[Abstract Title]. - Society for Neuroscience

Title: SKA-PD-01 attenuates behavioral impairments and neurotoxicities in MPTP- and 6-
OHDA-induced animal and cellular models of Parkinson‟s disease
Authors: J. LEE, J. CHUNG, C. RYU, M. JI, H. MIN, Y. YOON, M. LIM, *C. PARK;
Drug Dev Ctr., SK Corp., Daejeon, Republic of Korea
Abstract: Parkinson‟s disease (PD) is a progressive neurodegenerative disorder characterized by
motor abnormalities including resting tremor, rigidity, postural instability and bradykinesia. The
neuropathological feature is the selective loss of the nigrostiatal dopaminergic neurons within the
substantia nigra pars compacta (SNpc) and nerve terminals extended to the striatum. Recent
study suggests that inhibition of monoamine oxidase B (MAO-B) partially contributes to the
improvement of behavioral disturbances and prevention of neuronal loss by decreasing dopamine
metabolism and oxidative stress.
We investigated the anti-PD and neuroprotective efficacies of a new compound, SKA-PD-01, in
the MPTP and 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo models of PD. SKA-
PD-01 efficiently inhibited MAO-B activities with high selectivity (IC50 of MAO-A and MAO-B
is ~100 uM and 0.011 uM, respectively). Administration of SKA-PD-01 (20 mg/kg, ip) at 30 min
before and after MPTP treatment significantly ameliorated behavioral impairments, neuronal loss
in the SNpc, and dopamine depletion in the striatum of mice. In 6-OHDA-induced PD animal
models, dopaminergic activity by L-dopa was considerably increased by SKA-PD-1 treatment
(20 mg/kg, ip). MPP + or 6-OHDA-induced neuronal loss was attenuated by SKA-PD-1 treatment
in SH-SY5Y and C57BL6 mice. This compound also significantly reversed reserpine-induced
akinesia in reserpine akinesia model (140.1%* at 20mg/kg, ip), and reduced haloperidol-induced
catalepsy (ED50 was 3.55 mg/kg, ip and 4.54mg/kg, po).
In rat pharmacokinetic study, bioavailability was 21.1% and half-life was 0.6 hour. A single
neurotoxic dose was 210 mg/kg,ip in rotor rod test. Taken all together, our findings indicate that
SKA-PD-01 as a new selective MAO-B inhibitor and neuroprotectant might have therapeutic
potential for other neurodegenerative diseases as well as PD.
Disclosures: J. Lee, None; J. Chung, None; C. Ryu, None; M. Ji, None; H. Min, None; Y.
Yoon, None; M. Lim, None; C. Park , None.
Poster
247. Parkinson's Disease Interventions: Animal and Clinical Models
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 247.14/S9
Topic: C.02.d. Therapies
Support: SFI Grant 05/RF/ENM047