Pirlindole and dehydropirlindole protect rat cultured neuronal cells against oxidative stress-induced cell death through a mechanism unrelated to MAO-A inhibition
[en] 1 It has been shown that the MAO (monoamine oxidase)-B inhibitor deprenyl (DPR, selegiline) protects some cell types against oxidative stress. By decreasing H2O2 production, MAO-A inhibitors could also reduce oxidative stress. 2 This study reports the effect of the MAO-A inhibitors, pirlindole (PIR), dehydropirlindole (DHP), brofaromine (BRO) and moclobemide (MCL) on primary-cultured brain cells exposed to iron-mediated toxicity. A comparison with trolox (TRO), a hydrosoluble vitamin-E analogue that protects against such an induced stress, was performed. 3 Rat hippocampal or cortical cultured cells were exposed either to 2 mum FeSO4 alone or in the presence of PIR, DHP, BRO, DPR, MCL or TRO. Cell survival (lactate-dehydrogenase measurements, 16 h incubation), intracellular peroxide production (DCF-fluorescence. I h incubation), lipoperoxidation (TBARS-fluorescence, 6 h incubation) and mitochondrial function (MTT-test, 16 h incubation) were assessed. 4 PIR, DHP and TRO significantly protected cultures (P<0.05) against Fe2+-induced toxicity in a concentration-dependent manner. The EC50s of these compounds were 6, 12 and 19 muM, respectively, in hippocampal cells. For cortical cell cultures incubated in the presence of iron and PIR or DHP, EC50s were 5 and 6 muM respectively. All Hill coefficients were close to unity. BRO, MCL and DPR were not protective in any type of culture. The IC50s for the inhibition of MAO-A were 2, 2 and 0.2 muM for PIR, DHP and BRO, respectively. PIR, DHP and TRO, but not DPR, induced a significant decrease in both intracellular peroxide production and lipoperoxidation. They also improved mitochondrial function. 5 These experiments show that PIR and DHP can protect hippocampal and cortical neurons against oxidative stress at pharmacologically relevant concentrations. This protective effect seems unrelated to inhibition of MAO-A, but possibly involves free radical scavenging.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Boland, André ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Gerardy, J.
Breeur, Danielle ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Gabriel, Danielle ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Seutin, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie
Language :
English
Title :
Pirlindole and dehydropirlindole protect rat cultured neuronal cells against oxidative stress-induced cell death through a mechanism unrelated to MAO-A inhibition
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