SAR110894, a potent histamine H3-receptor antagonist, displays disease-modifying activity in a transgenic mouse model of tauopathy

详细信息    查看全文

• 作者：Philippe Delay-Goyet^a ; ^{philippe.delay-goyet@sanofi.com} ; Vé ; ronique Blanchard^a ; Nathalie Schussler^a ; Mati Lopez-Grancha^a ; Jean Mé ; nager^a ; Vé ; ronique Mary^a ; Eric Sultan^b ; Armelle Buzy^c ; Jean-Claude Guillemot^c ; Jeanne Stemmelin^a ; Philippe Bertrand^a ; Thomas Rooney^a ; Laurent Pradier^a ; Pascal Barné ; oud^a
• 关键词：Alzheimer's disease ; Tau pathology ; Cognition ; Histamine H3-receptor ; THY-Tau22 ; Transgenic
• 刊名：Alzheimer's & Dementia: Translational Research & Clinical Interventions
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：2
• 期：4
• 页码：267-280
• 全文大小：2363 K
• 卷排序：2

文摘

Tau hyperphosphorylation and neurofibrillary tangles are histopathologic hallmarks of tauopathies. Histamine H3-receptor antagonists have been proposed to reduce tau hyperphosphorylation in preclinical models.MethodsWe 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).ResultsSAR110894 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.DiscussionLong-term SAR110894 treatment could have potential disease modifying activity in neurodegenerative tauopathies.