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@ARTICLE{Ruoff:282576,
author = {Ruoff, Lisa Katharina and Bänfer, Irina Wanda Helene and
Liedtke, Djavid Elias and China, Sofie Elena and Wiltfang,
Jens and Bayer, Thomas A and Bock, Sören Frederik and
Spandau, Friederike and Bouter, Caroline and Beindorff,
Nicola and Bouter, Yvonne},
title = {{L}ong-term thiethylperazine treatment in the {T}g4-42
mouse model of {A}lzheimer's disease mouse: {T}herapeutic
potential vs. adverse effects.},
journal = {Pharmacology, biochemistry and behavior},
volume = {258},
issn = {0091-3057},
address = {Amsterdam [u.a.]},
publisher = {Elsevier Science},
reportid = {DZNE-2025-01336},
pages = {174127},
year = {2025},
abstract = {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.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.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.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.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.},
keywords = {(18)F-FDG PET (Other) / (Up to seven): Tg4-42 mouse model
(Other) / Dopamine receptor antagonist (Other) / Morris
water maze (Other) / Neurogenesis (Other) / Novel object
recognition (Other)},
cin = {AG Wiltfang},
ddc = {540},
cid = {I:(DE-2719)1410006},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41218709},
doi = {10.1016/j.pbb.2025.174127},
url = {https://pub.dzne.de/record/282576},
}