Differential modulation of hippocampal chemical-induced injury response by ebselen, pentoxifylline, and TNFalpha-, IL-1alpha-, and IL-6-neutralizing antibodies.
The proinflammatory cytokines tumor necrosis factor (TNFalpha), interleukin-1 (IL-1alpha), and interleukin-6 (IL-6) have been associated with various models of hippocampal damage. To examine their role in initiation of an acute hippocampal injury response, 21-day-old male CD-1 mice received an acute intraperitoneal (i.p.) injection of trimethyltin hydroxide (TMT; 2.0 mg/kg) to produce necrosis of dentate granule neurons, astrocyte, and microglia reactivity. Tremors and intermittent seizures were evident at 24 hr. Intercellular adhesion molecule-1 (ICAM-1), glial fibrillary acidic protein (GFAP), anti-apoptotic TNFalpha-inducible early response gene (A-20), macrophage inflammatory protein (MIP)-1alpha, TNFalpha, IL-1alpha, IL-6, and caspase 3 mRNA levels were significantly elevated. Pretreatment with the antioxidant, ebselen, decreased ICAM-1, A-20, and TNFbeta elevations. Pentoxifylline blocked elevations in A-20 and decreased elevations in GFAP mRNA levels. Neither prevented histopathology or behavioral effects. Intracisternal injection of TNFalpha-neutralizing antibody significantly inhibited both behavioral effects and histopathology. RNase protection assays showed that TMT-induced elevations in mRNA levels for ICAM-1, A-20, GFAP, MIP-1alpha, IL-1alpha, TNFalpha, TNFbeta, and caspase 3 were blocked by anti-TNFalpha. These data demonstrate a significant role for TNFalpha in an acute neuro-injury in the absence of contribution from infiltrating cells. The cerebellum shows limited if any damage after TMT; however, in combination with the i.c.v. injection, elevations were seen in GFAP and in EB-22, a murine acute-phase response gene homologous to the alpha (1)-antichymotrypsin gene. Elevations were similar for artificial cerebral spinal fluid and anti-IL-1alpha, and significantly increased with anti-TNFalpha, anti-IL-6, or the combination of antibodies. Responses seen in the cerebellum suggest synergistic interactions between the baseline state of the cell and manipulations in the cytokine environment. Data suggests a role for TNFalpha in the pathogenesis of hippocampal injury induced by TMT.
Jean Harry
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Neurotoxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. Harry@niehs.nih.gov
Bruccoleri
Alessandra
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Lefebvre d'Hellencourt
Christian
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D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001393:Azoles / Q000627:therapeutic use; D001930:Brain Injuries / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004338:Drug Combinations; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D054833:Isoindoles; D037102:Lectins / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009498:Neurotoxins / Q000633:toxicity; D023282:Nuclease Protection Assays / Q000379:methods; D016566:Organoselenium Compounds / Q000627:therapeutic use; D010431:Pentoxifylline / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D014298:Trimethyltin Compounds / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D001393:Azoles; D016207:Cytokines; D004338:Drug Combinations; D005904:Glial Fibrillary Acidic Protein; D007375:Interleukin-1; D015850:Interleukin-6; D054833:Isoindoles; D037102:Lectins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D014298:Trimethyltin Compounds; D014409:Tumor Necrosis Factor-alpha; C037718:trimethyltin hydroxide; C042986:ebselen; D010431:Pentoxifylline