Sulfanegen, a 3‐mercaptopyruvate sulfurtransferase substrate, as a therapeutic option for Alzheimer’s disease

Abstract

AbstractBackgroundThe oxidative stress evident in the Alzheimer’s disease (AD) brain leads to compromised 3‐mercaptopyruvate sulfurtransferase (3MST) function, one of the endogenous hydrogen sulfide (H2S) producing enzymes.1,2 Impaired 3MST function is expected to contribute toward potentiation of oxidative stress by depleting cellular glutathione (GSH) stores, and exacerbation of AD pathology by enhancing Aβ aggregation resulting in neurodegeneration. Preclinical studies with H2S donors such as NaSH have been promising,3,4 however further clinical translation efforts are thwarted due to their poor chemical stability, bioavailability, and dose‐limiting toxicities. We have developed a stable, bioavailable prodrug of 3MST substrate 3‐mercaptopyruvate, named sulfanegen, which can supplement the enzymatic reaction releasing H2S.2 Thus provision of sulfanegen could prove beneficial in mitigating AD‐related neurodegenerative consequences.MethodAged, symptomatic cohorts APP/PS1 mice (7 and 12 month old) were treated with saline (N = 8) or sulfanegen (75 mg/kg, i.p., N = 8) for 12 weeks. Cognitive behavioral assessments (T‐maze) were conducted 10‐11 weeks after treatment initiation. Equal numbers of both sexes of mice were used as much as possible. The harvested brain tissues were analyzed biochemically for cortical/hippocampal Aβ1‐42 burden, oxidative stress and inflammatory markers (protein carbonyls, lipid peroxidation, glutathione assay, TNF‐α and IL6. Quantitative stereological analysis of Aβ pathology, neuroinflammation and progressive neurodegeneration were also conducted.ResultTreatment of symptomatic Alzheimer’s mice with sulfanegen prevented cognitive impairment resulting from AD pathology (Figure 1).2 This was corroborated by reduced brain amyloid load as well as the reversal of oxidative stress and neuroinflammation. Neuropathological analysis also displayed modest, but significant effect of sulfanegen on Aβ levels, reactive astrogliosis and microglial reactivity. More importantly, sulfanegen caused attenuation of progressive degeneration of noradrenergic system in the LC. Additionally, administration of sulfanegen supplemented brain 3MP levels, resulting in restoration of brain 3MST function.ConclusionCollectively, our results show that the provision of a 3MST substrate, sulfanegen, exhibits neuroprotective effects, along with restoration of cognitive function in an AD mouse model. This study suggests an important role of 3MST in AD pathophysiology and potential therapeutic utility of sulfanegen as a disease‐modifying treatment.