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

AbstractThe 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 μmol/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 aminoindan‐induced cell survival. Aminoindan markedly elevated pPKC(pan) and specifically that of the pro‐survival PKC isoform, PKCε. 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.