Abstract
In view of the significant role of H(2)S in brain functioning, it is proposed that H(2)S may also possess protective effects against adverse effects of neurotoxicants. Therefore, the objective of the present review is to discuss the neuroprotective effects of H(2)S against toxicity of a wide spectrum of endogenous and exogenous agents involved in the pathogenesis of neurological diseases as etiological factors or key players in disease pathogenesis. Generally, the existing data demonstrate that H(2)S possesses neuroprotective effects upon exposure to endogenous (amyloid β, glucose, and advanced-glycation end-products, homocysteine, lipopolysaccharide, and ammonia) and exogenous (alcohol, formaldehyde, acrylonitrile, metals, 6-hydroxydopamine, as well as 1-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenyl pyridine ion (MPP)) neurotoxicants. On the one hand, neuroprotective effects are mediated by S-sulfhydration of key regulators of antioxidant (Sirt1, Nrf2) and inflammatory response (NF-κB), resulting in the modulation of the downstream signaling, such as SIRT1/TORC1/CREB/BDNF-TrkB, Nrf2/ARE/HO-1, or other pathways. On the other hand, H(2)S appears to possess a direct detoxicative effect by binding endogenous (ROS, AGEs, Aβ) and exogenous (MeHg) neurotoxicants, thus reducing their toxicity. Moreover, the alteration of H(2)S metabolism through the inhibition of H(2)S-synthetizing enzymes in the brain (CBS, 3-MST) may be considered a significant mechanism of neurotoxicity. Taken together, the existing data indicate that the modulation of cerebral H(2)S metabolism may be used as a neuroprotective strategy to counteract neurotoxicity of a wide spectrum of endogenous and exogenous neurotoxicants associated with neurodegeneration (Alzheimer's and Parkinson's disease), fetal alcohol syndrome, hepatic encephalopathy, environmental neurotoxicant exposure, etc. In this particular case, modulation of H(2)S-synthetizing enzymes or the use of H(2)S-releasing drugs should be considered as the potential tools, although the particular efficiency and safety of such interventions are to be addressed in further studies.