Protective Roles of Hydrogen Sulfide in Alzheimer’s Disease and Traumatic Brain Injury

Abstract

The gaseous signaling molecule hydrogen sulfide (H2S) critically modulates a plethora of physiological processes across evolutionary boundaries. These include responses to stress and other neuromodulatory effects that are typically dysregulated in aging, disease, and injury. H2S has a particularly prominent role in modulating neuronal health and survival under both normal and pathologic conditions. Although toxic and even fatal at very high concentrations, emerging evidence has also revealed a pronounced neuroprotective role for lower doses of endogenously generated or exogenously administered H2S. Unlike traditional neurotransmitters, H2S is a gas and, therefore, is unable to be stored in vesicles for targeted delivery. Instead, it exerts its physiologic effects through the persulfidation/sulfhydration of target proteins on reactive cysteine residues. Here, we review the latest discoveries on the neuroprotective roles of H2S in Alzheimer’s disease (AD) and traumatic brain injury, which is one the greatest risk factors for AD.

The Role of TNF-α in Alzheimer’s Disease: A Narrative Review

“…Furthermore, NaHS treatment induced a reduction in the expression of TNF-α and IL-1β mRNA, as determined by RT-PCR analysis [ 118 ]. The collective results strongly suggest that pre-treatment with NaHS proves successful in enhancing learning and memory capabilities while concurrently diminishing neuroinflammation levels and implies a possible future therapeutical role for NaHS in neuroinflammatory conditions [ 119 , 120 ].…”

Mitochondrial Targeting against Alzheimer’s Disease: Lessons from Hibernation

“…AD patients show lower levels and reduced activity of the H 2 S-producing enzyme CBS and lower levels of H 2 S in the brain, which correlate to AD severity [ 125 , 126 , 127 ]. Increasing H 2 S levels as a therapeutic strategy against AD has been extensively reviewed [ 128 , 129 ]. Indeed, increasing H 2 S levels similar to what is seen during hibernation leads to the relief of AD-related pathophysiologic outcomes in various animal and cell models of AD.…”

“…For example, NaHS, a H 2 S donor, ameliorated Aβ-induced damage in PC12 cells by reducing the loss of mitochondrial membrane potential and attenuating the increase in intracellular ROS [ 128 ]. In addition, increasing H 2 S levels in the brain of AD animal models via a donor or through a diet rich in taurine, cysteine, folate, B12, and betaine, has been shown to be beneficial against oxidative stress, neurodegeneration and cognitive impairment [ 129 , 130 ]. However, the clinical translation of these results is hindered by the complex dosage regimen of a H 2 S donor, requiring multiple high doses, and H 2 S’s potential toxicity at such high doses [ 129 ].…”

“…In addition, increasing H 2 S levels in the brain of AD animal models via a donor or through a diet rich in taurine, cysteine, folate, B12, and betaine, has been shown to be beneficial against oxidative stress, neurodegeneration and cognitive impairment [ 129 , 130 ]. However, the clinical translation of these results is hindered by the complex dosage regimen of a H 2 S donor, requiring multiple high doses, and H 2 S’s potential toxicity at such high doses [ 129 ]. Currently, an H 2 S-targeting compound, the CBS activator s-adenosyl methionine (SAM), has entered a phase II clinical trial, studying its effects in patients with mild cognitive impairment.…”

Hydrogen Sulfide: An Emerging Regulator of Oxidative Stress and Cellular Homeostasis—A Comprehensive One-Year Review

“…This enzyme takes center stage in the transsulfuration pathway, an essential biochemical pathway in the human body involving the interconversion of sulfur-containing amino acids, methionine, and cysteine [ 24 ]. CBS initiates the transsulfuration pathway by catalyzing its first step [ 25 , 26 , 27 , 28 ].…”