[en] 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.
Disciplines :
Neurology
Author, co-author :
HENEKA, Michael ; Department of Neurology, University of Bonn, Germany. Michael.Heneka@ukb.uni-bonn.de
Gavrilyuk, Vitaliy; Department of Anesthesiology, University of Illinois, W. Side Veteran's Aff. Res. Division, Chicago, IL, United States
Landreth, Gary E; Department of Neurosciences, Case Western Reserve University, Cleveland, OH, United States
O'Banion, M Kerry; Department of Neurobiology, Univ. of Rochester Medical Center, Rochester, NY, United States
Weinberg, Guy; Department of Anesthesiology, University of Illinois, W. Side Veteran's Aff. Res. Division, Chicago, IL, United States
Feinstein, Douglas L; Department of Anesthesiology, University of Illinois, W. Side Veteran's Aff. Res. Division, Chicago, IL, United States
External co-authors :
yes
Language :
English
Title :
Noradrenergic depletion increases inflammatory responses in brain: effects on IkappaB and HSP70 expression.
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