The anti-cancer agent SU4312 unexpectedly protects against MPP+-induced neurotoxicity via selective and direct inhibition of neuronal NOS
- Authors
- Cui, W., Zhang, Z., Li, W., Hu, S., Mak, S., Zhang, H., Han, R., Yuan, S., Li, S., Sa, F., Xu, D., Lin, Z., Zuo, Z., Rong, J., Ma, E.D., Choi, T.C., Lee, S.M., and Han, Y.
- ID
- ZDB-PUB-121019-21
- Date
- 2013
- Source
- British journal of pharmacology 168(5): 1201-1214 (Journal)
- Registered Authors
- Keywords
- SU4312, neuroprotection, Parkinson's disease, neuronal NOS, angiogenesis, MPP+
- MeSH Terms
-
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- 1-Methyl-4-phenylpyridinium/toxicity*
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use*
- Behavior, Animal/drug effects
- Brain/metabolism
- Cell Death/drug effects
- Cell Line, Tumor
- Embryo, Nonmammalian/anatomy & histology
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/physiology
- Enzyme Inhibitors/pharmacology
- Enzyme Inhibitors/therapeutic use
- Humans
- Indoles/pharmacology
- Indoles/therapeutic use*
- Molecular Docking Simulation
- Motor Activity/drug effects
- Neurons/drug effects
- Neuroprotective Agents/pharmacology
- Neuroprotective Agents/therapeutic use*
- Nitric Oxide/metabolism
- Nitric Oxide Synthase Type I/antagonists & inhibitors*
- PC12 Cells
- Rats
- Rats, Sprague-Dawley
- Zebrafish
- PubMed
- 23062100 Full text @ Br. J. Pharmacol.
- CTD
- 23062100
Background and purpose
SU4312, a potent and selective inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we investigated the neuroprotection of SU4312 against 1-methyl-4-phenylpyridinium ion (MPP+)-induced neurotoxicity, and further explored its underlying mechanisms.
Experimental approach
MPP+-treated neurons and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated zebrafish were used to study the neuroprotection of SU4312. Moreover, in vitro assay of nitric-oxide synthase (NOS) activity was used to examine the direct interaction between SU4312 and NOS isoforms.
Key results
SU4312 unexpectedly prevented MPP+-induced neuronal apoptosis in vitro, and decreased MPTP-induced loss of dopaminergic neurons, reduced expression of tyrosine hydroxylase gene, and impaired swimming behavior in zebrafish. In contrast, PTK787/ZK222584, a well studied VEGFR-2 inhibitor, failed to prevent neurotoxicity, suggesting the neuroprotection of SU4312 is independent from its anti-angiogenic action. Furthermore, SU4312 appeared to be a non-competitive inhibitor of purified neuronal NOS (nNOS) with the IC50 value of 19.0 μM, but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and heme group within the active center of nNOS.
Conclusions and Implication
Our findings demonstrated that SU4312 exhibits neuroprotection against MPP+ at least partially via selectively and directly inhibiting nNOS. In view of the capability of SU4312 to reach the brain in rats, our study also offered a support for further development of SU4312 to treat neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity.