Neuroprotective effects of hydrogen sulfide on Parkinson's disease rat models.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN). The present study was designed to examine the therapeutic effect of hydrogen sulfide (H(2)S, a novel biological gas) on PD. The endogenous H(2)S level was markedly reduced in the SN in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. Systemic administration of NaHS (an H(2)S donor) dramatically reversed the progression of movement dysfunction, loss of tyrosine-hydroxylase positive neurons in the SN and the elevated malondialdehyde level in injured striatum in the 6-OHDA-induced PD model. H(2)S specifically inhibited 6-OHDA evoked NADPH oxidase activation and oxygen consumption. Similarly, administration of NaHS also prevented the development of PD induced by rotenone. NaHS treatment inhibited microglial activation in the SN and accumulation of pro-inflammatory factors (e.g. TNF-alpha and nitric oxide) in the striatum via NF-kappaB pathway. Moreover, significantly less neurotoxicity was found in neurons treated with the conditioned medium from microglia incubated with both NaHS and rotenone compared to that with rotenone only, suggesting that the therapeutic effect of NaHS was, at least partially, secondary to its suppression of microglial activation. In summary, we demonstrate for the first time that H(2)S may serve as a neuroprotectant to treat and prevent neurotoxin-induced neurodegeneration via multiple mechanisms including anti-oxidative stress, anti-inflammation and metabolic inhibition and therefore has potential therapeutic value for treatment of PD.
Hu
Li-Fang
LF
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Lu
Ming
M
Tiong
Chi Xin
CX
Dawe
Gavin S
GS
Hu
Gang
G
Bian
Jin-Song
JS
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D002460:Cell Line; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D050356:Lipid Metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use; D010084:Oxidation-Reduction; D016627:Oxidopamine / Q000378:metabolism; D010101:Oxygen Consumption; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone
D016328:NF-kappa B; D018696:Neuroprotective Agents; D012402:Rotenone; D016627:Oxidopamine; D000255:Adenosine Triphosphate; D019255:NADPH Oxidases; D006862:Hydrogen Sulfide