Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible
monoamine oxidase B (
MAO B) inhibitor which has been developed as an anti-Parkinson
drug. In controlled monotherapy and as adjunct to
L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and
neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and anti-apoptotic activity against several
neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and
ischemia. In vivo, it reduces the sequelae of
traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from
MAO B inhibition, since its S-enantiomer,
TVP1022, which has 1000-fold weaker
MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a
carbamate moiety into the
rasagiline molecule to confer
cholinesterase inhibitory activity for the treatment of
Alzheimer's disease, resulted in compounds
TV3326 [(
N-Propargyl-(3R)Aminoindan-5-YL)-Ethyl
Methyl Carbamate] and its S-enantiomer
TV3279 [(
N-Propargyl-(3S)Aminoindan-5-YL)-Ethyl
Methyl Carbamate], which retain the neuroprotective activities of
rasagiline and
TVP1022. They also antagonize
scopolamine-induced impairments in spatial memory. In addition,
TV3326 exhibits brain-selective
MAO A and B inhibitory activity after chronic administration and has
antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of
serotonin. The anti-apoptotic activity of these
propargylamine-containing derivatives may be related to their ability to delay the opening of
voltage-dependent anion channels (VDAC), which are part of the
mitochondrial permeability transition pore. The
propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2
proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of
caspase 3, and of translocation of
glyceraldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with
neurotoxin-induced apoptosis.
Rasagiline interacts with and prevents the binding of PKI 1195 to the pro-apoptotic peripheral
benzodiazepine receptor, which together with Bcl-2,
hexokinase,
porin, and
adenine nucleotide translocator constitutes part of the VDAC. Furthermore,
rasagiline,
TV3326 and
TV3279 are able to influence the processing of
amyloid precursor
protein by activation of
alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human
neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP
kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by
rasagiline and
TV3326 is closely linked to the anti-apoptotic action of these drugs and their ability to process APP by activation of
alpha-secretase.