Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, People's Republic of China.
Antioxid Redox Signal. 2012 Sep 15;17(6):849-59. doi: 10.1089/ars.2011.4507. Epub 2012 Apr 20.
Hydrogen sulfide (H(2)S), 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 H(2)S 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 H(2)S.
Systemic administration of sodium hydrosulfide (NaHS) (an H(2)S 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 H(2)S 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, H(2)S 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.
H(2)S 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 H(2)S in terms of opening up new therapeutic avenues for PD.
硫化氢（H₂S）作为一种新型气体递质，已被证实可通过增强三磷酸腺苷敏感性钾（K-ATP）通道的活性来保护神经元免受过度兴奋。然而，尚无直接证据表明 K-ATP 通道有助于 H₂S 在神经退行性变中的神经保护作用。在此，我们使用野生型和 Kir6.2 敲除（Kir6.2（-/-））小鼠建立 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病（PD）小鼠模型，以研究 K-ATP 通道是否参与 H₂S 的神经保护作用。
7 天内系统给予硫氢化钠（NaHS）（H₂S 供体，5.6mg/kg/天）可挽救 Kir6.2（+/+）和 Kir6.2（-/-）小鼠黑质致密部多巴胺能神经元因 MPTP 诱导的丢失。同样，NaHS（100μM）可保护原代中脑神经元免受两种基因型中 1-甲基-4-苯基吡啶（MPP(+））诱导的细胞毒性。我们进一步发现，解偶联蛋白 2（UCP2）的缺失减少了活性氧（ROS）的产生，作为决定多巴胺神经元易感性的 K-ATP 通道的上游，消除了 H₂S 对 PD 小鼠模型中多巴胺神经元变性或 MPP(+）诱导的原代中脑神经元损伤的保护作用。合理地，UCP2 引起轻度解偶联，从而减少多巴胺神经元中 ROS 的积累。此外，H₂S 通过增强 UCP2 介导的抗氧化作用发挥神经保护作用，进而抑制 ROS 触发的内质网应激，最终抑制半胱氨酸天冬氨酸蛋白酶 12 诱导的神经元凋亡。
H₂S 通过 UCP2 而非 Kir6.2/K-ATP 通道依赖性机制保护多巴胺神经元免受变性，这将使我们深入了解 H₂S 在 PD 治疗方面的潜力。
