title: Noradrenergic depletion increases inflammatory responses in brain: effects on IkappaB and HSP70 expression.
abstract: 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.
authors.affiliation: Department of Neurology, University of Bonn, Germany. Michael.Heneka@ukb.uni-bonn.de
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Gavrilyuk
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
authors.forename: M Kerry
authors.initials: MK
authors.lastname: O'Banion
authors.forename: Guy
authors.initials: G
authors.lastname: Weinberg
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D016229:Amyloid beta-Peptides; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism*; D007375:Interleukin-1; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008125:Locus Coeruleus / Q000187:drug effects; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009638:Norepinephrine / Q000378:metabolism*; D010446:Peptide Fragments; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D014157:Transcription Factors / Q000819:agonists
chemical_list: D016229:Amyloid beta-Peptides; D001596:Benzylamines; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D018840:HSP70 Heat-Shock Proteins; D007004:Hypoglycemic Agents; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007375:Interleukin-1; D007527:Isoenzymes; D016328:NF-kappa B; D009498:Neurotoxins; C000606206:Nfkbia protein, rat; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); D000072000:NF-KappaB Inhibitor alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C012102:DSP 4; D009638:Norepinephrine