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1. Neurodegener Dis. 2012 Feb 1. [Epub ahead of print]

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

Holthoewer D, Endres K, Schuck F, Hiemke C, Schmitt U, Fahrenholz F.

Department of Psychiatry and Psychotherapy, Medical Center of the Johannes
Gutenberg University, Mainz, Germany.

Background: ADAM10 (a disintegrin and metalloproteinase 10) has been demonstrated
to act as the main physiological α-secretase. Enzymatic activity of the
α-secretase on the one hand prevents the formation of toxic Aβ peptides and on
the other hand promotes the secretion of a neurotrophic and neuroprotective
amyloid precursor protein fragment (APPs-α) by cleaving the amyloid precursor
protein within its Aβ sequence. Enhancement of ADAM10's gene expression may
therefore present a valuable therapeutic approach for the treatment of
Alzheimer's disease (AD), where Aβ 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.

Copyright © 2012 S. Karger AG, Basel.

PMID: 22301853 [PubMed - as supplied by publisher]