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 mumol/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, PKCepsilon. 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.