Two novel neuroprotective
cholinesterase (ChE) inhibitors,
TV3326 and
TV3279 [(
N-propargyl-(3R) and (3S) aminoindan-5-yl)-ethyl
methyl carbamate], respectively were derived from
rasagiline, for the treatment of
Alzheimer's disease (AD).
TV3326 also inhibits
monoamine oxidase (
MAO)-A and B, while its S-isomer,
TV3279, lacks
MAO-inhibitory activity. The actions of these drugs in the regulation of the
amyloid precursor
protein (APP) processing using rat PC12 and human SH-SY5Y
neuroblastoma cells were examined. Both isomers stimulated the release of the non-amyloidogenic
alpha-secretase form of soluble APP (sAPPalpha) from these cell lines. The increases in sAPPalpha, induced by
TV3326 and
TV3279, were dose-dependent (0.1-100 micro M) and blocked by the
hydroxamic acid-based
metalloprotease inhibitor, Ro31-9790, suggesting mediation via
alpha-secretase activity. Using several signal transduction inhibitors, the involvement of
protein kinase C (PKC),
mitogen-activated
protein (MAP)
kinase, and
tyrosine kinase-dependent pathways in the enhancement of sAPPalpha release by
TV3326 and
TV3279 was identified. In addition, both drugs directly induced the phosphorylation of p44 and
p42 MAP kinase, which was abolished by the specific inhibitors of MAP
kinase activation,
PD98059 and
U0126. These data suggest a novel pharmacological mechanism, whereby these ChE inhibitors regulate the secretary processes of APP via activation of the MAP
kinase pathway.