Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/18426
Title: Role of hydrogen sulfide in the pathogenesis of Parkinson's disease
Authors: HU LIFANG
Keywords: hydrogen sulfide, parkinson's disease, neuroprotection, anti-neuroinflammation, dopaminergic neuron, oxidative stress
Issue Date: 17-Mar-2010
Source: HU LIFANG (2010-03-17). Role of hydrogen sulfide in the pathogenesis of Parkinson's disease. ScholarBank@NUS Repository.
Abstract: H2S is a novel endogenous gaseous mediator alongside nitric oxide and carbon monoxide. It serves as an important neuromodulator in regulation of brain functions. PD, characterized by the progressive loss of DA neurons in midbrain, is the second most common neurodegenerative disorder among old population. In this thesis, the therapeutic effect of H2S on neurodegeneration and the underlying mechanisms were investigated in both in vitro and in vivo studies. Neuroinflammation is one of the main pathological causes/features of PD. In this thesis, the effect of H2S on neuroinflammation was first examined in glial cells. It was found that both endogenous and exogenous application of H2S ameliorated LPS-stimulated production of nitric oxide and TNF-a, two important pro-inflammatory factors, in primary cultured microglia and BV2 cells. Similar results were also observed in primary cultured astrocytes. NaHS, an H2S donor, also attenuated rotenone-induced intracellular reactive oxygen species and extracellular superoxide accumulation in microglia. This implies that H2S plays an anti-inflammatory role in central nervous system. The underlying mechanisms for the anti-neuroinflammatory role of H2S were demonstrated to be associated with its inhibitory effect on p38 MAPK and NF-?B signaling pathway. In addition, H2S was also found to alleviate inflammation-mediated neurotoxicity on SH-SY5Y cells. These data suggest that H2S may produce neuroprotective effects via its anti-neuroinflammatory action. Apart from the indirect neuroprotection, the direct effect of H2S on neuronal cells was also investigated. It was found that H2S concentration-dependently suppressed rotenone-induced cellular injury and apoptotic cell death. NaHS also prevented rotenone-induced p38- and JNK- MAPK phosphorylation and changes in Bcl-2/Bax levels, ??m dissipation, cytochrome c release, caspase-9/3 activation as well as PARP cleavage. This effect was mediated by mitoKATP channels. Therefore, H2S may protect neuronal cells against rotenone-induced apoptosis through preservation of mitochondrial integrity and inhibition on mitochondrial apoptotic pathways. The potential neuroprotection of H2S was further confirmed in vivo with the rotenone-induced rat PD model. It was found that both endogenous H2S level and its biosynthesis activity were reduced in rotenone-induced PD rats, implying that the impaired endogenous H2S production may contribute to the development of PD. Interestingly, NaHS treatment significantly alleviated rotenone-induced behavioral deficits, DA neuronal loss in substantia nigra, microglial activation as well as elevation of nitric oxide and TNF-a content in the nigrostriatal tract in rat. These data clearly suggest that H2S has the potential to be developed as a new agent to treat neurodegenerative diseases. In summary, the present study demonstrates for the first time that H2S may serve as a neuroprotectant to treat and prevent neurotoxin-induced neurodegeneration via anti-inflammatory and anti-apoptotic mechanisms, and therefore has the potential therapeutic value for PD treatment.
URI: http://scholarbank.nus.edu.sg/handle/10635/18426
Appears in Collections:Ph.D Theses (Open)

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