We have previously demonstrated the unexpected neuroprotection of the anti-
cancer agent
SU4312 in cellular models associated with
Parkinson's disease (PD). However, the precise mechanisms underlying its neuroprotection are still unknown, and the effects of
SU4312 on rodent models of PD have not been characterized. In the current study, we found that the protection of
SU4312 against
1-methyl-4-phenylpyridinium ion (MPP+)-induced neurotoxicity in PC12 cells was achieved through the activation of
transcription factor myocyte enhancer factor 2D (MEF2D), as evidenced by the fact that
SU4312 stimulated
myocyte enhancer factor 2 (MEF2) transcriptional activity and prevented the inhibition of
MEF2D protein expression caused by MPP+, and that
short hairpin RNA (
ShRNA)-mediated knockdown of MEF2D significantly abolished the neuroprotection of
SU4312. Additionally, Western blotting analysis revealed that
SU4312 potentiated pro-survival PI3-K/Akt pathway to down-regulate MEF2D inhibitor
glycogen synthase kinase-3beta (GSK3β). Furthermore, using the in vivo PD model of C57BL/6 mice insulted with
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP), we found that intragastrical administration of
SU4312 (0.2 and 1 mg/kg) greatly ameliorated Parkinsonian motor defects, and restored
protein levels of MEF2D, phosphorylated-Ser473-Akt and phosphorylated-Ser9-GSK3β. Meanwhile,
SU4312 effectively reversed the decrease in
protein expression of
tyrosine hydroxylase in substantia nigra pars compacta dopaminergic neurons, inhibited oxidative stress, maintained mitochondrial biogenesis and partially prevented the depletion of
dopamine and its metabolites. Very encouragingly,
SU4312 was able to selectively inhibit
monoamine oxidase-B (
MAO-B) activity both in vitro and in vivo, with an IC50 value of 0.2 μM. These findings suggest that
SU4312 provides therapeutic benefits in cellular and animal models of PD, possibly through multiple mechanisms including enhancement of MEF2D through the activation of PI3-K/Akt pathway, maintenance of mitochondrial biogenesis and inhibition of
MAO-B activity.
SU4312 thus may be an effective drug candidate for the prevention or even modification of the
pathological processes of PD.