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This Article Summary Full Text Full Text (PDF) All Versions of this Article: fj.05-4910fjev1 20/12/2177    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yogev-Falach, M. Articles by Youdim, M. B. H. Search for Related Content PubMed PubMed Citation Articles by Yogev-Falach, M. Articles by Youdim, M. B. H.

A multifunctional, neuroprotective drug, ladostigil (TV3326), regulates holo-APP translation and processing

Eve Topf Center of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel

²Correspondence: Dept. of Pharmacology, Technion-Faculty of Medicine P.O.B. 9697, 31096 Haifa, Israel. E-mail: youdim{at}tx.technion.ac.il

ABSTRACT

The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of the bifunctional drug ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate]. Ladostigil combines the neuroprotective effects of the antiparkinson drug rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine in a single molecule, as a potential treatment for Alzheimer’s disease (AD) and Lewy Body disease. Here, we assessed the dual effects of lodostigil in terms of the molecular mechanism of neuroprotection and amyloid precursor protein (APP) regulation/processing by using an apoptotic model of neuroblastoma SK-N-SH cells. Ladostigil dose-dependently decreased cell death via inhibition of the cleavage and prevention of caspase-3 activation (IC50=1.05 µM) through a mechanism related to regulation of the Bcl-2 family proteins, which resulted in reduced levels of Bad and Bax and induced levels of Bcl-2 gene and protein expression. We have also followed APP regulation/processing and found that ladostigil markedly decreased apoptotic-induced levels of holo-APP protein without altering APP mRNA levels, suggesting a posttranscriptional mechanism. In addition, the drug-elevated phosphorylated protein kinase C (pPKC) levels and stimulated the release of the nonamyloidogenic -secretase proteolytic pathway. Similar to ladostigil, its S-isomer, TV3279, which is a ChE inhibitor but lacks MAO inhibitory activity, exerted neuroprotective properties and regulated APP processing, indicating that these effects are independent of MAO inhibition.—Yogev-Falach, M., Bar-Am, O., Amit, T., Weinreb, O., Youdim, M. B. H. The multifunctional neuroprotective anti-Alzheimer/anti-Parkinson drug ladostigil (TV3326) regulates holo-APP translation and processing.