Scholarlink

Background <p>Alzheimer’s disease (AD) is the leading cause of dementia. There are limited approved medications that delay cognitive decline or lessen neuropsychiatric symptoms. Numerous clinical trials for AD using a single drug administration have failed to meet therapeutic endpoints, which is most likely due to the complexity of AD. A multimodal therapeutic intervention is more likely to improve symptoms by targeting multiple targets implicated in AD. Here, we investigated if targeting both N-Methyl-D-aspartic acid receptors (NMDARs) and serotonin type 4 receptors (5-HT<sub>4</sub>R) may have beneficial effects in a mouse model of AD, as they have separately been shown to improve cognition and/or mood.</p> Methods <p>Male and female control (Ctrl) or APP/PS1 mice were administered single, intermittent, or chronic administration of 1) saline; 2) (<i>R</i>,<i>S</i>)-ketamine, an NMDAR antagonist; 3) prucalopride, a 5-HT<sub>4</sub>R agonist; or 4) (<i>R</i>,<i>S</i>)-ketamine + prucalopride to simultaneously target co-morbid neuropsychiatric and cognitive deficits. Behavioral assays were then administered to measure cognition, perseverative behavior, hyponeophagia, and/or sleep. Brains were processed for glial fibrillary acidic protein (GFAP) immunohistochemistry.</p> Results <p>Single and chronic administration of (<i>R</i>,<i>S</i>)-ketamine + prucalopride administration improved cognitive decline by increasing memory retrieval in a contextual fear conditioning (CFC) paradigm in APP/PS1 mice. Drug efficacy was less effective in females than in males and was age dependent. Hippocampal GFAP immunoreactivity was decreased by chronic (<i>R</i>,<i>S</i>)-ketamine + prucalopride treatment in females.</p> Conclusions <p>Our results indicate that combined administration of (<i>R</i>,<i>S</i>)-ketamine + prucalopride is a novel multimodal therapeutic strategy to treat cognitive decline in AD. Future work will further characterize these interactions with the goal of clinical development.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Combinatorial targeting of NMDARs and 5-HT4Rs exerts beneficial effects in a mouse model of Alzheimer’s disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月15日

查看全文
  • Briana K. Chen,
  • Holly C. Hunsberger,
  • Alicia Whye,
  • Louise C. Matthews,
  • Alyson Yook,
  • Moshe J. Willner,
  • Ryan W. Logan,
  • Stefanie Johns,
  • Eric Weisblum,
  • Christine A. Denny

摘要

Background

Alzheimer’s disease (AD) is the leading cause of dementia. There are limited approved medications that delay cognitive decline or lessen neuropsychiatric symptoms. Numerous clinical trials for AD using a single drug administration have failed to meet therapeutic endpoints, which is most likely due to the complexity of AD. A multimodal therapeutic intervention is more likely to improve symptoms by targeting multiple targets implicated in AD. Here, we investigated if targeting both N-Methyl-D-aspartic acid receptors (NMDARs) and serotonin type 4 receptors (5-HT4R) may have beneficial effects in a mouse model of AD, as they have separately been shown to improve cognition and/or mood.

Methods

Male and female control (Ctrl) or APP/PS1 mice were administered single, intermittent, or chronic administration of 1) saline; 2) (R,S)-ketamine, an NMDAR antagonist; 3) prucalopride, a 5-HT4R agonist; or 4) (R,S)-ketamine + prucalopride to simultaneously target co-morbid neuropsychiatric and cognitive deficits. Behavioral assays were then administered to measure cognition, perseverative behavior, hyponeophagia, and/or sleep. Brains were processed for glial fibrillary acidic protein (GFAP) immunohistochemistry.

Results

Single and chronic administration of (R,S)-ketamine + prucalopride administration improved cognitive decline by increasing memory retrieval in a contextual fear conditioning (CFC) paradigm in APP/PS1 mice. Drug efficacy was less effective in females than in males and was age dependent. Hippocampal GFAP immunoreactivity was decreased by chronic (R,S)-ketamine + prucalopride treatment in females.

Conclusions

Our results indicate that combined administration of (R,S)-ketamine + prucalopride is a novel multimodal therapeutic strategy to treat cognitive decline in AD. Future work will further characterize these interactions with the goal of clinical development.