The Neuroprotection of Hydrogen Sulfide Against MPTP-Induced Dopaminergic Neuron Degeneration Involves Uncoupling Protein 2 Rather Than ATP-Sensitive Potassium Channels

Aims: Hydrogen sulfide (H2S), a novel gaseous mediator, has been recognized to protect neurons from over-excitation by enhancing the activity of the adenosine triphosphate-sensitive potassium (K-ATP) channel. However, no direct evidence supports that the K-ATP channel contributes to the neuroprotective effect of H2S in neurodegeneration. Herein, wild-type and Kir6.2 knockout (Kir6.2(-/-)) mice were used to establish the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD) so as to investigate the involvement of K-ATP channels in the neuroprotection of H2S. Results: Systemic administration of sodium hydrosulfide (NaHS) (an H2S donor, 5.6mg/kg/day) for 7 days rescued MPTP-induced loss of dopaminergic (DA) neurons in substantia nigra compacta of both Kir6.2(+/+) and Kir6.2(-/-) mice. Consistently, NaHS (100 mu M) protected primary mesencephalic neurons against 1-methyl-4-phenylpyridinium (MPP+)-induced cytotoxicity in both genotypes. We further found that deficiency of mitochondrial uncoupling protein 2 (UCP2), which reduces reactive oxygen species (ROS) production and functions as upstream to the K-ATP channel in determining vulnerability of DA neurons, abolished the protective effects of H2S against either DA neuron degeneration in the PD mouse model or MPP+-induced injury in primary mesencephalic neurons. Rationally, UCP2 evokes mild uncoupling, which in turn diminishes ROS accumulation in DA neurons. Furthermore, H2S exerted neuroprotective effect via enhancing UCP2-mediated antioxidation and subsequently suppressing ROS-triggered endoplasmic reticulum stress as well as ultimately inhibiting caspase 12-induced neuronal apoptosis. Innovation and Conclusion: H2S protects DA neurons against degeneration in a UCP2 rather than Kir6.2/K-ATP channel-dependent mechanism, which will give us an insight into the potential of H2S in terms of opening up new therapeutic avenues for PD. Antioxid. Redox Signal. 17, 849-859.