Noradrenergic depletion increases inflammatory responses in brain:: effects on IκB and HSP70 expression

被引:109
作者
Heneka, MT
Gavrilyuk, V
Landreth, GE
O'Banion, MK
Weinberg, G
Feinstein, DL
机构
[1] Univ Bonn, Dept Neurol, D-5300 Bonn, Germany
[2] Univ Illinois, Dept Anesthesiol, Chicago, IL USA
[3] W Side Vet Affairs Res Div, Chicago, IL USA
[4] Case Western Reserve Univ, Dept Neurosci, Cleveland, OH 44106 USA
[5] Case Western Reserve Univ, Dept Neurol, Cleveland, OH 44106 USA
[6] Univ Rochester, Med Ctr, Dept Neurobiol & Anat, Rochester, NY 14642 USA
关键词
Alzheimer's disease; amyloid; cytokines; locus ceruleus; nitric oxide; noradrenaline;
D O I
10.1046/j.1471-4159.2003.01694.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The inflammatory responses in many cell types are reduced by noradrenaline (NA) binding to beta-adrenergic receptors. We previously demonstrated that cortical inflammatory responses to aggregated amyloid beta (Abeta) are increased if NA levels were first depleted by lesioning locus ceruleus (LC) noradrenergic neurons, which replicates the loss of LC occurring in Alzheimer's disease. To examine the molecular basis for increased responses, we used the selective neurotoxin DSP4 to lesion the LC, and then examined levels of putative anti-inflammatory molecules. Inflammatory responses were achieved by injection of aggregated Abeta1-42 peptide and IL-1beta into frontal cortex, which induced neuronal inducible nitric oxide synthase (iNOS) and microglial IL-1beta expression. DSP4-treatment reduced basal levels of nuclear factor kappa B (NF-kappaB) inhibitory IkappaB proteins, and of heat shock protein (HSP)70. Inflammatory responses were prevented by co-injection (ibuprofen or ciglitzaone) or oral administration (pioglitazone) of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Treatment with PPARgamma agonists restored IkappaBalpha, IkappaBbeta, and HSP70 levels to values equal or above those observed in control animals, and reduced activation of cortical NF-kappaB. These results suggest that noradrenergic depletion reduces levels of anti-inflammatory molecules which normally limit cortical responses to Abeta, and that PPARgamma agonists can reverse that effect. These findings suggest one mechanism by which PPARgamma agonists could provide benefit in neurological diseases having an inflammatory component.
引用
收藏
页码:387 / 398
页数:12
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