Aminoindan and hydroxyaminoindan, metabolites of rasagiline and ladostigil, respectively, exert neuroprotective properties in vitro

Abstract

The anti-Parkinson, selective irreversible monoamine oxidase B inhibitor drug, rasagiline (Azilect), recently approved by the US Food and Drug Administration, has been shown to possess neuroprotective-neurorescue activities in in vitro and in vivo models. Recent preliminary studies indicated the potential neuroprotective effect of the major metabolite of rasagiline, 1-(R)-aminoindan. In the current study, the neuroprotective properties of 1-(R)-aminoindan were assessed employing a cytotoxic model of human neuroblastoma SK-N-SH cells in high-density culture-induced neuronal death. We show that aminoindan (0.1-1 lmol/L) significantly reduced the apoptosis-associated phosphorylated protein, H2A.X (Ser139), decreased the cleavage of caspase 9 and caspase 3, while increasing the anti-apoptotic proteins, Bcl-2 and Bcl-xl. Protein kinase C (PKC) inhibitor, GF109203X, prevented the neuroprotection, indicating the involvement of PKC in aminoindaninduced cell survival. Aminoindan markedly elevated pPKC(pan) and specifically that of the pro-survival PKC isoform, PKCe. Additionally, hydroxyaminoindan, a metabolite of a novel bifunctional drug, ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], combining cholinesterase and monoamine oxidase inhibitor activity, exerted similar neuroprotective properties. Aminoindan and hydroxyaminoindan also protected rat pheochromacytoma PC-12 cells against the neurotoxin, 6-hydroxydopamine. Our findings suggest that both metabolites may contribute to the overall neuroprotective activity of their respective parent compounds, further implicating rasagiline and ladostigil as potentially valuable drugs for treatment of a wide variety of neurodegenerative disorders of aging.

Effects of rasagiline, its metabolite aminoindan and selegiline on glutamate receptor mediated signalling in the rat hippocampus slice in vitro

“…Both are believed to act by inhibition of monoamine oxidase B (MAO B). However, both are metabolized in a different way: rasagiline gives rise to aminoindan, a compound reported to have neuroprotective capabilities of its own, whereas selegiline gives rise to the neurotoxic metabolite methamphetamine [1,2]. Similar electropharmacograms obtained by quantitative brain field potential analysis were obtained from freely moving rats in the presence of rasagiline and its metabolite aminoindan (not inhibiting monoamine oxidase B).…”

Differential modulation of unapposed connexin 43 hemichannel electrical conductance by protein kinase C isoforms

“…Preservation of Cx43 phosphorylation by selective activation of the ɛPKC isoform occurs in response to ischemic pre- [11,34,60] and postconditioning [39,40,61], in which brief episodes of ischemia reduce the adverse effects of subsequent or preceding myocardial ischemia, respectively. PKC isoform-selective modulator drugs are currently under development for the treatment of a variety of diseases [3,10,48]. As the function of a multiple proteins may be affected by such drugs, delineation of the isoform-specific regulation of downstream targets, e.g., Cx43Hc, is important to improve our understanding of the pathogenesis of ischemic heart disease and to identify new opportunities for drug development.…”

The scientific and clinical basis for the treatment of Parkinson disease (2009)

“…209 Recent studies have demonstrated that the rasagiline metabolite aminoindan exerts protective effects that might also contribute to the benefits provided by rasagiline. 210 To test for a possible neuroprotective effect in patients with PD, a novel study design, the "delayed start," was used in an attempt to avoid the confounding symptomatic effects seen with other clinical trial designs 211 (figure 8). The delayed-start study is conducted in two stages.…”