The anti‐cancer agent SU4312 unexpectedly protects against MPP⁺‐induced neurotoxicity via selective and direct inhibition of neuronal NOS

Abstract

BACKGROUND AND PURPOSESU4312, a potent and selective inhibitor of VEGF 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 assessed neuroprotection by SU4312 against 1-methyl-4-phenylpyridinium ion (MPP + )-induced neurotoxicity and further explored the underlying mechanisms. EXPERIMENTAL APPROACHMPP + -treated neurons and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated zebrafish were used to study neuroprotection by SU4312. NOS activity was assayed in vitro to examine direct interactions between SU4312 and NOS isoforms. KEY RESULTSSU4312 unexpectedly prevented MPP + -induced neuronal apoptosis in vitro and decreased MPTP-induced loss of dopaminergic neurons, reduced expression of mRNA for tyrosine hydroxylase and impaired swimming behaviour in zebrafish. In contrast, PTK787/ZK222584, a well-studied VEGFR-2 inhibitor, failed to prevent neurotoxicity, suggesting that the neuroprotective actions of SU4312 were independent of its anti-angiogenic action. Furthermore, SU4312 exhibited non-competitive inhibition of purified neuronal NOS (nNOS) with an IC50 value of 19.0 mM but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and the haem group within the active centre of nNOS. CONCLUSIONS AND IMPLICATIONSU4312 exhibited neuroprotection against MPP + at least partly via selective and direct inhibition of nNOS. Because SU4312 could 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. Abbreviations

Canonical and Noncanonical Vascular Endothelial Growth Factor Pathways

“…For instance, the VEGFR2 inhibitor SU5416 (which has gone to Phase III clinical trials), is also a potent agonist of the aryl hydrocarbon receptor which regulates immune function 56 . Similarly, SU4312, another VEGFR2 inhibitor, directly inhibits neuronal nitrogen-oxygen synthase in cerebellar granule neurons 57 . Because several of the VEGFR inhibitors used in basic research have been approved for human trials, these molecules are now being closely scrutinized for other functions.…”

Discovery of a novel neuroprotectant, BHDPC, that protects against MPP+/MPTP-induced neuronal death in multiple experimental models

“…Through drug screening in this model, several compounds with neuroprotective effects such as iNOS inhibitors and anticancer agents have been successfully identified [34][35][36][37][38][39].…”

Identification of compounds that modulate retinol signaling using a cell-based qHTS assay

“…This tyrosine kinase inhibitor is a selective inhibitor of the vascular endothelial growth factor (VEGF) receptors and has been used to treat cancers based on its anti-angiogenic properties 61 . It also has protective effects on neurons 62 . Although retinoids are also reported to have anti-angiogenic 63 and neuroprotective 64 properties, whether there is a correlation between the mechanisms of SU432 and retinoids is unknown.…”