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.