Estudio de los mecanismos moleculares y celulares implicados en los efectos citotóxicos inducidos por metadona y lactacistina

Abstract

Neurodegenerative diseases and addictive disorders are the most common pathologies in the developed countries. Both, involve a high cost to the public health. The aim of this thesis is evaluate the molecular pathways molecular and cellular mechanisms involved in methadone and lactacystin-induced cell death. Lactacystin is a proteasome inhibitor which appears to reproduce many of the important behavioral, imaging, pathological and biochemical features of Parkinson's disease. However, the mechanisms involved in the lactacystin-induced, mitochondria-mediated apoptotic pathway remain poorly defined. To clarify this mechanism we used lactacystin as a specific inhibitor of the 20S proteasome in the dopaminergic neuroblastoma cell line SH-SY5Y, and analyzed the role of reactive oxygen species in these pathways. The results show lactacystin triggered a concentration-dependent increase in cell death mediated by the mitochondrial apoptotic pathway, and induced a change in mitochondrial membrane permeability accompanied by cytochrome c release. The participation of Bax protein was more critical than the formation of the permeability transition pore in mitochondria. This translocation was mediated by ROS due to use different antioxidant prevent the translocation of Bax to mitochondria.