title: Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson's disease.
abstract: Microglial activation has been associated with the pathogenesis of Parkinson's disease (PD). Among the many components of this reaction, cytokines have been proposed as candidates to mediate neurodegenerative or neuroprotective effects. We investigated the interleukin-1 system and tumour necrosis factor-alpha mRNA and protein levels at different time intervals in the subacute intrastriatal 6-hydroxydopamine rat model of PD, in parallel with the inflammatory response. Immunohistochemistry showed that microglial cells were activated from days 6-30 postlesion in the substantia nigra pars compacta. This microglial activation was accompanied by an atypical proinflammatory cytokine production: Interleukin-1alpha and beta mRNAs were found to be elevated 30 days post-6-hydroxydopamine injection (2- and 16-fold, respectively), but no induction for interleukin-1alpha or beta at the protein level was detected by ELISA. As a control, a classical proinflammatory stimulus, namely endotoxin, was capable of inducing these cytokines at similar mRNA levels but also at the protein level. In addition, tumour necrosis factor-alpha mRNA was hardly or not detected in the substantia nigra at any time point studied. Our data point out a tight control of key proinflammatory cytokine production in our model of PD. This work supports the notion that chronic neuronal death per se does not induce secretion of these proinflammatory cytokines but that an additional stimulus is necessary to stimulate proinflammatory cytokine production. The production of proinflammatory cytokines from "primed" microglia may in turn modulate disease progression as has been recently proposed in a model of prion disease.
authors.affiliation: Institute Leloir Foundation-CONICET-University of Buenos Aires, Avenue Patricias Argentinas 435, (1405) Buenos Aires, Argentina.
authors.forename: Amaicha M
authors.initials: AM
authors.lastname: Depino
authors.forename: Chris
authors.initials: C
authors.lastname: Earl
authors.forename: Elke
authors.initials: E
authors.lastname: Kaczmarczyk
authors.forename: Carina
authors.initials: C
authors.lastname: Ferrari
authors.forename: Hugo
authors.initials: H
authors.lastname: Besedovsky
authors.forename: Adriana
authors.initials: A
authors.lastname: del Rey
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Pitossi
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Oertel
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D015152:Blotting, Northern; D001973:Bromodeoxyuridine / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D053331:Ectodysplasins; D004731:Endotoxins / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D007839:Functional Laterality; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006023:Glycoproteins; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D053331:Ectodysplasins; C506019:Eda protein, mouse; D004731:Endotoxins; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D007375:Interleukin-1; D037102:Lectins; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C473590:isolectin B4-binding glycoprotein, mouse; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001973:Bromodeoxyuridine