The Role of Hydrogen Sulfide in Regulation of Cell Death following Neurotrauma and Related Neurodegenerative and Psychiatric Diseases

Abstract

Injuries of the central (CNS) and peripheral nervous system (PNS) are a serious problem of the modern healthcare system. The situation is complicated by the lack of clinically effective neuroprotective drugs that can protect damaged neurons and glial cells from death. In addition, people who have undergone neurotrauma often develop mental disorders and neurodegenerative diseases that worsen the quality of life up to severe disability and death. Hydrogen sulfide (H₂S) is a gaseous signaling molecule that performs various cellular functions in normal and pathological conditions. However, the role of H₂S in neurotrauma and mental disorders remains unexplored and sometimes controversial. In this large-scale review study, we examined the various biological effects of H₂S associated with survival and cell death in trauma to the brain, spinal cord, and PNS, and the signaling mechanisms underlying the pathogenesis of mental illnesses, such as cognitive impairment, encephalopathy, depression and anxiety disorders, epilepsy and chronic pain. We also studied the role of H₂S in the pathogenesis of neurodegenerative diseases: Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, we reviewed the current state of the art study of H₂S donors as neuroprotectors and the possibility of their therapeutic uses in medicine. Our study showed that H₂S has great neuroprotective potential. H₂S reduces oxidative stress, lipid peroxidation, and neuroinflammation; inhibits processes associated with apoptosis, autophagy, ferroptosis and pyroptosis; prevents the destruction of the blood-brain barrier; increases the expression of neurotrophic factors; and models the activity of Ca²⁺ channels in neurotrauma. In addition, H₂S activates neuroprotective signaling pathways in psychiatric and neurodegenerative diseases. However, high levels of H₂S can cause cytotoxic effects. Thus, the development of H₂S-associated neuroprotectors seems to be especially relevant. However, so far, all H₂S modulators are at the stage of preclinical trials. Nevertheless, many of them show a high neuroprotective effect in various animal models of neurotrauma and related disorders. Despite the fact that our review is very extensive and detailed, it is well structured right down to the conclusions, which will allow researchers to quickly find the proper information they are interested in.

Keywords: anxiety disorders; apoptosis; autophagy; cognitive impairment; depression; encephalopathy; epilepsy; ferroptosis; glial cells; hydrogen sulfide; neurodegenerative diseases; neuron; neurotrauma; pyroptosis.

Figure 1

Biosynthesis of H₂S in the body. Cystathionine-β-synthase (CBS) catalyzes the condensation of homocysteine (Hcy) with serine to form cystathionine, which cleaves cystathionine-γ-lyase (CSE). This results in the synthesis of H₂S. CBS, CSE and 3-mercaptopyruvate sulfurtransferase (3-MST) catalyze the conversion of cysteine to H₂S.

Figure 2

H₂S catabolism pathways in the body: oxidation, methylation and exhalation. TSMT, thiol-S-methyl transferase; SQR, quinone oxidoreductase; SDO, sulfur deoxygenase; SO, sulfite oxidase.

Figure 3

The participation of H₂S in normal and pathological conditions in the brain, heart, blood vessels, gastrointestinal tract, liver, kidneys, and lungs.

Figure 4

The role of H₂S in neuroprotection and neurodegeneration in neurotrauma. Arrows with a sharp end—positive regulation; arrows with a blunt end—negative regulation.

Figure 5

The role of H₂S in oxidative stress in neurotrauma. H₂S can directly react with and quench ROS and NO. In addition, H₂S can increase the level of intracellular reduced glutathione (GSH), which is an antioxidant. However, H₂S can activate γ-glutamylcysteine synthase (γ-GSC), which limits GSH synthesis. H₂S is involved in the activation of a number of antioxidant defense enzymes: γ-glutamylcysteine synthase (γ-GSC), thioredoxin (Trx-1), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and p66Shc.

Figure 6

The role of H₂S in inflammation in neurotrauma. TNF, tumor necrosis factor; COX, cyclooxygenase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; iNOS, inducible nitric oxide synthase; NO, nitric oxide; IL-1β, interleukin-1 beta; NLRP, nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing; GSDMD, Gasdermin D; Casp1, caspase-1; Casp3, caspase-3; PKC, protein kinase C; Ca²⁺, calcium ions; CaM, calmodulin; p38, p38 mitogen-activated protein kinase; CD11b\CD18, Mac-1β2 integrin; CcO, cytochrome-c-oxidase. Arrows with a sharp end—positive regulation; arrows with a blunt end—negative regulation.

Figure 7

The role of H₂S in apoptosis in neurotrauma. NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; iNOS, inducible nitric oxide synthase; NO, nitric oxide; Casp1, caspase-1; Casp3, caspase-3; NOX, NADPH-oxidase; Bcl-2, B-cell lymphoma 2; Bax, bcl-2-like protein 4; Akt, protein kinase B; p53, tumor protein p53; Nfr2, nuclear factor erythroid 2–related factor 2; p65, RelA; RPS3, ribosomal protein S3; lncRNA CasC7, long non-coding RNA CasC7. Arrows with a sharp end—positive regulation; arrows with a blunt end—negative regulation; dotted line—alternative regulation.

