Acitretin, an Enhancer of Alpha-Secretase Expression, Crosses the Blood-Brain Barrier and Is Not Eliminated by P-Glycoprotein

作者：Holthoewer David; Endres Kristina; Schuck Florian; Hiemke Christoph; Schmitt Ulrich; Fahrenholz Falk^*

来源：Neurodegenerative Diseases, 2012, 10(1-4): 224-228.

DOI：10.1159/000334300

• Alzheimer%26apos
• s disease
• A disintegrin and metalloproteinase 10
• Retinoids
• Blood-brain barrier
• P-glycoprotein
• Clinical trial

Background: ADAM10 (a disintegrin and metalloproteinase 10) has been demonstrated to act as the main physiological alpha-secretase. Enzymatic activity of the alpha-secretase on the one hand prevents the formation of toxic A beta peptides and on the other hand promotes the secretion of a neurotrophic and neuroprotective amyloid precursor protein fragment (APPs-alpha) by cleaving the amyloid precursor protein within its A beta sequence. Enhancement of ADAM10%26apos;s gene expression may therefore present a valuable therapeutic approach for the treatment of Alzheimer%26apos;s disease (AD), where A beta peptides are severely involved in the pathogenesis. Objective: In cell culture and in a transgenic mouse model of AD, retinoids led to increased ADAM10 expression and activity. We therefore endeavor to develop a clinical application of synthetic retinoids such as acitretin in AD. Methods: The effect of synthetic retinoids on ADAM10 gene expression was analyzed by reporter gene assays in human neuroblastoma cell line SH-SY5Y. Penetrance of acitretin into the murine brain was analyzed by high-performance liquid chromatography. P-glycoprotein (P-gp) double-knockout mice with a deficiency in both isoforms, mdr1a and 1b, were used to analyze a possible role of P-gp-dependent efflux on acitretin distribution. Results: Acitretin and tamibarotene are both potent activators of ADAM10 promoter activity. Acitretin crosses the murine blood-brain barrier and its level in the mouse brain is not reduced by P-gp. Conclusion: Synthetic retinoids and especially acitretin seem to be ideal candidates to establish an ADAM10-based AD treatment, and therefore have already entered first clinical trials.

• 出版日期2012