The neuroprotective mechanism of action of the multimodal drug ladostigil.
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 multimodal drug, ladostigil (TV3326) ((N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate). Ladostigil combines neuroprotective effects with monoamine oxidase -A and -B and cholinesterase inhibitory activities in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy Body disease. Preclinical studies show that ladostigil has antidepressant and anti-AD activities and the clinical development is planned for these dementias. In this review, we discuss the multimodal effects of ladostigil in terms of neuroprotective molecular mechanism in vivo and in vitro, which include the amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase pathways; regulation of the Bcl-2 family members; inhibition of cell death markers and up-regulation of neurotrophic factors. Altogether, these scientific findings make ladostigil a potentially valuable drug for the treatment of AD.
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, 31096, Israel. worly@tx.technion.ac.il
Orly
O
Weinreb
Tamar
T
Amit
Orit
O
Bar-Am
Merav
M
Yogev-Falach
Moussa B H
MB
Youdim
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; D007189:Indans; D018696:Neuroprotective Agents; D053829:Amyloid Precursor Protein Secretases