Pharmacology, biochemistry, and behavior · 2025
Long-term thiethylperazine treatment in the Tg4-42 mouse model of Alzheimer's disease mouse: Therapeutic potential vs. adverse effects.
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Ruoff Lisa Katharina, Bänfer Irina Wanda Helene, Liedtke Djavid Elias, China Sofie Elena, Wiltfang Jens, Bayer Thomas A, Bock Sören Frederik, Spandau Friederike, Bouter Caroline, Beindorff Nicola, Bouter Yvonne
Аннотация
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments. Thiethylperazine, a dopamine receptor antagonist with antiemetic and antidopaminergic properties, has been proposed as a potential therapeutic agent for AD. However, its impact on cognitive function in AD remains unclear.
AIMS: This study investigated the long-term effects of thiethylperazine on memory, anxiety-like behavior, motor function, and AD pathology in Tg4-42 mice, a model characterized by Aβ4-42 overexpression and progressive neurodegeneration. Additionally, the impact of prolonged thiethylperazine treatment on behavioral outcomes and cerebral glucose metabolism in healthy adult C57BL/6J wild-type (WT) mice were examined.
METHODS: Tg4-42 and WT mice were treated daily with 10 mg/kg thiethylperazine for 6 months, starting at 10 weeks of age. Memory, anxiety-related, and motor tests were performed at 7.5 months. Immunohistochemical analyses were conducted to quantify effects on Aβ pathology, neurogenesis, neuron number, and neuroinflammation. Additionally, 18F-FDG-PET imaging was used to evaluate metabolic activity in WT mice following treatment.
RESULTS: Thiethylperazine improved recognition memory in Tg4-42 mice in the Novel Object Recognition test and exhibited anxiolytic properties. However, it impaired spatial learning in the Morris Water Maze (MWM), reduced locomotion, and failed to mitigate motor impairments. No effects on neuron loss or neuroinflammation were observed. In WT mice, thiethylperazine altered learning processes in the MWM, as indicated by shifts in search strategies, induced hypometabolism and increased neurogenesis.
CONCLUSION: Although thiethylperazine offers mild cognitive benefits in Tg4-42, its adverse effects on learning strategies and locomotion raise questions about its potential as a therapeutic option for AD.
AIMS: This study investigated the long-term effects of thiethylperazine on memory, anxiety-like behavior, motor function, and AD pathology in Tg4-42 mice, a model characterized by Aβ4-42 overexpression and progressive neurodegeneration. Additionally, the impact of prolonged thiethylperazine treatment on behavioral outcomes and cerebral glucose metabolism in healthy adult C57BL/6J wild-type (WT) mice were examined.
METHODS: Tg4-42 and WT mice were treated daily with 10 mg/kg thiethylperazine for 6 months, starting at 10 weeks of age. Memory, anxiety-related, and motor tests were performed at 7.5 months. Immunohistochemical analyses were conducted to quantify effects on Aβ pathology, neurogenesis, neuron number, and neuroinflammation. Additionally, 18F-FDG-PET imaging was used to evaluate metabolic activity in WT mice following treatment.
RESULTS: Thiethylperazine improved recognition memory in Tg4-42 mice in the Novel Object Recognition test and exhibited anxiolytic properties. However, it impaired spatial learning in the Morris Water Maze (MWM), reduced locomotion, and failed to mitigate motor impairments. No effects on neuron loss or neuroinflammation were observed. In WT mice, thiethylperazine altered learning processes in the MWM, as indicated by shifts in search strategies, induced hypometabolism and increased neurogenesis.
CONCLUSION: Although thiethylperazine offers mild cognitive benefits in Tg4-42, its adverse effects on learning strategies and locomotion raise questions about its potential as a therapeutic option for AD.