TY  - JOUR
AU  - Ruoff, Lisa Katharina
AU  - Bänfer, Irina Wanda Helene
AU  - Liedtke, Djavid Elias
AU  - China, Sofie Elena
AU  - Wiltfang, Jens
AU  - Bayer, Thomas A
AU  - Bock, Sören Frederik
AU  - Spandau, Friederike
AU  - Bouter, Caroline
AU  - Beindorff, Nicola
AU  - Bouter, Yvonne
TI  - Long-term thiethylperazine treatment in the Tg4-42 mouse model of Alzheimer's disease mouse: Therapeutic potential vs. adverse effects.
JO  - Pharmacology, biochemistry and behavior
VL  - 258
SN  - 0091-3057
CY  - Amsterdam [u.a.]
PB  - Elsevier Science
M1  - DZNE-2025-01336
SP  - 174127
PY  - 2025
AB  - 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.
KW  - (18)F-FDG PET (Other)
KW  - (Up to seven): Tg4-42 mouse model (Other)
KW  - Dopamine receptor antagonist (Other)
KW  - Morris water maze (Other)
KW  - Neurogenesis (Other)
KW  - Novel object recognition (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41218709
DO  - DOI:10.1016/j.pbb.2025.174127
UR  - https://pub.dzne.de/record/282576
ER  -