Open AccessSAR110894, a potent histamine H3‐receptor antagonist, displays disease‐modifying activity in a transgenic mouse model of tauopathy
Author(s) -
DelayGoyet Philippe,
Blanchard Véronique,
Schussler Nathalie,
LopezGrancha Mati,
Ménager Jean,
Mary Véronique,
Sultan Eric,
Buzy Armelle,
Guillemot JeanClaude,
Stemmelin Jeanne,
Bertrand Philippe,
Rooney Thomas,
Pradier Laurent,
Barnéoud Pascal
Publication year - 2016
Publication title -
alzheimer's and dementia: translational research and clinical interventions
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.49
H-Index - 30
ISSN - 2352-8737
DOI - 10.1016/j.trci.2016.10.002
Subject(s) - tauopathy , hippocampus , hyperphosphorylation , histamine h3 receptor , genetically modified mouse , antagonist , neuroscience , tau protein , transgene , receptor , cortex (anatomy) , histamine , medicine , endocrinology , biology , alzheimer's disease , chemistry , microbiology and biotechnology , disease , neurodegeneration , phosphorylation , biochemistry , gene
Tau hyperphosphorylation and neurofibrillary tangles are histopathologic hallmarks of tauopathies. Histamine H3‐receptor antagonists have been proposed to reduce tau hyperphosphorylation in preclinical models. Methods We evaluated the ability of SAR110894, a selective histamine H3‐receptor antagonist, to inhibit tau pathology and prevent cognitive deficits in a tau transgenic mouse model (THY‐Tau22). Results SAR110894 treatment for 6 months (but not 2 weeks) in THY‐Tau22 mice decreased both tau hyperphosphorylation at pSer396‐pSer404 (AD2 signal) in the hippocampus and the number of AT8 (pSer199/202‐Thr205) positive cells in the cortex and decreased the formation of neurofibrillary tangles in the cortex, hippocampus, and amygdala. Macrophage inflammatory protein 1‐alpha messenger RNA expression was decreased in the hippocampus. SAR110894 also prevented episodic memory deficits, and this effect was still detected after treatment washout. Discussion Long‐term SAR110894 treatment could have potential disease modifying activity in neurodegenerative tauopathies.