Pirlindole and dehydropirlindole protect rat cultured neuronal cells against oxidative stress-induced cell death through a mechanism unrelated to MAO-A inhibition.
It has been shown that the MAO (monoamine oxidase)-B inhibitor deprenyl (DPR, selegiline) protects some cell types against oxidative stress. By decreasing H(2)O(2) production, MAO-A inhibitors could also reduce oxidative stress. 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. Rat hippocampal or cortical cultured cells were exposed either to 2 microM FeSO(4) 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, 1 h incubation), lipoperoxidation (TBARS-fluorescence, 6 h incubation) and mitochondrial function (MTT-test, 16 h incubation) were assessed. PIR, DHP and TRO significantly protected cultures (P<0.05) against Fe(2+)-induced toxicity in a concentration-dependent manner. The EC(50s) of these compounds were 6, 12 and 19 microM, respectively, in hippocampal cells. For cortical cell cultures incubated in the presence of iron and PIR or DHP, EC(50s) were 5 and 6 microM respectively. All Hill coefficients were close to unity. BRO, MCL and DPR were not protective in any type of culture. The IC(50s) for the inhibition of MAO-A were 2, 2 and 0.2 microM 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. 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.
Boland
A
A
Research Center for Cellular and Molecular Neurobiology (CNCM), Laboratory of Pharmacology, Institute of Pathology B23, University of Liège, B-4000 Sart-Tilman Liège 1, Belgium.
Gérardy
J
J
Mossay
D
D
Delapierre
D
D
Seutin
V
V
D000818:Animals; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D002227:Carbazoles; D008996:Monoamine Oxidase Inhibitors; C067315:3,3a-dehydropyrazidol; D008995:Monoamine Oxidase; C009830:pirlindole