Differential modulation of hippocampal chemical-induced injury response by ebselen, pentoxifylline, and TNFalpha-, IL-1alpha-, and IL-6-neutralizing antibodies.

Abstract

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.

• Authors: G Jean Harry, Alessandra Bruccoleri, Christian Lefebvre d'Hellencourt
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 73 Issue 4 Pg. 526-36 (Aug 15 2003) ISSN: 0360-4012 [Print] United States
• PMID: 12898537 (Publication Type: Comparative Study, Journal Article)
• Copyright: Published 2003 Wiley-Liss, Inc.

Chemical References

• Antibodies
• Azoles
• Cytokines
• Drug Combinations
• Glial Fibrillary Acidic Protein
• Interleukin-1
• Interleukin-6
• Isoindoles
• Lectins
• Neuroprotective Agents
• Neurotoxins
• Organoselenium Compounds
• RNA, Messenger
• Trimethyltin Compounds
• Tumor Necrosis Factor-alpha
• trimethyltin hydroxide
• ebselen
• Pentoxifylline

Topics

• Animals
• Antibodies (immunology)
• Azoles (therapeutic use)
• Brain Injuries (chemically induced, immunology, prevention & control)
• Cerebellum (drug effects, metabolism)
• Cytokines (genetics, immunology, metabolism)
• Disease Models, Animal
• Drug Combinations
• Gene Expression Regulation (drug effects)
• Glial Fibrillary Acidic Protein (metabolism)
• Hippocampus (drug effects, metabolism, pathology)
• Interleukin-1 (immunology, metabolism)
• Interleukin-6 (immunology, metabolism)
• Isoindoles
• Lectins (metabolism)
• Male
• Mice
• Mice, Inbred Strains
• Microglia (drug effects, metabolism)
• Neuroprotective Agents (therapeutic use)
• Neurotoxins (toxicity)
• Nuclease Protection Assays (methods)
• Organoselenium Compounds (therapeutic use)
• Pentoxifylline (therapeutic use)
• RNA, Messenger (biosynthesis)
• Trimethyltin Compounds (toxicity)
• Tumor Necrosis Factor-alpha (immunology, metabolism)