
The present study investigated the role of pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid tetrasodium salt (PPADS), a P2 receptor antagonist, in protecting mouse cerebellar granule neurons (CGNs) against glutamate/NMDA-induced neuronal death. Neurotoxicity caused by 50 microM glutamate or 200 microM NMDA was significantly reduced in CGNs treated with PPADS. Such neuroprotection was in a time- and dose-dependent manner. The possibility that PPADS may block glutamate/NMDA-mediated intracellular Ca2+ influx to CGNs was investigated using temperature-controlled platereader measurements of fluorescence intensity of CGNs loaded with Ca2+-sensitive fluorescent dye Fluo-4AM. Interestingly, the rapid increase of calcium influx following glutamate/NMDA treatment was not significantly affected by prior treatment with PPADS. In contrast, MK801, a specific NMDA receptor antagonist, completely blocked intracellular Ca2+ influx. Taken together, these data suggest that inhibition of the P2 receptor may directly modulate NMDA receptor-mediated neurotoxicity through a Ca2+-independent mechanism.
Lin
Yanpeng
Y
Department of Clinical Neurological Sciences, The No 252 Hospital of P.L.A., 81 Huayuan Street, Baoding City 071000, Hebei Province, PR China.
Desbois
Angele
A
Jiang
Susan
S
Hou
Sheng T
ST
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000633:toxicity*; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000502:physiology
D018696:Neuroprotective Agents; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D018698:Glutamic Acid; D011732:Pyridoxal Phosphate; D016202:N-Methylaspartate