Zebrafish as a model to study nitrite neuroprotection in Parkinson's disease

Nitrite oral administration has been proposed as therapeutic avenue in cardiac ischemia due to its ability to decrease mitochondrial production of reactive oxygen species (ROS) via transient inhibition of respiratory complex-I (C-I). Augmented ROS and mitochondrial C-I dysfunction are also hallmarks of Parkinson’s disease (PD). We explored the neuroprotective capacity of nitrite administration in cellular and animal models of PD. In dopaminergic neurons, nitrite administration ameliorates MPP+-induced cell death. Bioenergetics analysis indicates that MPP+ perturbs mitochondrial respiration and the defect is reversed by nitrite treatment. In zebrafish embryos, nitrite pre-treatment ameliorates the reduced locomotor activity after MPP+ exposure, improves viability, and reduces DA neuron loss in the brain. We observed significant protection in the toxin 6-hydroxydopamine (6-OHDA) rat model of PD. Protection occurred both 24 hours before treatment with 6-OHDA and when nitrite is administered for 3 weeks through drinking water, starting one week after the generation of the striatal lesion with the 6-OHDA, indicating that nitrite administration may halt the disease progression after its beginning. We showed that nitrite ameliorates mitochondrial respiratory profile in primary fibroblasts from LRRK2 genetic PD cases by modifying the functional activity of mitochondrial C-I. Altogether suggesting that nitrite administration might constitute an amenable neuroprotective strategy in PD.