Suramin prevents cerebellar granule cell-death induced by dequalinium.
In this study, we demonstrated that an anticancer drug, dequalinium, a bisquaternary ammonium compound, is a potent neurotoxicant with IC(50) of 0.46 microM on the cultured cerebellar granule neurons. Its selective neurotoxicity revealed by 100-fold more toxic than the other two analogs, pancuronium and vecuronium. The mechanisms underlying dequalinium (DQ)-induced neurotoxicity were explored and found to be associated with decreased mitochondrial membrane potential, increased free radical production and ATP depletion. Suramin (a nonselective purinergic P(2) receptor antagonist and an anticancer drug) but not the glutamate receptor antagonists, MK-801, NBQX (1,2,3,4 tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium), and DNQX (6,7-dinitroquinoxaline-2,3-dione) significantly prevents the DQ-induced neurotoxicity. By means of microfluorometric image-processing technique using the fluorescent probes, fluorescein diacetate/propidium iodide and Hoechst 33258, respectively, we showed that 1 microM DQ for 24 h induced about 53.5% of apoptosis and 37.5% of necrosis. All of these effects of DQ can be completely prevented by suramin. From these results, we conclude that DQ-induced neurotoxicity was not mediated by glutamate receptor, but by increasing free radical productions and cell energy depletion. Suramin with its beneficial antagonistic effects on DQ-induced neurotoxicity may provide an effective approach for neurodegeneration.
Chan
C F
CF
College of Medicine, Institute of Toxicology, National Taiwan University, Taipei.
Lin-Shiau
S Y
SY
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology*; D003868:Dequalinium / Q000494:pharmacology*; D004553:Electric Conductivity; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000502:physiology; D018048:Receptors, Purinergic P2 / Q000502:physiology; D013498:Suramin / Q000494:pharmacology*
D009498:Neurotoxins; D015221:Potassium Channels; D017470:Receptors, Glutamate; D018048:Receptors, Purinergic P2; D013498:Suramin; D000255:Adenosine Triphosphate; D003868:Dequalinium