Effects of U-83836E on glutamate-induced neurotoxicity in dissociated rat cerebellar granule cells.
The effects of the lazaroid compound U-83836E on the glutamate-induced production of reactive oxygen species (ROS) were studied in dissociated rat cerebellar granule cells by flow cytometry. U-83836E completely inhibited ROS production with an estimated IC50 value of 21.7 +/- 9.1 nM. However, U-83836E did not inhibit the glutamate-evoked decrease in mitochondrial membrane potential (MMP). Nevertheless, U-83836E (10 nM to 10 microM) prevented cell death induced by 10 mM of glutamate. At concentrations above 10 microM, U-83836E by itself showed slight cytotoxicity, which was significant at a 100 microM concentration. U-83836E (25 to 200 microM) also increased the cytosolic calcium levels in a concentration-dependent manner. Our results indicate that the cytotoxic effects found at micromolar concentrations of U-83836E could be explained by an increase in [Ca2+]i. Finally, since U-83836E did not prevent the MMP decrease evoked by glutamate, it is suggested that antioxidant pharmacotherapy would not be sufficient to block the neurotoxic effects of glutamate.
Sureda
F X
FX
Facultat de Farmàcia, Nucli Universitari de Pedralbes, Barcelona, 08028, Spain.
Gabriel
C
C
Pubill
D
D
Pallás
M
M
Escubedo
E
E
Camarasa
J
J
Camins
A
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity*; D008564:Membrane Potentials / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D002839:Chromans; D018696:Neuroprotective Agents; D010879:Piperazines; D017382:Reactive Oxygen Species; C066382:U 78517F; D018698:Glutamic Acid; D002118:Calcium