Title:Hydrogen Sulfide (H2S) Signaling as a Protective Mechanism against Endogenous
and Exogenous Neurotoxicants
Volume: 20
Issue: 10
Author(s): Michael Aschner*, Anatoly V. Skalny, Tao Ke, Joao BT da Rocha, Monica MB Paoliello, Abel Santamaria, Julia Bornhorst, Lu Rongzhu, Andrey A. Svistunov, Aleksandra B. Djordevic and Alexey A. Tinkov
Affiliation:
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Keywords:
Hydrogen sulfide, sodium hydrosulfide, alcohol, amyloid, metals, neurotoxicants.
Abstract: In view of the significant role of H2S in brain functioning, it is proposed that H2S may
also possess protective effects against adverse effects of neurotoxicants. Therefore, the objective of
the present review is to discuss the neuroprotective effects of H2S 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 H2S 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, H2S 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 H2S metabolism through the inhibition of H2S-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 H2S 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 H2S-synthetizing enzymes or the use of H2S-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.
