title: Extract of Caragana sinica as a potential therapeutic option for increasing alpha-secretase gene expression.
abstract: BACKGROUND
  Alzheimer's disease represents one of the main neurological disorders in the aging population. Treatment options so far are only of symptomatic nature and efforts in developing disease modifying drugs by targeting amyloid beta peptide-generating enzymes remain fruitless in the majority of human studies. During the last years, an alternative approach emerged to target the physiological alpha-secretase ADAM10, which is not only able to prevent formation of toxic amyloid beta peptides but also provides a neuroprotective fragment of the amyloid precursor protein - sAPPalpha.
  
  
  OBJECTIVE
  To identify novel alpha-secretase enhancers from a library of 313 extracts of medicinal plants indigenous to Korea, a screening approach was used and hits were further evaluated for their therapeutic value.
  
  
  METHODS
  The extract library was screened for selective enhancers of ADAM10 gene expression using a luciferase-based promoter reporter gene assay in the human neuroblastoma cell line SH-SY5Y. Candidate extracts were then tested in wild type mice for acute behavioral effects using an open field paradigm. Brain and liver tissue from treated mice was biochemically analyzed for ADAM10 gene expression in vivo. An in vitro blood-brain barrier model and an in vitro ATPase assay were used to unravel transport properties of bioactive compounds from extract candidates. Finally, fractionation of the most promising extract was performed to identify biologically active components.
  
  
  RESULTS
  The extract of Caragana sinica (Buc'hoz) Rehder was identified as the best candidate from our screening approach. We were able to demonstrate that the extract is acutely applicable in mice without obvious side effects and induces ADAM10 gene expression in peripheral tissue. A hindered passage across the blood-brain barrier was detected explaining lack of cerebral induction of ADAM10 gene expression in treated mice. By fractionating C. sinica extract we identified alpha-viniferin as one of the biologically active components.
  
  
  CONCLUSIONS
  The extract of C. sinica and alpha-viniferin as one of its bioactive constituents might serve as novel therapeutic options for treating Alzheimer's disease by increasing ADAM10 gene expression. The identification of alpha-viniferin represents a promising starting point to achieve blood-brain barrier penetrance in the future.
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg University, Untere Zahlbacher Strasse 8, 55131 Mainz, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Schuck
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg University, Untere Zahlbacher Strasse 8, 55131 Mainz, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schmitt
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg University, Untere Zahlbacher Strasse 8, 55131 Mainz, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Reinhardt
authors.affiliation: REPAIR-lab, Institute of Pathology, University Medical Center of the Johannes Gutenberg University and European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Langenbeckstrasse 1, 55101 Mainz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Freese
authors.affiliation: College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, South Korea.
authors.forename: Ik-Soo
authors.initials: IS
authors.lastname: Lee
authors.affiliation: Institute of Biotechnology and Drug Research, Johannes Gutenberg University, Duesbergweg 10-14, 55128 Mainz, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thines
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg University, Untere Zahlbacher Strasse 8, 55131 Mainz, Germany. Electronic address: kristina.endres@unimedizin-mainz.de.
authors.forename: Kristina
authors.initials: K
authors.lastname: Endres
mesh_terms: D051722:ADAM Proteins; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier; D032602:Caragana / Q000737:chemistry*; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000819:agonists*; D051379:Mice; D018345:Mice, Knockout; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry*; D011401:Promoter Regions, Genetic
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D001572:Benzofurans; D008565:Membrane Proteins; D010936:Plant Extracts; C064176:alpha-viniferin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse
keywords: ADAM10; Alpha-viniferin; Alzheimer's disease; Blood–brain barrier; Caragana sinica; Medicinal plant extracts