Involvement of MAP kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline.
Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326, (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate, and TV3279, (N-propargyl-(3S) aminoindan-5-yl)-ethyl methyl carbamate, were derived from rasagiline for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)-A and -B, whereas its S-isomer, TV3279, lacks MAO inhibitory activity. The action of these drugs in the regulation of amyloid precursor protein (APP) processing, using rat PC12 and human SH-SY5Y neuroblastoma cells, was examined. Both isomers stimulated the release of the non-amyloidogenic a-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 mM) and blocked by the hydroxamic acid-based metalloprotease inhibitor, Ro31-9790, suggesting mediation via a-secretase activity. Using several signal transduction inhibitors, we identified 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. 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 secretory processes of APP via activation of the MAP kinase pathway.
Technion-Faculty of Medicine, Eve Topf and NPF Centers for Neurodegenerative Diseases Department of Pharmacology Haifa, Israel.
Merav
M
Yogev-Falach
Tamar
T
Amit
Orit
O
Bar-Am
Marta
M
Weinstock
Moussa B H
MB
Youdim
D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016716:PC12 Cells; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007189:Indans; D007211:Indoles; D008301:Maleimides; D008996:Monoamine Oxidase Inhibitors; D009281:Naphthalenes; D018696:Neuroprotective Agents; C031967:rasagiline; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C058819:calphostin C; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one