Rasagiline: Neurodegeneration, neuroprotection, and mitochondrial permeability transition

Abstract

Mitochondria are involved directly in cell survival and death. The assumption has been made that drugs that protect mitochondrial viability and prevent apoptotic cascade-induced mitochondrial permeability transition pore (MPTp) opening will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor anti-Parkinson drug. Unlike selegiline, it is not derived from amphetamine, and is not metabolized to neurotoxic L-methamphetamine derivative. In addition, it does not have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to levodopa for patients with early and late Parkinson's disease (PD) and adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Phase III controlled studies indicate that it might have a disease-modifying effect in PD that may be related to its neuroprotective activity. Its S isomer, TVP1022, is more than 1,000 times less potent as an MAO inhibitor. Both drugs, however, have neuroprotective activity in neuronal cell cultures in response to various neurotoxins, and in vivo in response to global ischemia, neurotrauma, head injury, anoxia, etc., indicating that MAO inhibition is not a prerequisite for neuroprotection. Their neuroprotective effect has been demonstrated to be associated directly with the propargylamine moiety, which protects mitochondrial viability and MTPp by activating Bcl-2 and protein kinase C (PKC) and by downregulating the proapoptotic FAS and Bax protein families. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective, neurotrophic, soluble APP alpha (sAPPalpha) by PKC- and MAP kinase-dependent activation of alpha-secretase. The identification of the propargylamine moiety as the neuroprotective component of rasagiline has led us to development of novel bifunctional anti-Alzheimer drugs (ladostigil) possessing cholinesterase and brain-selective MAO inhibitory activity and a similar neuroprotective mechanism of action.

Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway

“…MAO inhibitors, at lower concentration, have shown antineuronal apoptosis and neuro-protection effects, independent of MAO inhibition (19)(20)(21)(22). Our study using higher concentrations of MAO A inhibitor, which inhibits MAO A catalytic activity, also produced effects on antineuronal apoptosis and neuro-protection.…”

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

“…The non-amyloidogenic pathway, in which APP is sequentially cleaved by α-and γ-secretase, may prevent the production of Aβ (116,117). Several studies have reported that propargylamine-containing compounds, including ladostigil and M30, irreversible and selective MAO-B inhibitors, act as modulators of the proteolytic cleavage of APP via activation of the p42/44MAPK and PKC signaling pathways (61,(118)(119)(120). It was also demonstrated that M30 effectively inhibited Aβ accumulation and tau phosphorylation in APP/presenilin 1 mice, where it markedly downregulated the levels of phosphorylated cyclin-dependent kinase 5 and increased PKC and glycogen synthase kinase-3β phosphorylation (121).…”

TVP1022 Attenuates Cardiac Remodeling and Kidney Dysfunction in Experimental Volume Overload-Induced Congestive Heart Failure

“…Previously, we demonstrated that the neuroprotective efficacies of the monoamine oxidase (MAO)-B inhibitor rasagiline are similar to those of the non-MAO inhibitor TVP1022, suggesting that cytoprotection is not due to MAO inhibition. 8,10 Furthermore, we recently reported that pretreat-ment of neonatal rat ventricular myocytes with TVP1022 or propargylamine attenuated doxorubicin and serum starvationinduced apoptosis. 9 More recently, we reported that TVP1022 increased phospho-protein kinase C and phospho-(Ser 9) glycogen synthase kinase-3␤ levels in H9c2 cardiomyoblasts and neonatal rat ventricular myocytes and prevented H 2 O 2 -induced damage in H9c2 by preserving the mitochondrial membrane potential and inhibiting cytochrome c release from the mitochondria.…”

“…[7][8][9] On the basis of the cytoprotective efficacies of propargylamines in neurodegenerative processes, 8,9 we tested the hypothesis that TVP1022 (the S-isomer of rasagiline; Azilect) will alleviate cardiac and renal dysfunction in experimental CHF in rats. Previously, we demonstrated that the neuroprotective efficacies of the monoamine oxidase (MAO)-B inhibitor rasagiline are similar to those of the non-MAO inhibitor TVP1022, suggesting that cytoprotection is not due to MAO inhibition.…”