Site of action of suramin and reactive blue 2 in preventing neuronal death induced by dequalinium.
Dequalinium (DQ, an anticancer drug) is a potent neurotoxicant in the cultured developing cerebellar granule neurons (CGNs) with an IC(50) of 1.31. M after 24 hr incubation. By utilizing fluorometric technique, we found that DQ initially induced apoptosis and then necrosis associated with a marked decrease in ATP contents. The purinergic P(2) receptor antagonists (suramin, and reactive blue 2) prevented DQ-cytotoxicity, although glutamate ionotropic receptor antagonists (MK 801 and NBQX) could not. Furthermore, we quantitatively determined a reduction of mitochondrial membrane potential and an increase of free radical production induced by DQ. Suramin abolished these detrimental events of DQ. This suggests that neuronal death induced by DQ is mediated, at least in part, through a signaling pathway of free radical production-mitochondrial dysfunction. Further evidence supporting this contention is that CGN progressively became more sensitive to both DQ-induced cytotoxicity and reduced mitochondrial membrane potential. This implies that neuronal mitochondria are apparently one of the target sites for DQ and suramin and directly or indirectly induce neurotoxicity and neuroprotection respectively. The alteration in mitochondrial membrane potential during neuronal maturation may be one of the determinants accounting for the increased susceptibility to neurotoxicants such as DQ.
Chan
C F
CF
Institute of Toxicology, National Taiwan University, College of Medicine, Taipei, Taiwan.
Lin-Shiau
S Y
SY
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003868:Dequalinium / Q000633:toxicity*; D005470:Fluorometry; D008928:Mitochondria / Q000187:drug effects; D009336:Necrosis; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D013498:Suramin / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D058919:Purinergic P2 Receptor Antagonists; D014227:Triazines; C012842:Cibacron Blue F 3GA; D013498:Suramin; D000255:Adenosine Triphosphate; D003868:Dequalinium