Involvement of orexin nerves in early stage of Alzheimer’s disease model mice and preventive effect of orexin receptor antagonists

Abstract Background Mild cognitive impairment (MCI) is a condition between healthy cognition and dementia with a high probability of progression to Alzheimer’s disease (AD). Elevated levels of orexin (OX) have been reported in the cerebrospinal fluid of patients with MCI and AD. Objective To investigate the efficacy of dual OX receptor antagonists (suvorexant and lemborexant) in an early-stage AD mouse model (App-KI). Methods The expression of the OX receptor gene, the levels of suvorexant and lemborexant in the brain after a single oral dose, and their effects on locomotor activity were investigated in wild-type mice. In addition, the cognitive function of wild-type and App-KI mice was assessed using the Y-maze test after oral administration of suvorexant or lemborexant once a day for 60 d. After the behavioral test, amyloid-beta levels were quantified in the hippocampal CA1 region of App-KI mice. Results The expression of the OX receptor gene was highest in the lateral hypothalamus and was also observed in other brain regions. Drug levels peaked at 20–40 min for suvorexant and 15 min for lemborexant and declined, still detectable 24 h later. Locomotor activity was reduced after suvorexant or lemborexant administration; however, 24 h after administration, locomotor activity did not differ from the control group. In particular, the Y-maze test showed that suvorexant and lemborexant prevented cognitive impairment in App-KI mice. Furthermore, suvorexant and lemborexant suppressed amyloid-beta accumulation in the hippocampal CA1 region of App-KI mice. Conclusion The results suggest that suvorexant and lemborexant effectively suppress the early stages of AD.