Estudio de las rutas celulares antiapoptóticas moduladas por minociclina y piruvato en su acción neuroprotectora

Zusammenfassung

Introduction: Current Challenges in Pharmacology focuses upon the search for new potential drugs against neurodegenerative diseases. The current goal is to avoid the appearance of symptoms, as well as to stop the progression of the neuropathology. Objective: The bulk of our work is directed towards elucidating the pathways involved in excitotoxicity induced by 6-hydroxydopamine in rat cerebellar granular cells, and the neuroprotective effects of minocycline and pyruvate. Results: Minocycline exerts its neuroprotective action in cell cultures challenged with NMDA by modulating the mitochondrial function. Minocycline induces mitochondrial collapse, preventing the uptake of Ca2+ inside the organelle. This tetracycline also inhibits mitochondrial respiration in a manner that is much more pronounced when malate-glutamate is used as a substrate, perhaps due to selective action on Complex I. Furthermore, minocycline has antioxidant effects due to its ability to prevent the generation of reactive oxygen species (ROS) induced by the addition of NMDA to cells, and in isolated mitochondria exposed to high Ca2+ concentrations. While minocycline provides a direct antioxidant effect against DPPH (2,2-Diphenyl-1-Picrylhydrazyl ) radicals and ferrum cations, our data indicate mitochondrial involvement as a consequence of the depolarization of the organelle. Pyruvate protects neuronal cultures against cell death induced by 6-hydroxydopamine. Our results show, for the first time in the literature, the participation of the PI3K-Akt intracellular survival pathway and the over-expression of glutathione peroxidase as a consequence of the cytoprotective effects mediated by this alpha-ketoacid. Conclusion: The heterogeneity of mechanisms and pathways modulated by these two drugs in their role as neuroprotective agents show a wide range of plausible therapeutic approaches available. However, it is necessary to elucidate the suitability of these two drugs for each distinct neurodegenerative process neurological disorder.