Sunitinib Produces Neuroprotective Effect Via Inhibiting Nitric Oxide Overproduction

Summary Background Sunitinib is an inhibitor of the multiple receptor tyrosine kinases ( RTK s) for cancer therapy. Some sunitinib analogues could prevent neuronal death induced by various neurotoxins. However, the neuroprotective effects of sunitinib have not been reported. Methods Cerebellar granule neurons ( CGN s) and SH ‐ SY 5 Y cells were exposed to low‐potassium and MPP + challenges, respectively. MTT assay, FDA / PI staining, H oechst staining, DAF ‐ FM , colorimetric nitric oxide synthase ( NOS ) activity assay, and W estern blotting were applied to detect cell viability, NO production, NOS activity, and neuronal NOS (n NOS ) expression. Short hairpin RNA was used to decrease n NOS expression. In vitro NOS enzyme activity assay was used to determine the direct inhibition of n NOS by sunitinib. Results Sunitinib prevented low‐potassium‐induced neuronal apoptosis in CGN s and MPP + ‐induced neuronal death in SH ‐ SY 5 Y cells. However, PTK 787, another RTK inhibitor, failed to decrease neurotoxicity in the same models. Sunitinib reversed the increase in NO levels, NOS activity, and n NOS expression induced by low potassium or MPP + . Knockdown of n NOS expression partially abolished the neuroprotective effects of sunitinib. Moreover, sunitinib directly inhibited n NOS enzyme activity. Conclusions Sunitinib exerts its neuroprotective effects by inhibiting NO overproduction, possibly via the inhibition of n NOS activity and the decrease in n NOS expression.