Endogenous Hydrogen Sulfide is Involved in Asymmetric Dimethylarginine-induced Protection Against Neurotoxicity of 1-Methyl-4-phenyl-pyridinium Ion

Abstract

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is profoundly protective against 1-methy-4-phenylpyridinium ion (MPP+)-induced neurotoxicity. Reactive oxygen species (ROS) overproduction contributes to the neurotoxicity of MPP+; while hydrogen sulfide (H₂S) is a pivotal endogenous antioxidant. This study is to assess the potential role of endogenous H₂S in the neuroprotection of ADMA against MPP+-induced toxicity in PC12 cells. We showed that ADMA prevented MPP+-induced inhibition of endogenous H₂S generation through inhibiting the down-regulation of cystathionine-β-synthetase (CBS, the major enzyme responsible for endogenous H₂S generation in PC12 cells) expression and activity elicited by MPP+. ADMA obviously attenuated MPP+-triggered accumulation of intracellular ROS, dissipation of mitochondrial membrane potential (MMP), release of cytochrome c (Cyt-c), and downregulation of Bcl-2 protein expression in PC12 cells. Inhibition of CBS activity by amino-oxyacetate and CBS silencing with a short hairpin RNA vector targeting rat CBS gene reversed the protective action of ADMA against MPP+-caused cytotoxicity, ROS overproduction, and MMP loss in PC12 cells. These results indicate that the protection of ADMA against MPP+-mediated neurotoxicity involves the melioration of MPP+-induced inhibition of endogenous H₂S generation. Our findings suggest that modulation of H₂S production provide new therapeutic targets for the treatment of neurodegenerative disease, such as Parkinson's disease.

Asymmetric Dimethylarginine Protects Neurons from Oxygen Glucose Deprivation Insult by Modulating Connexin-36 Expression

“…Cardounel and Zweier showed that ADMA protected neurons from NMDA-induced neurotoxicity [ 28 ]. Tang et al demonstrated that ADMA attenuated ROS accumulation in MPP+-treated PC12 cells and protected neurons from MPP+-triggered cell death [ 29 , 30 ]. However, Wang et al reported that exogenous ADMA may induce apoptosis in PC12 cells in a concentration- and time-dependent manner [ 31 ].…”

Targeted metabolomic analysis of nitric oxide/L-arginine pathway metabolites in dementia: association with pathology, severity, and structural brain changes

“…The ADMA decrease has been observed also in other neurodegenerative conditions 27 . Moreover, a neuroprotective role for ADMA in Parkinson’s disease has even been suggested 28 .…”

Hydrogen Sulfide (H2S) Signaling as a Protective Mechanism against Endogenous and Exogenous Neurotoxicants

“…MPP + was shown to down-regulate CBS expression and activity, thus resulting in decreased H 2 S production in PC12 cells, whereas the improvement of H 2 S levels ameliorated MPP + cytotoxicity and oxidative stress [ 158 ]. Concomitantly, the prevention of oxidative stress, mitochondrial membrane potential loss, cytochrome c release, and decreased Bcl2 expression followed by improved cell viability by asymmetric dimethylarginine in MPP + -exposed PC122 cells was shown to be dependent on CBS expression and subsequent release of H2S [ 159 ], thus being indicative of the beneficial role of H2S in protection against MPP + -induced neuronal apoptosis [ 160 ].…”