The role of macrophages and eicosanoids in the pathogenesis of experimental allergic neuritis. Serial clinical, electrophysiological, biochemical and morphological observations.
Experimental allergic neuritis (EAN) can be prevented or ameliorated by global blockade of macrophages. How these cells damage peripheral nervous tissue in this autoimmune demyelinating polyneuropathy is not fully understood. Since macrophages exert a number of their inflammatory actions by the release of arachidonic acid-derived eicosanoids, we investigated the possible role of these mediators in the pathogenesis of EAN. Lewis rats with myelin-induced EAN were treated before and after onset of clinical signs. Administration of corticosteroids or of the cyclo-oxygenase inhibitors indomethacin and BW755c before the onset of neurological signs suppressed the disease, as judged by clinical assessment, serial electrophysiological testing and histological examination, while initiation of drug treatment on day 13 postimmunization still markedly attenuated the course of EAN. The selective lipoxygenase blocker nafazatrom had only a slight effect. Determination of the production by macrophages ex vivo of eicosanoids corroborated the predicted site of action of the pharmacological compounds applied. We infer that macrophage-derived proinflammatory arachidonic acid metabolites significantly contribute to functional and tissue damage in EAN. Our results may be relevant to future pharmacological treatment of the acute Guillain-Barré syndrome.
Hartung
H P
HP
Department of Neurology, University of Düsseldorf, FRG.
Schäfer
B
B
Heininger
K
K
Stoll
G
G
Toyka
K V
KV
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D003907:Dexamethasone / Q000627:therapeutic use; D005260:Female; D007213:Indomethacin / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D009444:Neuritis, Autoimmune, Experimental / Q000188:drug therapy / Q000209:etiology* / Q000517:prevention & control; D011720:Pyrazoles / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D012822:Silicon Dioxide / Q000627:therapeutic use
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D016718:Arachidonic Acid; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D012822:Silicon Dioxide; D003907:Dexamethasone; D007213:Indomethacin