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<p>Risk factors for developing dementia include type 2 diabetes and obesity. Streptozotocin (STZ) intracerebroventricularly (icv) treated rats are a well-accepted animal model for the sporadic Alzheimer`s disease (sAD). STZ-icv treatment results in an insulin-resistant brain state, cognitive deficits, and reduced hippocampal adult neurogenesis (AN). As the antidiabetic drug liraglutide (LIR) has been shown to improve AN, and spatial learning in an AD mouse model, we have investigated the effects of LIR treatment on spatial and fear-motivated learning, AN, and gene expression profiles in STZ-icv treated rats. Male Wistar rats were injected icv with STZ (f.c. 3&#xa0;mg/kg) or vehicle. Two months later, four weeks of subcutaneous treatment with LIR (0.3&#xa0;mg/kg) began. Cognitive abilities were assessed with the Morris water maze (MWM) and passive avoidance (PA) test. We performed quantitative immunohistochemistry to evaluate AN, and quantitative real-time PCR to determine the expression levels of genes involved in insulin signaling, glucose uptake, and neuroinflammation. STZ-icv rats showed significantly impaired spatial learning performance in the MWM and fear-motivated memory deficits in the PA test accompanied by reduced AN, downregulated insulin system- and glucose metabolism-related genes in the hippocampus and prefrontal cortex. LIR treatment did not reverse these cognitive deficits of STZ-icv rats in the MWM, and did even worsen PA performance. However, LIR partially restored dysregulated gene expression, however, additionally stimulated neuroinflammation. Refined experimental designs, e.g., refined dosing, should help to further clarify the therapeutic potential of LIR in the future. </p>

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Approaching therapy of Alzheimer’s disease via the antidiabetic drug liraglutide—a study with streptozotocin intracerebroventricularly treated Wistar rats

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月12日

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  • Ana Knezovic,
  • Michael Hosch,
  • Catharina Sophia Hamann,
  • Sandy Popp,
  • Gabriela Ortega,
  • Jelena Osmanovic-Barilar,
  • Edna Grünblatt,
  • Camelia Monoranu,
  • Peter Riederer,
  • Melita Salkovic-Petrisic,
  • Angelika Schmitt-Böhrer

摘要

Risk factors for developing dementia include type 2 diabetes and obesity. Streptozotocin (STZ) intracerebroventricularly (icv) treated rats are a well-accepted animal model for the sporadic Alzheimer`s disease (sAD). STZ-icv treatment results in an insulin-resistant brain state, cognitive deficits, and reduced hippocampal adult neurogenesis (AN). As the antidiabetic drug liraglutide (LIR) has been shown to improve AN, and spatial learning in an AD mouse model, we have investigated the effects of LIR treatment on spatial and fear-motivated learning, AN, and gene expression profiles in STZ-icv treated rats. Male Wistar rats were injected icv with STZ (f.c. 3 mg/kg) or vehicle. Two months later, four weeks of subcutaneous treatment with LIR (0.3 mg/kg) began. Cognitive abilities were assessed with the Morris water maze (MWM) and passive avoidance (PA) test. We performed quantitative immunohistochemistry to evaluate AN, and quantitative real-time PCR to determine the expression levels of genes involved in insulin signaling, glucose uptake, and neuroinflammation. STZ-icv rats showed significantly impaired spatial learning performance in the MWM and fear-motivated memory deficits in the PA test accompanied by reduced AN, downregulated insulin system- and glucose metabolism-related genes in the hippocampus and prefrontal cortex. LIR treatment did not reverse these cognitive deficits of STZ-icv rats in the MWM, and did even worsen PA performance. However, LIR partially restored dysregulated gene expression, however, additionally stimulated neuroinflammation. Refined experimental designs, e.g., refined dosing, should help to further clarify the therapeutic potential of LIR in the future.