Regulation of protein kinase C by the anti-Parkinson drug, MAO-B inhibitor, rasagiline and its derivatives, in vivo.
We have recently shown that the anti-Parkinson-propargyl-containing monoamine oxidase B (MAO-B) inhibitor drug, rasagiline [N-propargyl-(1R)-aminoindan], and its cholinesterase inhibitor derivatives TV3326 and TV3279, regulate amyloid precursor protein (APP) processing by a protein kinase C (PKC)-dependent mechanism in SH-SY5Y neuroblastoma and PC12 cells. In the present study, we investigated the effect of rasagiline and its derivatives on the regulation of the PKC-dependent mechanism and APP processing under in vivo conditions. Administration of rasagiline (0.1 mg/kg) to male C57/BL mice for 14 days significantly decreased membrane-bound holoprotein APP levels in the hippocampus. Additionally, we observed that rasagiline up-regulated p-PKC levels and the expression of alpha and epsilon PKC isozymes in the hippocampus, indicating that the mechanism by which rasagiline affects APP processing may be related to PKC-associated signalling. The results also demonstrate that rasagiline treatment significantly elevated the levels of phosphorylated myristoylated alanine-rich C kinase substrate (p-MARCKS), a major substrate for PKC, as well as the levels of receptors for activated C kinase 1 (RACK1). Similar effects on APP and PKC levels were also demonstrated for the two cholinesterase inhibitor derivatives of rasagiline, TV3326 and TV3279. These results indicate that rasagiline and its derivatives regulate PKC-dependent mechanisms and APP processing. The activation and induction of PKC and MARCKS by these drugs may have a crucial role not only in their neuroprotective activity, but also in their ability to affect neuronal plasticity and spatial learning processes.
Bar-Am
Orit
O
Technion-Faculty of Medicine, Eve Topf and NPF Centers for Neurodegenerative Diseases, Department of Pharmacology, Haifa, Israel.
Yogev-Falach
Merav
M
Amit
Tamar
T
Sagi
Yotam
Y
Youdim
Moussa B H
MB
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D005959:Glucosidases; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007189:Indans / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism
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; D000978:Antiparkinson Agents; D002219:Carbamates; D007189:Indans; D047908:Intracellular Signaling Peptides and Proteins; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D008996:Monoamine Oxidase Inhibitors; D010750:Phosphoproteins; C512949:Prkcsh protein, mouse; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; C031967:rasagiline; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D011493:Protein Kinase C; D005959:Glucosidases