Antioxidant properties of the triaminopyridine, flupirtine.
Flupirtine is a triaminopyridine-derived centrally acting analgesic, which interacts with mechanisms of noradrenergic pain modulation. Recently, it has been found to display neuroprotective effects in various models of excitotoxic cell damage, global and focal ischemia. Although this profile suggests that flupirtine acts as an antagonist of the N-methyl-D-aspartate (NMDA) and glutamate-triggered Ca2+ channel, there is no direct interaction with the receptor. In this paper, we examined whether flupirtine can act as an antioxidant and prevent free radical-mediated structural damage. Flupirtine at 5-30 microM inhibited ascorbate/ Fe2+ (1-10 microM)-stimulated formation of thiobarbituric reactive substances, an indicator of lipid peroxidation, in rat brain mitochondria. Interestingly, we found an increasing effectiveness of the drug at higher iron concentrations. Additionally, higher concentrations of flupirtine also provided protection against protein oxidation, as demonstrated by a decrease in protein carbonyls formed after treatment of rat brain homogenates with ascorbate/Fe2+. In PC12 cell culture, flupirtine at 10-100 microM was able to attenuate H2O2-stimulated cell death and improve the survival by 33%.
Gassen
M
M
Department of Pharmacology, Eve Topf Center, Bruce Rappaport Family Research Institute, Faculty of Medicine, Technion, Haifa, Israel.
Pergande
G
G
Youdim
M B
MB
D000631:Aminopyridines / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley
D000631:Aminopyridines; D000700:Analgesics; D000975:Antioxidants; D018696:Neuroprotective Agents; D006861:Hydrogen Peroxide; C034161:flupirtine