A novel role of microglial NADPH oxidase in mediating extra-synaptic function of norepinephrine in regulating brain immune homeostasis.
Although the peripheral anti-inflammatory effect of norepinephrine (NE) is well documented, the mechanism by which this neurotransmitter functions as an anti-inflammatory/neuroprotective agent in the central nervous system (CNS) is unclear. This article aimed to determine the anti-inflammatory/neuroprotective effects and underlying mechanisms of NE in inflammation-based dopaminergic neurotoxicity models. In mice, NE-depleting toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was injected at 6 months of lipopolysaccharide (LPS)-induced neuroinflammation. It was found that NE depletion enhanced LPS-induced dopaminergic neuron loss in the substantia nigra. This piece of in vivo data prompted us to conduct a series of studies in an effort to elucidate the mechanism as to how NE affects dopamine neuron survival by using primary midbrain neuron/glia cultures. Results showed that submicromolar concentrations of NE dose-dependently protected dopaminergic neurons from LPS-induced neurotoxicity by inhibiting microglia activation and subsequent release of pro-inflammatory factors. However, NE-elicited neuroprotection was not totally abolished in cultures from β2-adrenergic receptor (β2-AR)-deficient mice, suggesting that novel pathways other than β2-AR are involved. To this end, It was found that submicromolar NE dose-dependently inhibited NADPH oxidase (NOX2)-generated superoxide, which contributes to the anti-inflammatory and neuroprotective effects of NE. This novel mechanism was indeed adrenergic receptors independent since both (+) and (-) optic isomers of NE displayed the same potency. We further demonstrated that NE inhibited LPS-induced NOX2 activation by blocking the translocation of its cytosolic subunit to plasma membranes. In summary, we revealed a potential physiological role of NE in maintaining brain immune homeostasis and protecting neurons via a novel mechanism.
Institute of Toxicology, School of Public Health, Shandong University, Jinan, Shandong, 250012, China; Neuropharmacology Section, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, 27709.
Lulu
L
Jiang
Shih-Heng
SH
Chen
Chun-Hsien
CH
Chu
Shi-Jun
SJ
Wang
Esteban
E
Oyarzabal
Belinda
B
Wilson
Virginia
V
Sanders
Keqin
K
Xie
Qingshan
Q
Wang
Jau-Shyong
JS
Hong
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D019556:COS Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D006706:Homeostasis / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D011916:Rats, Inbred F344; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism
D001596:Benzylamines; D008070:Lipopolysaccharides; D014179:Neurotransmitter Uptake Inhibitors; D018343:Receptors, Adrenergic, beta-2; D019255:NADPH Oxidases; C012102:DSP 4; D009638:Norepinephrine
DSP-4; extra-synaptic; neurodegeneration; neurotransmitter; volume transmission