Amyloid processing and signal transduction properties of antiparkinson-antialzheimer neuroprotective drugs rasagiline and TV3326.
Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326 and TV3279 [(N-propargyl-(3R) and (3S) 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 alpha-secretase form of soluble APP (sAPPalpha) from these cell lines. The increases in sAPPalpha, induced by TV3326 and TV3279, were dose-dependent (0.1-100 micro M) and blocked by the hydroxamic acid-based metalloprotease inhibitor, Ro31-9790, suggesting mediation via alpha-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 sAPPalpha 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.
Youdim
Moussa B H
MB
Department of Pharmacology, Technion-Faculty of Medicine, Haifa, Israel. youdim@tx.technion.ac.il
Amit
Tamar
T
Bar-Am
Orit
O
Weinstock
Marta
M
Yogev-Falach
Merav
M
D000544:Alzheimer Disease / Q000188:drug therapy; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy; D051381:Rats; D015398:Signal Transduction
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; C476551:(N-propargyl-(3R) and (3S) aminoindan-5-yl)-ethyl methyl carbamate; D016564:Amyloid beta-Protein Precursor; D002219:Carbamates; D004791:Enzyme Inhibitors; D007189:Indans; D018696:Neuroprotective Agents; C031967:rasagiline; D020928:Mitogen-Activated Protein Kinases