almorexant and Alzheimer-Disease

To explore the effects of different doses of almorexant (an dual orexin receptor antagonist) on learning and memory in Alzheimer's disease (AD) mice.. Forty-four APP/PS1 (model of Alzheimer's disease; AD) mice were randomly divided into 4 groups: the control group (CON) and those that received 10 mg/kg almorexant (low dose; LOW), 30 mg/kg almorexant (medium dose; MED) and 60 mg/kg almorexant (high dose; HIGH). During the 28-day intervention period, mice received an intraperitoneal injection at the beginning of the light period (6:00 am). The effects of different doses of almorexant on learning and memory and 24-hour sleep-wake behaviour were assessed by immunohistochemical staining. The above continuous variables are expressed as the mean ± standard deviation (SD), and then univariate regression analysis and generalized estimating equations were performed to compare the groups; these results are expressed as the mean difference (MD) and 95% confidence interval (CI). The statistical software used STATA 17.0 MP.. Forty-one mice completed the experiment (3 died: 2 mice in the HIGH group and 1 mouse in the CON group). Compared with the CON group, the LOW group (MD=6803 s, 95% CI: 4470 to 9137 s), MED group (MD=14,473 s, 95% CI: 12,140-16,806 s) and the HIGH group (MD=24,505 s, 95% CI: 22,052-26,959 s) had significantly longer sleep durations. The Y maze results showed that LOW group (MD=0.14,95%CI: 0.078-0.20) and MED group (MD=0.14,95%CI = 0.074-0.20) mice compared to the CON group, and the low-medium dose of Almorexant did not damage the short-term learning and memory performance of APP / PS1 (AD) mice.Compared with the CON, LOW, and MED groups, the HIGH group exhibited a significant decrease in the Aβ plaque-positive area in the cortex (MD= -0.030, 95% CI: -0.035 to -0.025; MD=-0.049, 95% CI: -0.054 to -0.044; and MD=-0.07, 95% CI: -0.076 to -0.066, respectively).. The moderate dose of almorexant (30 mg/kg) prolonged the sleep duration of APP/PS1 (AD) mice to a greater extent than the low dose (10 mg/kg) without altering learning and memory. The MED mice showed a good sleep response and a small residual effect on the next day. High-dose (60 mg / kg) almorexant impaired behavioral learning and memory performance in mice.Compared to the CON group and the LOW group, the MED group exhibited improved working memory. Thus, treatment with almorexant may reduce β-amyloid deposition in AD, slowing neurodegeneration. Additional studies are needed to determine the mechanism of action.

Topics: Acetamides; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Hippocampus; Maze Learning; Mice; Mice, Transgenic

Amyloid-beta (Abeta) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease. The factors regulating this process are only partly understood. Abeta aggregation is a concentration-dependent process that is likely responsive to changes in brain interstitial fluid (ISF) levels of Abeta. Using in vivo microdialysis in mice, we found that the amount of ISF Abeta correlated with wakefulness. The amount of ISF Abeta also significantly increased during acute sleep deprivation and during orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, Abeta plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease.

Topics: Acetamides; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antigens, Surface; Circadian Rhythm; Disease Models, Animal; Extracellular Fluid; Female; Hippocampus; Humans; Intracellular Signaling Peptides and Proteins; Isoquinolines; Light; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuropeptides; Orexin Receptors; Orexins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Signal Transduction; Sleep; Sleep Deprivation; Wakefulness