Effects of long-term thiethylperazine treatment on Alzheimer's pathology in Tg4-42 mice: Therapeutic Potential vs. Adverse Effects

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder causing cognitive decline and behavioral impairments. Despite recent FDA approval of lecanemab (Leqembi) and donanemab (Kisunla), no universal or easily accessible treatment exists. Thiethylperazine, a dopamine receptor antagonist, has been proposed as a potential therapeutic agent for AD by promoting Amyloid beta export across the blood-brain barrier, but its cognitive effects remain unclear. A Phase 2 clinical study (ClinicalTrials.gov ID: NCT03417986) was initiated by Immunogenetics AG to assess the effects and safety of thiethylperazine in a total of 20 AD patients. However, the results have not yet been published. This study examined its long-term impact on memory, anxiety, 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 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 intraperitoneally for six months, starting at 10 weeks of age. Behavioral tests assessed motor function, learning, anxiety, and memory at an age of 7,5 months. Immunohistochemical analyses were conducted to quantify the effects on Aβ pathology, neurogenesis, neuron number, and neuroinflammation.

Additionally, ¹⁸F-FDG-PET imaging evaluated metabolic activity in WT mice post-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 shows mild cognitive benefits in Tg4-42 as well as non- specific anxiolytic effects, adverse effects on learning strategies and locomotion raise questions about its potential as a therapeutic option for AD.

Publication History

Article published online:
30 April 2025