title: Sunitinib produces neuroprotective effect via inhibiting nitric oxide overproduction.
abstract: BACKGROUND
  Sunitinib is an inhibitor of the multiple receptor tyrosine kinases (RTKs) 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 (CGNs) and SH-SY5Y cells were exposed to low-potassium and MPP(+) challenges, respectively. MTT assay, FDA/PI staining, Hoechst staining, DAF-FM, colorimetric nitric oxide synthase (NOS) activity assay, and Western blotting were applied to detect cell viability, NO production, NOS activity, and neuronal NOS (nNOS) expression. Short hairpin RNA was used to decrease nNOS expression. In vitro NOS enzyme activity assay was used to determine the direct inhibition of nNOS by sunitinib.
  
  
  RESULTS
  Sunitinib prevented low-potassium-induced neuronal apoptosis in CGNs and MPP(+) -induced neuronal death in SH-SY5Y cells. However, PTK787, another RTK inhibitor, failed to decrease neurotoxicity in the same models. Sunitinib reversed the increase in NO levels, NOS activity, and nNOS expression induced by low potassium or MPP(+) . Knockdown of nNOS expression partially abolished the neuroprotective effects of sunitinib. Moreover, sunitinib directly inhibited nNOS enzyme activity.
  
  
  CONCLUSIONS
  Sunitinib exerts its neuroprotective effects by inhibiting NO overproduction, possibly via the inhibition of nNOS activity and the decrease in nNOS expression.
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China; State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Zai-Jun
authors.initials: ZJ
authors.lastname: Zhang
authors.forename: Sheng-Quan
authors.initials: SQ
authors.lastname: Hu
authors.forename: Shing-Hung
authors.initials: SH
authors.lastname: Mak
authors.forename: Da-Ping
authors.initials: DP
authors.lastname: Xu
authors.forename: Chung-Lit
authors.initials: CL
authors.lastname: Choi
authors.forename: Yu-Qiang
authors.initials: YQ
authors.lastname: Wang
authors.forename: Wah-Keung
authors.initials: WK
authors.lastname: Tsim
authors.forename: Ming-Yuen
authors.initials: MY
authors.lastname: Lee
authors.forename: Jian-Hui
authors.initials: JH
authors.lastname: Rong
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Han
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077210:Sunitinib; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D007211:Indoles; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011758:Pyrroles; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C080122:7-nitroindazole; D000077210:Sunitinib
keywords: Cancer; Neuroprotection; Nitric oxide; Nitric oxide synthase; Receptor tyrosine kinase; Sunitinib