A multifunctional, neuroprotective drug, ladostigil (TV3326), regulates holo-APP translation and processing.
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.
Yogev-Falach
Merav
M
Eve Topf Center of Excellence for Neurodegenerative Diseases Research and Dept. of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, 31096 Haifa, Israel.
Bar-Am
Orit
O
Amit
Tamar
T
Weinreb
Orly
O
Youdim
Moussa B H
MB
D000544:Alzheimer Disease / Q000188:drug therapy; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008995:Monoamine Oxidase; D009447:Neuroblastoma / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000032:analysis
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; D016564:Amyloid beta-Protein Precursor; D061945:Caspase Inhibitors; D007189:Indans; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D008995:Monoamine Oxidase; C505407:CASP3 protein, human; D053148:Caspase 3