RESUMEN
Valproic acid (VPA)-a short branched chain fatty acid (BCFA), is widely recognized as an anticonvulsant and a mood-stabilizing drug, but various adverse effects of VPA have also been investigated. However, the impact of BCFAs aggregation on brain cells, in the pathogenesis of neurodegeneration remains elusive. The objective of this study is to understand the cellular mechanisms underlying VPA-induced neuronal cell death mediated by oxidative stress, and the neuroprotective role of exogenous melatonin treatment on VPA-induced cell death. Neurotoxicity of VPA and protective role exerted by melatonin were assessed in vitro in SH-SY5Y cells and in vivo in the cerebral cortex and cerebellum regions of Wistar rat brain. The results show that melatonin pre-treatment protects the cells from VPA-induced toxicity by exerting an anti-apoptotic and anti-inflammatory effect by regulating apoptotic proteins and pro-inflammatory cytokines. The findings of the present study emphasize novel insights of melatonin as a supplement for the prevention and treatment of neuronal dysfunction induced by VPA.
Asunto(s)
Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Ácidos Grasos/metabolismo , Melatonina/farmacología , Neuronas/efectos de los fármacos , Síndromes de Neurotoxicidad/prevención & control , Animales , Conducta Animal/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Cerebelo/patología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Humanos , Neuronas/metabolismo , Neuronas/patología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Ácido Valproico/metabolismo , Ácido Valproico/toxicidadRESUMEN
Oxaliplatin (Oxa) treatment to SH-SY5Y human neuroblastoma cells has been shown by previous studies to induce oxidative stress, which in turn modulates intracellular signaling cascades resulting in cell death. While this phenomenon of Oxa-induced neurotoxicity is known, the underlying mechanisms involved in this cell death cascade must be clarified. Moreover, there is still little known regarding the roles of neuronal mitochondria and cytosolic compartments in mediating Oxa-induced neurotoxicity. With a better grasp of the mechanisms driving neurotoxicity in Oxa-treated SH-SY5Y cells, we can then identify certain pathways to target in protecting against neurotoxic cell damage. Therefore, the purpose of this study was to determine whether one such agent, melatonin (Mel), could confer protection against Oxa-induced neurotoxicity in SH-SY5Y cells. Results from the present study found Oxa to significantly reduce SH-SY5Y cell viability in a dose-dependent manner. Alternatively, we found Mel pre-treatment to SH-SY5Y cells to attenuate Oxa-induced toxicity, resulting in a markedly increased cell viability. Mel exerted its protective effects by regulating reactive oxygen species (ROS) production and reducing superoxide radicals inside Oxa-exposed. In addition, we observed pre-treatment with Mel to rescue Oxa-treated cells by protecting mitochondria. As Oxa-treatment alone decreases mitochondrial membrane potential (Δψm), resulting in an altered Bcl-2/Bax ratio and release of sequestered cytochrome c, so Mel was shown to inhibit these pathways. Mel was also found to inhibit proteolytic activation of caspase 3, inactivation of Poly (ADP Ribose) polymerase, and DNA damage, thereby allowing SH-SY5Y cells to resist apoptotic cell death. Collectively, our results suggest a role for melatonin in reducing Oxa induced neurotoxicity. Further studies exploring melatonin's protective effects may prove successful in eliciting pathways to further alter the neurotoxic pathways of platinum compounds in cancer treatment.