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

Abstract

In view of significant role of H2S in brain functioning through, it is proposed that H2S may also possess protective effects against adverse effects of neurotoxicants. Therefore, the objective of the present review is discussion of neuroprotective effects of H2S against toxicity of a wide spectrum of endogenous and exogenous agents, involved in 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 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 direct detoxicative effect through binding of endogenous (ROS, AGEs, Aβ) and exogenous (MeHg) neurotoxicants, thus reducing their toxicity. Moreover, alteration of H2S metabolism through inhibition of H2S-synthetizing enzymes in brain (CBS, 3-MST) may be considered as a significant mechanism of neurotoxicity. Taken together, the existing data indicate that 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 particular efficiency and safety of such interventions are to be addressed in further studies.

Hydrogen Sulfide Attenuates Lipopolysaccharide-Induced Inflammation via the P-glycoprotein and NF-κB Pathway in Astrocytes

“…Therefore, nuclear translocation of P65, or phosphorylation of P65, is often used to assess the activation of NF-κB. Since it has been reported that NF-κB can be S-sulfhydrated [ 32 ], to explore whether H 2 S affects the nuclear translocation of NF-κB, we used the nuclear translocation of P65 and assessed NF-κB activation. The results show that H 2 S reduces NF-κB 65 entry into the nucleus, inhibiting NF-κB pathway activation.…”

Advances of H2S in Regulating Neurodegenerative Diseases by Preserving Mitochondria Function

“…The physiological levels of H 2 S in human brain tissue are nearly 50–160 μM, which suggests that H 2 S may exert a possible biological function in neurons [ 16 ]. Subsequently, numerous researchers have reported that the possible physiological functions of H 2 S in the brain mainly include potentiating long-term potential (LTP) through activation of the NMDA receptors [ 16 ], thus inhibiting mitochondrial dysfunction and oxidative damage by directly or indirectly scavenging free radicals and reactive species [ 73 , 74 , 75 , 76 , 77 ], activating Ca 2+ influx waves in astrocytes [ 78 ], initiating anti-neuroinflammatory responses in both astrocyte and microglia [ 79 , 80 , 81 ], and modulating apoptotic response signaling in neurons [ 81 , 82 ]. These studies highlight the potential neuroprotective role of H 2 S in regulating neurodegenerative diseases through anti-oxidative, anti-inflammatory, or anti-apoptotic effects ( Table 1 ).…”

Bioinformatics analysis of the clinical value and potential mechanisms of CBS/H2S in Glioma through 1027 samples.

“…Cystathionine beta-synthase (CBS),encoded by the CBS gene on human chromosome,primarily facilitates endogenous H2S production in the nervous system (4). CBS/H2S serves as a neurotransmitter and exerts various biological effects, including the inhibiting neuroin ammatory reactions, enhancing neuroprotective functions through cell apoptosis and antioxidative stress damage (5). Decreased H2S levels and downregulation of CBS expression and activity are frequently observed in degenerative diseases like Parkinson's and Alzheimer's (6, 7).Conversely, Down syndrome (DS) is associated with elevated CBS expression and subsequent overproduction of H2S(8).Additionally,CBS has been implicated in the onset and advancement of diverse malignant neoplasms (9).High CBS expression has been observed in thyroid malignancies, gallbladder adenocarcinomas, and square cells/adenosquamus carinomas, while downregulated in liver cancer, all of which are linked to unfavorable prognoses (10)(11)(12).Limited reports exist on the mechanistic role of CBS in tumors, hindering a comprehensive understanding of its involvement in tumor occurrence and development.…”