MK 801 and dexamethasone reduce both tumor necrosis factor levels and infarct volume after focal cerebral ischemia in the rat brain

1998 ◽  
Vol 246 (1) ◽  
pp. 41-44 ◽  
Author(s):  
Rosalia Bertorelli ◽  
Marina Adami ◽  
Elena Di Santo ◽  
Pietro Ghezzi
Keyword(s):  
Cerebral Ischemia ◽  
Tumor Necrosis Factor ◽  
Rat Brain ◽  
Tumor Necrosis ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Mk 801 ◽  
Necrosis Factor

scholarly journals Microglial—Macrophage Synthesis of Tumor Necrosis Factor after Focal Cerebral Ischemia in Mice is Strain Dependent

2002 ◽  
Vol 22 (7) ◽  
pp. 785-797 ◽  
Author(s):  
Kate Lykke Lambertsen ◽  
Rikke Gregersen ◽  
Bente Finsen
Keyword(s):  
Cerebral Ischemia ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Border Zone ◽  
Mouse Strains ◽  
Strain Dependent ◽  
Necrosis Factor ◽  
Is Strain

Commonly used inbred mouse strains display substantial differences in sensitivity to focal cerebral ischemia. Such differences can often be ascribed to differences in vascular anatomy. The authors investigated whether a contributing factor could be strain-related differences in cellular synthesis of the pleiotropic and potential neurotoxic cytokine tumor necrosis factor (TNF) in the border zone of and within the focal cerebral infarct. In all mouse strains investigated they found that TNF was synthesized by infarct and periinfarct infiltrating Mac-1 immunopositive microglia—macrophages. BALB/c mice, which developed the largest infarcts, contained significantly fewer TNF-producing microglia—macrophages compared with SJL and C57BL/6 mice at both 12 and 24 hours after permanent occlusion of the distal part of the middle cerebral artery. SJL mice developed larger infarcts than C57BL/6 mice, whereas the number of TNF-producing microglia—macrophages per infarct volume unit was comparable. Western blotting data confirmed the increased TNF levels in SJL mice compared with BALB/c and C57BL/6 mice. Furthermore, mice with 12-hour postischemic survival consistently contained two-to threefold more TNF-producing microglia—macrophages than mice with 24-hour survival. The data show that the magnitude of the cellular TNF response to cerebral ischemia is strain dependent, while the time-profile and the cellular sources of TNF are similar irrespective of genetic background. Furthermore, the lack of correlation between infarct size and cellular TNF response suggests that the functionally important TNF is produced in the very early phase (minutes to a few hours) after induction of ischemia, just as it raises the possibility that different mouse strains display different sensitivities to TNF.

scholarly journals Tumor Necrosis Factor-α Neutralization Reduced Cerebral Edema Through Inhibition of Matrix Metalloproteinase Production After Transient Focal Cerebral Ischemia

2005 ◽  
Vol 25 (8) ◽  
pp. 959-967 ◽  
Author(s):  
Naohisa Hosomi ◽  
Camelia R Ban ◽  
Takayuki Naya ◽  
Tsutomu Takahashi ◽  
Peng Guo ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Tumor Necrosis Factor ◽  
Cerebral Edema ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neutralizing Antibody ◽  
Factor Α ◽  
Necrosis Factor

After focal cerebral ischemia, tumor necrosis factor-α deteriorates cerebral edema and survival rate. Therefore, tumor necrosis factor-α neutralization could reduce cerebral microvascular permeability in acute cerebral ischemia. Left middle cerebral artery occlusion for 120 mins followed by reperfusion was performed with the thread method under halothane anesthesia in Sprague-Dawley rats. Antirat tumor necrosis factor-α neutralizing monoclonal antibody with a rat IgG Fc portion (15 mg/kg) was infused intravenously right after reperfusion. Stroke index score, infarct volume, cerebral specific gravity, and the endogenous expression of tumor necrosis factor-α, matrix metalloproteinase (MMP)-2, MMP-9, and membrane type 1-MMP in the brain tissue were quantified in the ischemic and matched contralateral nonischemic hemisphere. In the antitumor necrosis factor-α neutralizing antibody-treated rats, infarct volume was significantly reduced ( P = 0.014, n = 7; respectively), and cerebral specific gravity was dramatically increased in the cortex and caudate putamen ( P<0.001, n = 7; respectively) in association with a reduction in MMP-9 and membrane type 1-MMP upregulation. Tumor necrosis factor-α in the brain tissue was significantly elevated in the ischemic hemisphere 6 h after reperfusion in the nonspecific IgG-treated rats ( P = 0.021, n = 7) and was decreased in the antitumor necrosis factor-α neutralizing antibody-treated rats ( P = 0.001, n = 7). Postreperfusion treatment with antirat tumor necrosis factor-α neutralizing antibody reduced brain infarct volume and cerebral edema, which is likely mediated by a reduction in MMP upregulation.

