Guanosine Protects Striatal Slices Against 6-OHDA-Induced Oxidative Damage, Mitochondrial Dysfunction, and ATP Depletion

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta which induces severe motor symptoms. 6-OHDA is a neurotoxin widely used in PD animal models due to its high affinity by dopamine transporter, its rapid non-enzymatic auto-oxidation which generates reactive oxygen species (ROS), oxidative stress, and for induced mitochondrial dysfunction. We previously reported an in vitro protocol of 6-OHDA-induced toxicity in brain regions slices, as a simple and sensitive assay to screen for protective compounds related to PD. Guanosine (GUO), a guanine-based purine nucleoside, is a neuroprotective molecule that is showing promising effects as an antiparkinsonian agent. To investigate the mechanisms involved on GUO-induced neuroprotection, slices of cortex, striatum, and hippocampus were incubated with GUO in the presence of 6-OHDA (100μM). 6-OHDA promoted a decrease in cellular viability and increased ROS generation in all brain regions. Disruption of mitochondrial potential, depletion in intracellular ATP levels, and increase in cell membrane permeabilization were evidenced in striatal slices. GUO prevented the increase in ROS generation, disruption in mitochondrial potential, and depletion of intracellular ATP induced by 6-OHDA in striatal slices. In conclusion, GUO was effective to prevent oxidative events before cell damage, such as mitochondrial disruption, intracellular ATP levels depletion, and ROS generation in striatal slices subjected to in vitro 6-OHDA-induced toxicity.