Linked Life Data

16935943

Source:http://linkedlifedata.com/resource/pubmed/id/16935943

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2006-10-2
pubmed:abstractText
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 microM) 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 alpha-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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1530-6860
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
20
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2177-9
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:16935943-Alzheimer Disease, pubmed-meshheading:16935943-Amyloid beta-Protein Precursor, pubmed-meshheading:16935943-Apoptosis, pubmed-meshheading:16935943-Caspase 3, pubmed-meshheading:16935943-Caspases, pubmed-meshheading:16935943-Cell Line, Tumor, pubmed-meshheading:16935943-Gene Expression Regulation, pubmed-meshheading:16935943-Humans, pubmed-meshheading:16935943-Indans, pubmed-meshheading:16935943-Monoamine Oxidase, pubmed-meshheading:16935943-Neuroblastoma, pubmed-meshheading:16935943-Neuroprotective Agents, pubmed-meshheading:16935943-Protein Biosynthesis, pubmed-meshheading:16935943-Protein Processing, Post-Translational, pubmed-meshheading:16935943-Proto-Oncogene Proteins c-bcl-2, pubmed-meshheading:16935943-RNA, Messenger, pubmed-meshheading:16935943-RNA Processing, Post-Transcriptional
pubmed:year
2006
pubmed:articleTitle
A multifunctional, neuroprotective drug, ladostigil (TV3326), regulates holo-APP translation and processing.
pubmed:affiliation
Eve Topf Center of Excellence for Neurodegenerative Diseases Research and Dept. of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, 31096 Haifa, Israel.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't