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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).

Synaptic plasticity is important for maintaining normal neuronal activity and proper neuronal functioning in the nervous system. It is crucial for regulating synaptic transmission or electrical signal transduction to neuronal networks, for sharing essential information among neurons, and for maintaining homeostasis in the body. Moreover, changes in synaptic or neural plasticity are associated with many neuropsychiatric conditions, such as schizophrenia (SCZ), bipolar disorder (BP), major depressive disorder (MDD), and Alzheimer’s disease (AD). The improper maintenance of neural plasticity causes incorrect neurotransmitter transmission, which can also cause neuropsychiatric conditions. Gas neurotransmitters (gasotransmitters), such as hydrogen sulfide (H2S), nitric oxide (NO), and carbon monoxide (CO), play roles in maintaining synaptic plasticity and in helping to restore such plasticity in the neuronal architecture in the central nervous system (CNS). Indeed, the upregulation or downregulation of these gasotransmitters may cause neuropsychiatric conditions, and their amelioration may restore synaptic plasticity and proper neuronal functioning and thereby improve such conditions. Understanding the specific molecular mechanisms underpinning these effects can help identify ways to treat these neuropsychiatric conditions.

To date, three main gasotransmitters, that is, hydrogen sulfide (H2S), carbon monoxide (CO), and nitric oxide (NO), have been discovered to play major bodily physiological roles. These gasotransmitters have multiple functional roles in the body including physiologic and pathologic functions with respect to the cellular or tissue quantities of these gases. Gasotransmitters were originally known to have only detrimental and noxious effects in the body but that notion has much changed with years; vast studies demonstrated that these gasotransmitters are precisely involved in the normal physiological functioning of the body. From neuromodulation, oxidative stress subjugation, and cardiovascular tone regulation to immunomodulation, these gases perform critical roles, which, should they deviate from the norm, can trigger the genesis of a number of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The purpose of this review is to discuss at great length physical and chemical properties and physiological actions of H2S, NO, and CO as well as shedding light on recently researched molecular targets. We particularly put emphasis on the roles in neuronal inflammation and neurodegeneration and neuronal repair.

Hydrogen sulfide (H2S) is an emerging neuromodulator that is considered to be a gasotransmitter similar to nitrogen oxide (NO) and carbon monoxide (CO). H2S exerts universal cytoprotective effects and acts as a defense mechanism in organisms ranging from bacteria to mammals. It is produced by the enzymes cystathionine β-synthase (CBS), cystathionine ϒ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (MST), and D-amino acid oxidase (DAO), which are also involved in tissue-specific biochemical pathways for H2S production in the human body. H2S exerts a wide range of pathological and physiological functions in the human body, from endocrine system and cellular longevity to hepatic protection and kidney function. Previous studies have shown that H2S plays important roles in peripheral nerve regeneration and degeneration and has significant value during Schwann cell dedifferentiation and proliferation but it is also associated with axonal degradation and the remyelination of Schwann cells. To date, physiological and toxic levels of H2S in the human body remain unclear and most of the mechanisms of action underlying the effects of H2S have yet to be fully elucidated. The primary purpose of this review was to provide an overview of the role of H2S in the human body and to describe its beneficial effects.

Neuronal inflammation is a systematically organized physiological step often triggered to counteract an invading pathogen or to rid the body of damaged and/or dead cellular debris. At the crux of this inflammatory response is the deployment of nonneuronal cells: microglia, astrocytes, and blood-derived macrophages. Glial cells secrete a host of bioactive molecules, which include proinflammatory factors and nitric oxide (NO). From immunomodulation to neuromodulation, NO is a renowned modulator of vast physiological systems. It essentially mediates these physiological effects by interacting with cyclic GMP (cGMP) leading to the regulation of intracellular calcium ions. NO regulates the release of proinflammatory molecules, interacts with ROS leading to the formation of reactive nitrogen species (RNS), and targets vital organelles such as mitochondria, ultimately causing cellular death, a hallmark of many neurodegenerative diseases. AD is an enervating neurodegenerative disorder with an obscure etiology. Because of accumulating experimental data continually highlighting the role of NO in neuroinflammation and AD progression, we explore the most recent data to highlight in detail newly investigated molecular mechanisms in which NO becomes relevant in neuronal inflammation and oxidative stress-associated neurodegeneration in the CNS as well as lay down up-to-date knowledge regarding therapeutic approaches targeting NO.

Studies have shown that lysosomal activation increases in Schwann cells after nerve injury. Lysosomal activation is thought to promote the engulfment of myelin debris or fragments of injured axons in Schwann cells during Wallerian degeneration. However, a recent interpretation of lysosomal activation proposes a different view of the phenomenon. During Wallerian degeneration, lysosomes become secretory vesicles and are activated for lysosomal exocytosis. The lysosomal exocytosis triggers adenosine 5′-triphosphate (ATP) release from peripheral neurons and Schwann cells during Wallerian degeneration. Exocytosis is involved in demyelination and axonal degradation, which facilitate nerve regeneration following nerve degeneration. At this time, released ATP may affect the communication between cells in peripheral nerves. In this review, our description of the relationship between lysosomal exocytosis and Wallerian degeneration has implications for the understanding of peripheral nerve degenerative diseases and peripheral neuropathies, such as Charcot-Marie-Tooth disease or Guillain-Barré syndrome.