Suvorexant ameliorates cognitive impairments and pathology in APP/PS1 transgenic mice

Neurobiol Aging. 2020 Jul;91:66-75. doi: 10.1016/j.neurobiolaging.2020.02.020. Epub 2020 Mar 3.

Abstract

Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-β protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-β plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD.

Keywords: APP/PS1 transgenic mice; Amyloid-β protein; Learning and memory; Long-term potentiation; Suvorexant; pCREB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / complications
  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Azepines / pharmacology*
  • Azepines / therapeutic use*
  • Chronobiology Disorders / drug therapy*
  • Chronobiology Disorders / etiology
  • Cognitive Dysfunction / cerebrospinal fluid
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / etiology
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Disease Models, Animal
  • Gene Expression / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Long-Term Potentiation / drug effects
  • Mice, Transgenic
  • Neuronal Plasticity / drug effects
  • Neuroprostanes*
  • Orexin Receptor Antagonists*
  • Orexins / cerebrospinal fluid
  • Triazoles / pharmacology*
  • Triazoles / therapeutic use*

Substances

  • Amyloid beta-Peptides
  • Azepines
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Neuroprostanes
  • Orexin Receptor Antagonists
  • Orexins
  • Triazoles
  • suvorexant