Extract of Caragana sinica as a potential therapeutic option for increasing alpha-secretase gene expression

Abstract

BackgroundAlzheimer'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. PurposeTo 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. MethodsThe 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. ResultsThe 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. ConclusionThe 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.