Beneficial Effects of Putative Hydrogen Sulfide (H2S) Donor POM16 in a Genetic Model of Amyotrophic Lateral Sclerosis, FUS [1-359]-Transgenic Mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by rapid motoneuron degeneration. Hydrogen sulfide (H2S), a signaling molecule that regulates post-translational modification, has recently been implicated in the pathophysiology of ALS. Our study aimed to design, synthesize, and investigate the potential effects of (2S)-2-aminopentanethioic S-acid (POM16), an isomer of the slow-releasing H2S donor thiovaline, in a genetic ALS model. FUS [1-359]-tg mice, which recapitulate ALS syndrome, and their wild-type (WT) littermates received POM16 (at a dose of 50/mg/kg) or standard ALS therapy riluzole (at a dose of 8 mg/kg/day) dissolved in drinking water, or vehicle, for six weeks starting at nine weeks of age. The onset of paralysis, physiological and motor functions, muscle atrophy, density of spinal cord motoneurons, gene expression of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF), and concentration of oxidative stress marker malondialdehyde (MDA) in the spinal cord were studied. POM16-treated mutants displayed significant improvements in body weight, water and diet intake, as well as behavior in the rotarod, wire, and pole tests. The percentage of mice with paralysis on the 6th week of dosing was reduced from 48% in vehicle-treated mutants to 16% in POM16-treated FUS [1-359]-tg mice, while in the riluzole-treated group, it was 38%, not reaching significance. Notably, muscle weight was not significantly improved by the latter treatment, unlike the dosing with POM16. In comparison with vehicle-treated FUS [1-359]-tg mice, POM16-treated mutants had significantly higher motor neuron density in the spinal cord, lower MDA levels, and reduced muscle atrophy ranking. Thus, new compound POM16 has a therapeutic potential to counteract ALS pathology that is likely mediated via anti-oxidative stress mechanisms. Given that any effective treatment of this devastating disease is currently lacking, it is hoped that POM16 can be a promising therapy for ALS.