Regulation of protein kinase C by the anti‐Parkinson drug, MAO‐B inhibitor, rasagiline and its derivatives, in vivo

Abstract

We have recently shown that the anti-Parkinson-propargylcontaining 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 a and e 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. Keywords: amyloid precursor protein, myristoylated alaninerich C kinase substrate, protein kinase C, rasagiline.

PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice

“…Previous studies used Western blot analysis to measure PKC and PKC ␣ in hippocampal neurons (Bar-Am et al, 2004). For these measurements, the entire hippocampal areas were assayed.…”

Multifunctional Neuroprotective Derivatives of Rasagiline as Anti-Alzheimer's Disease Drugs

“…19 -20 Rasagiline and propargylamine significantly attenuated cell death induced by serum deprivation in neuronal cells. 6,12,20 -23 The role for protein kinase C (PKC) activation in the neuroprotective mechanism of rasagiline and propargylamine was supported by results that both compounds can increase phosphorylated-PKC (p-PKC) levels and upregulate two essential PKC isoforms involved in cell survival pathways, PKC␣ and PKC, in mice hippocampus 19 and PC12 cells. 24 The inhibition of PKC activity blocked the neuroprotective action of rasagiline and its propargyl moiety in serum-deprived PC12 cells.…”

“…53,77 Consistent with this, a previous study showed that treatment with ladostigil clearly decreased the levels of cell-associated, holo-APP in the mice hippocampus, which indicates that APP expression can also be regulated by ladostigil under in vivo conditions. 19 Moreover, the observation that ladostigil did not alter APP mRNA levels, may suggest that the decrease in APP protein and A␤ levels can be attributed to suppression of APP translation, in analogy to another ChEI, phenserine. 78 A recent study demonstrated that selective butyrylcholinesterase (BuChE) inhibitors reduced APP and A␤ levels in vitro and in vivo.…”

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