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Amyloid Processing and Signal Transduction Properties of Antiparkinson‐Antialzheimer Neuroprotective Drugs Rasagiline and TV3326
Author(s) -
YOUDIM MOUSSA B.H.,
AMIT TAMAR,
BARAM ORIT,
WEINSTOCK MARTA,
YOGEVFALACH MERAV
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2003.tb07548.x
Subject(s) - rasagiline , neuroprotection , signal transduction , protein kinase c , chemistry , pharmacology , protein kinase a , kinase , monoamine oxidase , biochemistry , biology , enzyme , medicine , parkinson's disease , disease
A bstract : Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326 and TV3279 [( N ‐propargyl‐(3 R ) and (3 S ) aminoindan‐5‐yl)‐ethyl methyl carbamate], respectively were derived from rasagiline, for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)‐A and B, while its S ‐isomer, TV3279, lacks MAO‐inhibitory activity. The actions of these drugs in the regulation of the amyloid precursor protein (APP) processing using rat PC12 and human SH‐SY5Y neuroblastoma cells were examined. Both isomers stimulated the release of the non‐amyloidogenic α‐secretase form of soluble APP (sAPPα) from these cell lines. The increases in sAPPα, induced by TV3326 and TV3279, were dose‐dependent (0.1‐100 μM) and blocked by the hydroxamic acid‐based metalloprotease inhibitor, Ro31‐9790, suggesting mediation via α‐secretase activity. Using several signal transduction inhibitors, the involvement of protein kinase C (PKC), mitogen‐activated protein (MAP) kinase, and tyrosine kinase‐dependent pathways in the enhancement of sAPPα release by TV3326 and TV3279 was identified. In addition, both drugs directly induced the phosphorylation of p44 and p42 MAP kinase, which was abolished by the specific inhibitors of MAP kinase activation, PD98059 and U0126. These data suggest a novel pharmacological mechanism, whereby these ChE inhibitors regulate the secretary processes of APP via activation of the MAP kinase pathway.