title: Pre- and post-treatment with pirlindole and dehydropirlindole protects cultured brain cells against nitric oxide-induced death.
abstract: We have previously shown that pirlindole and dehydropirlindole, two monoamine oxidase type-A inhibitors, protect cultured brain cells against iron-induced toxicity through a mechanism unrelated to monoamine oxidase type-A inhibition. The current study was performed to test whether the protective effect of pirlindole and dehydropirlindole could be extended to a nitric oxide (NO)-induced insult. A comparison with other monoamine oxidase inhibitors (brofaromine, moclobemide and deprenyl) and with trolox was made. In a first series of experiments, rat hippocampal or cortical cultured cells were exposed to a drug for 3 h, then 5 microM sodium nitroprusside, a NO donor, was added and the incubation was continued for 16 h. Cell survival assessment showed that pirlindole, dehydropirlindole and trolox significantly protected cultures against NO-induced toxicity in a concentration-dependent manner with respective EC(50)'s of 7, 3 and 17 microM. Similarly, pirlindole, dehydropirlindole or trolox, at a concentration of 50 microM, significantly decreased both intracellular peroxide production and lipoperoxidation. Other drugs were ineffective. In a post-hoc treatment protocol (3- or 6-h pre-incubation in the presence of sodium nitroprusside, then addition of one of the above mentioned compounds), only pirlindole and dehydropirlindole significantly improved cell survival in a concentration-dependent manner with respective EC(50)'s of 9 and 4 microM. The maximal protection in terms of cell survival was 90% and 78% after 3 and 6 h, respectively. They also reduced the production of both lipoperoxides and endoperoxides. Our results show that pirlindole and dehydropirlindole protect neurons against NO-induced toxicity at pharmacologically relevant concentrations. Moreover, their protective effect is still apparent when they are applied after the start of the insult. Therefore, our preclinical study suggests a new strategy that may be efficient to reduce NO-induced damage in the central nervous system.
authors.affiliation: Center for Cellular and Molecular Neurobiology, Laboratory of Pharmacology, Institute of Pathology B23, University of Liège, B-4000 Sart-Tilman- 1, Liège, Belgium.
authors.forename: André
authors.initials: A
authors.lastname: Boland
authors.forename: Jean
authors.initials: J
authors.lastname: Gérardy
authors.forename: Danielle
authors.initials: D
authors.lastname: Mossay
authors.forename: Vincent
authors.initials: V
authors.lastname: Seutin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology*; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D015227:Lipid Peroxidation; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D010545:Peroxides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000975:Antioxidants; D002227:Carbazoles; D002839:Chromans; D008996:Monoamine Oxidase Inhibitors; D010545:Peroxides; D009569:Nitric Oxide; C067315:3,3a-dehydropyrazidol; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; C009830:pirlindole