scholarly journals Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

2016 ◽  
Vol 36 (9) ◽  
pp. 1553-1569 ◽  
Author(s):  
Pernille M Madsen ◽  
Bettina H Clausen ◽  
Matilda Degn ◽  
Stine Thyssen ◽  
Lotte K Kristensen ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Focal Cerebral Ischemia ◽  
Experimental Stroke ◽  
Lesion Volume ◽  
Mrna Levels ◽  
Protective Effects ◽  
Genetic Ablation ◽  
Necrosis Factor

Microglia respond to focal cerebral ischemia by increasing their production of the neuromodulatory cytokine tumor necrosis factor, which exists both as membrane-anchored tumor necrosis factor and as cleaved soluble tumor necrosis factor forms. We previously demonstrated that tumor necrosis factor knockout mice display increased lesion volume after focal cerebral ischemia, suggesting that tumor necrosis factor is neuroprotective in experimental stroke. Here, we extend our studies to show that mice with intact membrane-anchored tumor necrosis factor, but no soluble tumor necrosis factor, display reduced infarct volumes at one and five days after stroke. This was associated with improved functional outcome after experimental stroke. No changes were found in the mRNA levels of tumor necrosis factor and tumor necrosis factor-related genes (TNFR1, TNFR2, TACE), pro-inflammatory cytokines (IL-1β, IL-6) or chemokines (CXCL1, CXCL10, CCL2); however, protein expression of TNF, IL-1β, IL-6 and CXCL1 was reduced in membrane-anchored tumor necrosis factorΔ/Δ compared to membrane-anchored tumor necrosis factorwt/wt mice one day after experimental stroke. This was paralleled by reduced MHCII expression and a reduction in macrophage infiltration in the ipsilateral cortex of membrane-anchored tumor necrosis factorΔ/Δ mice. Collectively, these findings indicate that membrane-anchored tumor necrosis factor mediates the protective effects of tumor necrosis factor signaling in experimental stroke, and therapeutic strategies specifically targeting soluble tumor necrosis factor could be beneficial in clinical stroke therapy.

scholarly journals A Quantitative Study of Microglial—Macrophage Synthesis of Tumor Necrosis Factor during Acute and Late Focal Cerebral Ischemia in Mice

2005 ◽  
Vol 25 (1) ◽  
pp. 119-135 ◽  
Author(s):  
Kate Lykke Lambertsen ◽  
Michael Meldgaard ◽  
Rune Ladeby ◽  
Bente Finsen
Keyword(s):  
Cerebral Ischemia ◽  
Tumor Necrosis Factor ◽  
Real Time ◽  
Acute Phase ◽  
Reverse Transcription ◽  
Tumor Necrosis ◽  
Focal Cerebral Ischemia ◽  
Fold Increase ◽  
Pcr Analysis ◽  
Necrosis Factor

Understanding the role of tumor necrosis factor (TNF) in the life-death balance of ischemically injured neurons demands insight into the cellular synthesis of TNF, especially in the acute phase after induction of ischemia. Here, using approximated stereological methods and quantitative reverse transcription (RT) real-time polymerase chain reaction (PCR) analysis, the cellular synthesis of TNF from 30 mins to 10 days after induction of focal cerebral ischemia in mice was investigated. Reverse transcription real-time PCR analysis showed that TNF mRNA increased 2- to 3-fold within 1 hour after induction of ischemia. A significant 8-fold increase was observed at 4 hours when faintly labelled TNF mRNA-expressing and TNF immunoreactive microglial-like cells were easily identifiable in the peri-infarct and infarct. By 6 hours, TNF synthesizing cells were identified as Mac-1 immunopositive, glial fibrillary acidic protein immunonegative microglia-macrophages. The level of TNF mRNA and the numbers of TNF mRNA-expressing microglia-macrophages peaked at 12 hours, and the number of TNF immunoreactive cells at 24 hours. Neuronal TNF mRNA and TNF protein levels remained at constant, very low, levels. The data suggest that the pathophysiologically important TNF, produced in the acute phase from mins to 6 hours after an ischemic attack in mice, is synthesized by microglia-macrophages.

scholarly journals Inhibition of Tumor Necrosis Factor and Amelioration of Brain Infarction in Mice

1997 ◽  
Vol 17 (2) ◽  
pp. 229-232 ◽  
Author(s):  
Hiroshi Nawashiro ◽  
David Martin ◽  
John M. Hallenbeck
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Brain Infarction ◽  
Arterial Occlusion ◽  
Type I ◽  
Tnf Α ◽  
Cerebral Arterial Occlusion ◽  
Necrosis Factor

