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.

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).

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Oxidative phosphorylation is a source of energy production by which many cells satisfy their energy requirements. Endogenous reactive oxygen species (ROS) are by-products of oxidative phosphorylation. ROS are formed due to the inefficiency of oxidative phosphorylation, and lead to oxidative stress that affects mitochondrial metabolism. Chronic oxidative stress contributes to the onset of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The immediate consequences of oxidative stress include lipid peroxidation, protein oxidation, and mitochondrial deoxyribonucleic acid (mtDNA) mutation, which induce neuronal cell death. Mitochondrial binding of amyloid-β (Aβ) protein has been identified as a contributing factor in AD. In PD and HD, respectively, α-synuclein (α-syn) and huntingtin (Htt) gene mutations have been reported to exacerbate the effects of oxidative stress. Similarly, abnormalities in mitochondrial dynamics and the respiratory chain occur in ALS due to dysregulation of mitochondrial complexes II and IV. However, oxidative stress-induced dysfunctions in neurodegenerative diseases can be mitigated by the antioxidant function of hydrogen sulfide (H 2 S), which also acts through the potassium (K ATP /K +) ion channel and calcium (Ca 2+) ion channels to increase glutathione (GSH) levels. The pharmacological activity of H 2 S is exerted by both inorganic and organic compounds. GSH, glutathione peroxidase (Gpx), and superoxide dismutase (SOD) neutralize H 2 O 2-induced oxidative damage in mitochondria. The main purpose of this review is to discuss specific causes and effects of mitochondrial oxidative stress in neurodegenerative diseases, and how these are impacted by the antioxidant functions of H 2 S to support the development of advancements in neurodegenerative disease treatment.

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.

Mitophagy is activated by a number of stimuli, including hypoxia, energy stress, and increased oxidative phosphorylation activity. Mitophagy is associated with oxidative stress conditions and central neurodegenerative diseases. Proper regulation of mitophagy is crucial for maintaining homeostasis; conversely, inadequate removal of mitochondria through mitophagy leads to the generation of oxidative species, including reactive oxygen species and reactive nitrogen species, resulting in various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. These diseases are most prevalent in older adults whose bodies fail to maintain proper mitophagic functions to combat oxidative species. As mitophagy is essential for normal body function, by targeting mitophagic pathways we can improve these disease conditions. The search for effective remedies to treat these disease conditions is an ongoing process, which is why more studies are needed. Additionally, more relevant studies could help establish therapeutic conditions, which are currently in high demand. In this review, we discuss how mitophagy plays a significant role in homeostasis and how its dysregulation causes neurodegeneration. We also discuss how combating oxidative species and targeting mitophagy can help treat these neurodegenerative diseases.

Hydrogen sulfide (H2 S) functions as a physiological gas transmitter in both normal and pathophysiological cellular events. H2 S is produced from substances by three enzymes: cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MST). In human tissues, these enzymes are involved in tissue-specific biochemical pathways for H2 S production. For example, CBS and cysteine aminotransferase/MST are present in the brain, but CSE is not. Thus, we examined the expression of H2 S production-related enzymes in peripheral nerves. Here, we found that CSE and MST/cysteine aminotransferase, but not CBS, were present in normal peripheral nerves. In addition, injured sciatic nerves in vivo up-regulated CSE in Schwann cells during Wallerian degeneration (WD); however, CSE was not up-regulated in peripheral axons. Using an ex vivo sciatic nerve explant culture, we found that the inhibition of H2 S production broadly prevented the process of nerve degeneration, including myelin fragmentation, axonal degradation, Schwann cell dedifferentiation, and Schwann cell proliferation in vitro and in vivo. Thus, these results indicate that H2 S signaling is essential for Schwann cell responses to peripheral nerve injury. Hydrogen sulfide (H2 S) functions as a physiological gas transmitter in both normal and pathophysiological cellular events. H2 S is produced from cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfur transferase (MST). Here, we found that CSE and MST/CAT were present in normal peripheral nerves. Injured static nerves in vivo up-regulated CSE in Schwann cells during Wallerian degeneration, but CSE was not up-regulated in peripheral axons.

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.