TY - JOUR
T1 - Differences in the neurotoxicity profile induced by ATP and ATPγS in cultured cerebellar granule neurons
AU - Amadio, Susanna
AU - D'Ambrosi, Nadia
AU - Trincavelli, Maria Letizia
AU - Tuscano, Daniela
AU - Sancesario, Giuseppe
AU - Bernardi, Giorgio
AU - Martini, Claudia
AU - Volonté, Cinzia
PY - 2005/10
Y1 - 2005/10
N2 - Extracellular ATP and P2 receptors may play a crucial role in the neurodegeneration of the CNS. Here, we investigated in neuronal cerebellar granule cultures the biological effect of the quite stable P2 receptor agonist ATPγS and compare it to the cytotoxic action of ATP. Time-course experiments showed that 500 μM ATPγS causes 50-100% cell death in 15-24 h. As proved by pharmacological means, ATPγS toxicity apparently involves neither indirect activation of NMDA receptors, nor ectonucleotidase activities, nor nucleoside transport and intracellular purine metabolism. Moreover, ATPγS induces detrimental effects without modifying the expression of several P2X and P2Y receptor proteins. Cell death instead occurs after extracellular release of the cytosolic enzyme lactic dehydrogenase and inhibition of the overall activity of the intracellular dehydrogenases. Moreover, ATPγS causes transient outflow of cytochrome c from mitochondria (maximal 2.5-fold stimulation in 4 h), it raises the intracellular reactive oxygen species (about four-fold in 1 h) and cAMP levels (about 40% in 15 min-4 h). Among several P2 receptor antagonists, only pyridoxal-phosphate-6-azophenyl- 2′,4′-disulphonic acid 4-sodium promotes 80-100% neuroprotection.
AB - Extracellular ATP and P2 receptors may play a crucial role in the neurodegeneration of the CNS. Here, we investigated in neuronal cerebellar granule cultures the biological effect of the quite stable P2 receptor agonist ATPγS and compare it to the cytotoxic action of ATP. Time-course experiments showed that 500 μM ATPγS causes 50-100% cell death in 15-24 h. As proved by pharmacological means, ATPγS toxicity apparently involves neither indirect activation of NMDA receptors, nor ectonucleotidase activities, nor nucleoside transport and intracellular purine metabolism. Moreover, ATPγS induces detrimental effects without modifying the expression of several P2X and P2Y receptor proteins. Cell death instead occurs after extracellular release of the cytosolic enzyme lactic dehydrogenase and inhibition of the overall activity of the intracellular dehydrogenases. Moreover, ATPγS causes transient outflow of cytochrome c from mitochondria (maximal 2.5-fold stimulation in 4 h), it raises the intracellular reactive oxygen species (about four-fold in 1 h) and cAMP levels (about 40% in 15 min-4 h). Among several P2 receptor antagonists, only pyridoxal-phosphate-6-azophenyl- 2′,4′-disulphonic acid 4-sodium promotes 80-100% neuroprotection.
KW - Apoptosis
KW - cAMP
KW - Cytochrome c
KW - Extracellular nucleotides
KW - Necrosis
KW - Reactive oxygen species
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U2 - 10.1016/j.neuint.2005.05.008
DO - 10.1016/j.neuint.2005.05.008
M3 - Article
C2 - 16019114
AN - SCOPUS:22044441623
VL - 47
SP - 334
EP - 342
JO - Neurochemistry International
JF - Neurochemistry International
SN - 0197-0186
IS - 5
ER -