Resumen de Efecto neuroprotector y antipoptotico del compuesto pf9601n, un inhibidor de la mao-b de tipo no anfetamínico, en diferentes modelos celulares de enfermedad de parkinson
PF9601N[N-(2-propynyl) 2-(5-bensyloxyindol) methylamine] is a non-amphetamine type MAO-B inhibitor that has shown neuroprotective properties in vivo using different experimental models of Parkinson's disease. The mechanisms underlying its neuroprotective effects are poorly understood, but appear to be independent of MAO-B inhibition. We have studied its neuroprotective properties using the human SH-SY5Y dopaminergic cell line exposed to-methyl-4-phenylpyridinium(MPP+), a cellular model of Parkinson's disease. PF9601N pretreatment significantly reduced MPP+-induced cell death as well as the activation of one of the main executioner caspasas, caspase-3 MPP+ induced stabilization of transcription factor p53, its nuclear translocation and transactivation of p53 response elements, where as PF9601N prevented this increase, thus reducing its transcriptional activity. Additional results show that p53 may mediate its pro-apoptotic actions through caspase-2 under our experimental conditions. According to our data, PUMA- may also contribute to the p53-induced cell death. Since PF9601N significantly reduced MPP+-induced caspase-2 activity and PUMA-levels, this reduction may lead to increased cell survival. Thus, PF9601N is a novel molecule with an apparently novel mechanism of action which has a promising potential as a therapeutic agent in the treatment of neurodegenerative diseases. Additionally, Endoplasmic reticulum (ER) stress has recently been proposes as one of the factors contributing to apoptotic cell death in Parkinson's disease (PD). Although MAO-B inhibitors have been widely used in PD treatment, their effectiveness against ER stress has not been fully determined. Therefore, we have studied the potential usefulness of PF9601N, a non-amphetamine-like MAO-B inhibitor, in preventing cell death in a cell culture model of ER stress. Exposure to the ER stressor brefeldin A led to the activation of the unfolded protein response (UPR), as assessed by XBP1 splicing and elF2-phosphorylation, resulting in the expression of the URP-induced apoptotic mediator GADD153/CHOP. PF9601N pretreatment blocked brefeldin A-induced XBP1 splicing and partially prevented the phosphorylation of elF-2-, thus preventing the expression of GADD153/CHOP. Brefeldin A exposure also induced the activation of the initiator caspases, caspase-2 and caspase-9 , which was significantly prevented in cells pretreated with PF9601N. Both CHOP expression and initiator caspase activity are reported to lead to apoptosis in ER stress paradigms. In the regard, brefeldin-A-induced apoptotic cell death was prominently reduced in PF9601N-treated cells. In summary, our data suggests that PF9601N is able to block the responses elicited by ER stress, preventing apoptotic cell death in brefeldin A-treated cells, independently of its MAO-B inhibitory capability.
