Neuroprotective effects of the MAO-B inhibitors, selegiline and rasagiline, are dependent on their propargyl moiety and independent of their MAO inhibitory properties. The selegiline metabolite, desmethylselegiline, is responsible for the potential neuroprotective effects of selegiline. The S-isomer of rasagiline, TVP 1022, is one thousand times less potent at inhibiting MAO-B, yet demonstrates similar potential neuroprotective effects (27). Both selegiline and rasagiline have demonstrated neuroprotection in multiple in vitro and animal models (27-41). Selegiline and rasagiline inhibit apoptosis, or programmed cell death, in cell lines (28,30,34,35,42). Although the selegiline metabolite L-methamphetamine inhibits the anti-apoptotic activities of selegiline, the rasagiline metabolite aminoindan does not (43).
The mitochondrial permeability transition pore (MPTp) appears only in the setting of apoptosis (27). Anti-apoptotic proteins stabilize the MPTp whereas pro-apoptotic proteins allow pore opening, with loss of mitochondrial membrane potential (27,41). This causes an apoptotic cascade including release of cytochrome c and activation of caspases, particularly caspase-3. MAOIs increase the anti-apoptotic proteins Bcl-2, Bcl-XL, and Bcl-w, and downregulate the pro-apoptotic proteins Bad, Bax, and Fas (27,42). The "death receptor" Fas and its ligand FasL (which interact with pro-apoptotic proteins on the outer mitochondrial membrane) are downregulated by MAOIs (27,44).
Oxygen free radical (OFR) scavenging proteins, superoxide dismutase 1 (SOD 1), superoxide dismutase 2 (SOD 2), catalase, and glutathione are all increased with MAOIs (32,45). The MAOIs themselves may possess OFR scavenging ability (46). Trophic factors including glial derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), and basic fibroblast growth factor (FGF2) are also increased by MAOIs (37,47).
Other mechanisms of neuroprotection mediated by MAOIs include: protein kinase C (PKC) a- and e-activation that inhibit formation of the activated cleaved form of caspase-3; the cleavage of PARP-1, a caspase substrate; and Fas, the conversion of amyloid precursor protein (APP) into soluble (nonamyloidogenic) APPa, which itself has neurotrophic and neuroprotective properties; and the inhibition of nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (27,44).
Models that have demonstrated neuroprotection by either rasagiline or selegi-line include glutamate toxicity in hippocampal neurons (48), focal brain ischemia in rats (39,40), memory and learning tasks following anoxic brain injury (49) and motor and spatial memory in a rodent closed head injury model (50), optic nerve crush injury (51), rescue of dorsal root ganglia sensory neurons (52) and of axotomized motoneu-rons (53), and protection against cell death in rat pheochromocytoma PC-12 cells deprived of oxygen and glucose (54). Selegiline given after intrathecal injection of rat pups with cerebrospinal fluid from human amyotrophic lateral sclerosis (ALS) subjects protects against anterior horn cell loss (55). Pretreatment with rasagiline is neu-roprotective in primate MPTP (56) and rodent 6-OHDA models of PD (38). Primates treated with selegiline and MPTP simultaneously do not develop parkinsonism (57).
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