Figure 8

The role of H₂S in the regulation of autophagy in neurotrauma. miR-30c, micro-RNA 30c; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; Nfr2, nuclear factor erythroid 2–related factor 2; Beclin, the mammalian orthologue of yeast Atg6; LC3, Microtubule-associated protein 1A/1B-light chain 3. Arrows with a sharp end—positive regulation; arrows with a blunt end—negative regulation.

Figure 9

Possible H₂S-dependent signaling mechanisms that regulate cell death in the nervous tissue in cognitive impairment and encephalopathy. H₂S, hydrogen sulfide; CHOP, C/EBP homologous protein; Casp12, caspase-12; TRL4, toll like receptor 4; NF-ĸB, nuclear factor kappa-light-chain-enhancer of activated B cells; iNOS, inducible nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species; PSD-9, postsynaptic density protein 95; Bax, bcl-2-like protein 4; NMDAR, N-methyl-D-aspartate receptor; IL-6, interleukin-6; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; Syn1, synapsin 1; LDHA, lactate dehydrogenase A; mTOR, mammalian target of rapamycin; PDK, pyruvate dehydrogenase kinase 1; SOD, superoxide dismutase; GSH, glutathione; Aco, aconitase; CS, citrate synthase; Sirt1, NAD-dependent deacetylase sirtuin-1; CK, creatine kinase; NF-ĸB p65, RelA; PD, pyruvate dehydrogenase; Bcl-2, B-cell lymphoma 2; HO-2, heme oxygenase 2; M2-PK, pyruvate kinase M2; CPR78, cuticular protein RR-2 motif 78; Nrf2, nuclear factor erythroid 2–related factor 2; ARE, antioxidant response element.

Figure 10

Possible H₂S-dependent signaling mechanisms that regulate cell death in nervous tissue in depression, anxiety disorders, epilepsy, and chronic pain. H₂S, hydrogen sulfide; AMPAR, AMPA-type glutamate receptor; IL-4, interleukin-4; IL-6, interleukin-6; IL-1β, interleukin-1β; IL-10, interleukin-10; TNF-α, tumor necrosis factor-α; HO-2, heme oxygenase 2; PI3K, phosphatidylinositol 3-kinase; AKT, RAC-alpha serine/threonine-protein kinase; Sirt1, NAD-dependent deacetylase sirtuin-1; mTORC1, mammalian target of rapamycin complex 1; H3K9ac, acetylated histone H3 lysine 9; GPX4, Glutathione peroxidase 4; Kir6.2, major subunit of the ATP-sensitive K⁺ channel; SUR1, subunit of the ATP-sensitive K⁺ channel; GRP78, glucose-regulated protein 78; GSH, glutathione; PSD-9, postsynaptic density protein 95; NQO1, NAD(P)H quinone dehydrogenase 1; OPA1, optic atrophy 1; Beclin, mammalian orthologue of yeast Atg6; Mff, mitochondrial fission factor; ROS, reactive oxygen species; Sirt6, NAD-dependent deacetylase sirtuin-6; p-Akt, phosphorylated RAC-alpha serine/threonine-protein kinase; NOS2, inducible nitric oxide synthase; SLC7A11, solute carrier family 7 member 11; CCL2, C-C motif ligand 2; Fe²⁺, iron ion; Casp12, caspase-12; NMDAR, N-methyl-D-aspartate receptor; GSTA1, glutathione S-transferase A1; BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin receptor kinase B; c-fos, gene encoding c-fos protein; Notch1, Notch homolog 1; ACRP30, Adipocyte complement-related protein of 30 kDa; MFN2, Mitofusin-2; Syp, synaptophysin; Drp1, dynamin-related protein; CHOP, C\EBP homologous protein; PKC, protein kinase C; P62, sequestosome 1; GSTM1, glutathione s-transferase Mu 1; GABABR1\GABABR2, gamma-aminobutyric acid receptor subunits, GABABR1 and GABABR2.

Figure 11

Possible H₂S-dependent signaling mechanisms that regulate cell death in nervous tissue in neurodegenerative diseases. BACE1, beta-site amyloid precursor protein cleaving enzyme 1; p38 MAPK, p38 mitogen-activated protein kinase; Tau, microtubule-associated protein tau; GSK3β, glycogen synthase kinase-3 beta; JNK, c-Jun N-terminal kinase; Aβ, amyloid beta; Casp3, caspase-3; TNF-α, tumor necrosis factor-α; Akt, RAC-alpha serine/threonine-protein kinase; IL-6, interleukin-6; Bax, bcl-2-like protein 4; Bcl-2, B-cell lymphoma 2; PSD-95, postsynaptic density protein 95; Sirt1, NAD-dependent deacetylase sirtuin-1; TORC1, target of rapamycin kinase complex 1; CREB, cAMP response element-binding protein; BDNF, brain-derived neurotrophic factor; Nrf2, nuclear factor erythroid 2–related factor 2; ARE, antioxidant response element; HO-1, heme oxygenase 1; TrkB, tropomyosin receptor kinase B; Glu, glutamic acid; WE, Warburg effect; 5-HT, serotonin; miR-133a-5p, microRNA 133a-5p; K_ATP channel, ATP-sensitive K⁺ channel; PS1, presenilin-1; p65 NF-ĸB, nuclear factor kappa-light-chain-enhancer of activated B cells; miR-155, microRNA 155; ROS, reactive oxygen species; NO, nitric oxide; MDA, malonic dialdehyde; NMDAR, N-methyl-D-aspartate receptor; ROCK2, Rho associated coiled-coil containing protein kinase 2.