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

Abstract

Aims: Hydrogen sulfide (H₂S), a novel gaseous mediator, has been recognized to protect neurons from overexcitation 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, 5.6 mg/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 μM) 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.