NADPH oxidase inhibitor DPI is neuroprotective at femtomolar concentrations through inhibition of microglia over-activation.
In this paper we report that diphenyliodonium (DPI), a NADPH oxidase inhibitor, shows potent anti-inflammatory and neuroprotective effects at femtomolar concentrations (10(-13) to 10(-14) M) in primary midbrain cultures. Mechanistic studies revealed that DPI-elicited effects were mediated by the inhibition of LPS-induced microglial ROS production and the subsequent release of pro-inflammatory cytokine TNFa, and the production of nitric oxide. Further studies showed that 10(-14) M DPI significantly reduced LPS-induced ERK phosphorylation. Taken together, our results demonstrate that femtomolar concentrations of DPI exert potent anti-inflammatory and neuroprotective effects by inhibiting microglial activation through the inhibition of ERK-regulated PHOX activity.
Qian
Li
L
Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, NC 27599-7455, USA.
Gao
Xi
X
Pei
Zhong
Z
Wu
Xuefei
X
Block
Michelle
M
Wilson
Belinda
B
Hong
Jau-Shyong
JS
Flood
Patrick M
PM
D000704:Analysis of Variance; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009573:Nitrites; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C031291:diphenyliodonium; D013481:Superoxides; D019255:NADPH Oxidases; D004298:Dopamine