Tumor necrosis factor alpha (TNF- α) is expressed in the ischemic brain; however, its precise role is not fully understood. We studied the effect of the dimeric form of the type I soluble TNF receptor linked to polyethylene glycol (TNFbp) on focal cerebral ischemia in mice using a permanent middle cerebral arterial occlusion (MCAO) model. TNFbp was applied topically, intravenously, or intraperitoneally. TNFbp binds and inhibits TNF- α. The volume of cortical ischemic lesions was measured by means of 2,3,5-triphenyltetrazolium chloride 24 h after MCAO. TNFbp produced a significant reduction in the cortical infarct volume of vehicle-treated animals ( p < 0.001). The reduction in the volume of brain damage was 26% in animals that received 3 mg/kg of TNFbp topically. Further analysis of TNF- α inhibition following acute brain ischemia is indicated.

scholarly journals Microglia and Macrophages Are the Major Source of Tumor Necrosis Factor in Permanent Middle Cerebral Artery Occlusion in Mice

2000 ◽  
Vol 20 (1) ◽  
pp. 53-65 ◽  
Author(s):  
Rikke Gregersen ◽  
Kate Lambertsen ◽  
Bente Finsen
Keyword(s):  
In Situ Hybridization ◽  
Cerebral Ischemia ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Focal Cerebral Ischemia ◽  
Artery Occlusion ◽  
Time Points ◽  
Cerebral Artery Occlusion ◽  
Necrosis Factor

The proinflammatory cytokine tumor necrosis factor (TNF) is known to be expressed in brain ischemia; however, its cellular and temporal appearance is not fully settled. In this study, nonradioactive in situ hybridization for murine TNF mRNA was performed on brain sections from adult C57×129 mice at 6 hours, 12 hours, 24 hours, 2 days, 5 days, or 10 days (six to eight mice per group) after induction of permanent focal cerebral ischemia. Cortical infarct volumes were estimated, and TNF mRNA-expressing cells were counted within the infarct and infarct border using Cast-Grid analysis. At 12 hours, a peak of 19.2 ± 5.1 TNF mRNA-expressing cells/mm2 was counted, contrasting two to three times lower values at 6 and 24 hours (6.4 ± 4.6 and 9.2 ± 3.4 cells/mm2, respectively) and <2 cells/ mm2 at 48 hours and later stages. The TNF mRNA-expressing cells were distributed along the entire rostrocaudal axis of the cortical infarcts and occasionally within the caudate putamen. At all time points, TNF mRNA colocalized with Mac-1-positive microglia/macrophages but not with Ly-6G (Gr-1)-positive polymorphonuclear leukocytes. Similarly, combined in situ hybridization for TNF mRNA and immunohistochemistry for glial fibrillary acidic protein at 12 and 24 hours revealed no TNF mRNA-expressing astrocytes at these time points. Translation of TNF mRNA into bioactive protein was demonstrated in the neocortex of C57Bl/6 mice subjected to permanent middle cerebral artery occlusion. In summary, this study points to a time-restricted microglial/macrophage production of TNF in focal cerebral ischemia in mice.

scholarly journals Ischemic and Excitotoxic Brain Injury is Enhanced in Mice Lacking the p55 Tumor Necrosis Factor Receptor

1998 ◽  
Vol 18 (12) ◽  
pp. 1283-1287 ◽  
Author(s):  
Devin S. Gary ◽  
Annadora J. Bruce-Keller ◽  
Mark S. Kindy ◽  
Mark P. Mattson
Keyword(s):  
Brain Injury ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Wild Type ◽  
Necrosis Factor

Ischemic and excitotoxic insults to the brain induce rapid production of tumor necrosis factor-α (TNF), but the role of TNF in neuronal responses to brain injury are unclear. Two different TNF receptors (p55 and p75) are expressed in neurons and glia, To understand the role of TNF in brain injury, we generated mice that lack p55, p75, or both receptors, We report that neuronal damage after focal cerebral ischemia—reperfusion is significantly increased in mice lacking p55 receptors (85 ± 7 mm3 infarct volume; mean ± SD) compared with wild-type mice (70 ± 8 mm3) and mice lacking p75 receptors (72 ± 6 mm3). Moreover, mice lacking p55 receptors exhibited increased degeneration of CA3 hippocampal neurons after administration of the excitotoxin kainic acid compared with wild-type mice and mice lacking p75 receptors. When taken together with recent data showing that TNF can prevent apoptosis of cultured neurons exposed to oxidative and metabolic insults, our findings suggest that TNF plays a neuroprotective role after acute brain insults.

Sign in / Sign up

Export Citation Format

Share Document