Sovateltide (IRL‐1620) prevents oxidative damage, mitochondrial dysfunction, and memory loss in a transgenic mouse model of Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the sixth leading cause of death in the United States and has no treatment or cure. New treatments are urgently needed. We have demonstrated cerebral endothelin B receptors (ETBR) as a potential target to treat AD. However, the mechanism of ETBR‐mediated neural regeneration and repair remains elusive. Therefore, we investigated the effect of sovateltide on progenitor cells mediated neural regeneration and its effect on cerebral tissue repair and functional recovery in transgenic AD mice.MethodIn this study, APP/PS1 transgenic mice and C57BL/6 control mice were divided into two groups (vehicle and sovateltide). Sovateltide (5 µg/kg) was intravenously injected three times at 2‐hour intervals on days 1, 3, and 6 every month until study endpoints (3‐, 6‐, and 12‐months age). Memory deficit was assessed using the Morris water maze test. Separate sets of mice were sacrificed at the end of 3, 6, and 12 months and beta‐amyloid plaque formation, oxidative stress, mitochondrial dysfunction, and cell survival parameters were assessed in the brain.ResultAPP/PS1 transgenic mice showed significant (p<0.001) impairment in spatial memory with elevated amounts of Aβ plaque. Treatment with sovateltide rescued learning and memory deficits and significantly (p<0.001) decreased Aβ plaque load compared to vehicle in 6 months and 12 months aged transgenic mice. Moreover, vehicle‐treated animals had high oxidative stress levels, as indicated by increased lipid peroxidation, MDA, and decreased antioxidants, SOD, and GSH compared to the vehicle group. These effects were reversed (p<0.001) in sovateltide treated animals indicating reduced oxidative stress. Higher neuronal progenitor cells (NPCs) differentiation and better mitochondrial morphology in the brain of sovateltide mice were also noted. There were no changes in the expression of any of these markers at three months.ConclusionOur data collectively demonstrate that sovateltide can improve memory deficits and neuronal damage and reduce oxidative stress and Aβ plaques in APP/PS1 mice. Our findings also strongly support the potential of sovateltide as a new multi‐target drug that can be used for treating Alzheimer’s disease.