Antioxidant and Cell-Signaling Functions of Hydrogen Sulfide in the Central Nervous System

Abstract

Hydrogen sulfide (H₂S), a toxic gaseous molecule, plays a physiological role in regulating homeostasis and cell signaling. H₂S is produced from cysteine by enzymes, such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), cysteine aminotransferase (CAT), and 3-mercaptopyruvate sulfurtransferase (3MST). These enzymes regulate the overall production of H₂S in the body. H₂S has a cell-signaling function in the CNS and plays important roles in combating oxidative species such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the body. H₂S is crucial for maintaining balanced amounts of antioxidants to protect the body from oxidative stress, and appropriate amounts of H₂S are required to protect the CNS in particular. The body regulates CBS, 3MST, and CSE levels in the CNS, and higher or lower levels of these enzymes cause various neurodegenerative diseases. This review discusses how H₂S protects the CNS by acting as an antioxidant that reduces excessive amounts of ROS and RNS. Additionally, H₂S regulates cell signaling to combat neuroinflammation and protect against central neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).

Figure 1

Biosynthesis of hydrogen sulfide (H₂S) from the cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), cysteine aminotransferase (CAT), and 3-mercaptopyruvate sulfurtransferase (3MST). From the metabolism of methionine, homocysteine is converted to cystathionine and H₂S is produced from the L-cysteine and homocysteine by enzymes CBS and CSE. L-cysteine in converted to serine and H₂S with the enzyme CBS. Cystine is converted to pyruvate, ammonia (NH₃), and H₂S with enzymes CSE. 3MST works in two ways such as 3MST/CAT and 3MST/DAO (D-amino acid oxidase) pathways to produce H₂S from L-cysteine and D-cysteine. SAM: S-Adenosylmethionine synthase; SAH: S-Adenosyl homocysteine hydrolase; DAO: D-Amino acid oxidase.

Figure 2

Potential molecular targets in hydrogen sulfide (H₂S) signaling in the central nervous system (CNS). H₂S targets protein kinase A (PKA) and activates PKA stimulation or cyclic adenosine monophosphate (cAMP) upregulation which has effects on neurons, microglia, and the cell lines such as B12 and B49. It also activates mitogen and tyrosine kinases which initiates p38 mitogen-activated protein kinase (MAPK) inhibition as well as stimulation of the reducing activity in neurons, astrocytes, and microglia. Oxidative stress has activity on suppression of peroxynitrites (ONOO⁻), hydrogen peroxide (H₂O₂), and upregulation of glutathione (GSH) or glutamate. Additionally, H₂S activates on calcium (Ca²⁺), potassium (K⁺), and chloride (Cl⁻) channels in neurons, astrocytes, and cell lines such as HT22 and NG108–15. Moreover, H₂S has effects on neurons in neurotransmission such as gamma-aminobutyric acid (GABA) receptor inhibition, N-methyl-D-aspartic acid (NMDA) potentiation glutamate release, and monoamine oxidase (MAO) inhibition. In these ways, H₂S stimulates molecular targets on the CNS to impart their different functions.

Figure 3

Role of hydrogen sulfide (H₂S) as antioxidant in the neurodegenerative diseases Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). In AD, mitochondrial damage is caused by low levels of H₂S in the cerebral cortex and cerebellum whereas H₂S acts as antioxidant by GSH and amyloid beta-mediated oxidative damage. In PD, redox-sensitive proteins such as α-synuclein, parkin, and so on form Lewy bodies because of low levels of H₂S whereas H₂S imparts antioxidant functions by upregulation of antioxidant enzymes which inhibits reactive oxygen species (ROS) as well as lipid peroxidation products. In HD, elevated levels of ROS causes downregulation of activity in the striatum, hippocampus, and so on because of low supply of H₂S whereas H₂S acts as an antioxidant by reducing the excessive ROS. Lastly, in ALS, excessive amounts of proteins are downregulated because of low levels of H₂S and H₂S acts as antioxidant by proper regulation of antioxidant enzymes in ALS. In this ways, H₂S imparts antioxidant functions by modulating oxidative stress conditions in the neurodegenerative diseases.