Biomedical subjects

E Shohami

Publications and source records attributed to E Shohami.

At least 37 records · Page 2Linked to original sources

PubMed2000

Tau hyperphosphorylation in apolipoprotein E-deficient and control mice after closed head injury.

Apolipoprotein E (apoE)-deficient mice have learning and memory impairments that are associated with specific neurochemical changes and hyperphosphorylation of distinct epitopes of the cytoskeletal protein tau. Furthermore, such mice are highly susceptible to the sequelae of brain trauma and their ability to recover from head injury is impaired. In the present study we investigated the extent that the neuronal maintenance and repair impairments of apoE-deficient mice are related to aberrations at the tau phosphorylation level. This was pursued by subjecting control and apoE-deficient mice to closed head injury (CHI) and examination, utilizing immunoblot assays, of the resulting effects on tau phosphorylation. The results thus obtained revealed that tau of apoE-deficient mice is hyperphosphorylated before CHI and that this insult results in transient tau hyperphosphorylation, whose extent and time course in the two mouse groups varied markedly. Tau hyperphosphorylation in the injured controls was maximal by about 4 hr after injury and reverted to basal levels by 24 hr. In contrast, almost no head injury-induced tau hyperphosphorylation was observed in the apoE-deficient mice at 4 hr after injury. Some tau hyper-phosphorylation was detected in the head-injured apoE-deficient mice after longer time intervals, but its extent was markedly lower than the maximal values obtained in the head injured controls. These findings show that the chronic neuronal impairments brought about by apoE deficiency and the acute response to head injury are both associated with hyperphosphorylation of the same tau domain and that the ability of apoE-deficient mice to mount the acute tau hyperphosphorylation response to head injury is impaired.

Animals↗

PubMed2000

Closed head injury induces up-regulation of ErbB-4 receptor at the site of injury.

ErbB-4 receptor tyrosine kinase and its ligand neu differentiation factor (NDF/neuregulin) are widely expressed in the brain. The closed head injury model was used to investigate the possible role of ErbB-4 receptor in neurodegeneration. It is demonstrated that levels of ErbB-4 are dramatically increased at the site of injury. Activated microglia/macrophages constitute the major population of cells with the highest receptor levels at the site of injury. In addition ErbB-4 expression after injury is elevated also in neurons but not in astrocytes. Confocal microscopy analysis suggests that the high level of ErbB-4 protein in activated microglia/macrophages is probably due to phagocytosis of neuronal cells. These findings show for the first time that ErbB-4 receptors play a role in brain responses to head trauma. Overexpression of ErbB-4 receptors may be important for directing activated microglia/macrophages to the lesion site.

Animals↗

PubMed2000

Antisense prevention of neuronal damages following head injury in mice.

Closed head injury (CHI) is an important cause of death among young adults and a prominent risk factor for nonfamilial Alzheimer's disease. Emergency intervention following CHI should therefore strive to improve survival, promote recovery, and prevent delayed neuropathologies. We employed high-resolution nonradioactive in situ hybridization to determine whether a single intracerebro-ventricular injection of 500 ng 2'-O-methyl RNA-capped antisense oligonucleotide (AS-ODN) against acetylcholinesterase (AChE) mRNA blocks overexpression of the stress-related readthrough AChE (AChE-R) mRNA splicing variant in head-injured mice. Silver-based Golgi staining revealed pronounced dendrite outgrowth in somatosensory cortex of traumatized mice 14 days postinjury that was associated with sites of AChE-R mRNA overexpression and suppressed by anti-AChE AS-ODNs. Furthermore, antisense treatment reduced the number of dead CA3 hippocampal neurons in injured mice, and facilitated neurological recovery as determined by performance in tests of neuromotor coordination. In trauma-sensitive transgenic mice overproducing AChE, antisense treatment reduced mortality from 50% to 20%, similar to that displayed by head-injured control mice. These findings demonstrate the potential of antisense therapeutics in treating acute injury, and suggest antisense prevention of AChE-R overproduction to mitigate the detrimental consequences of various traumatic brain insults.

Acetylcholinesterase↗

PubMed2000

Induction of antitumor immunity by indomethacin.

Irradiated tumor cells given, together with indomethacin, to syngeneic mice induced an antitumor response and conferred protection against a challenge of a lethal dose of murine mammary (4T1) and lung (3LL) carcinoma cells. Continuous administration of indomethacin was crucial throughout the entire period of immunization and challenge, as no protection was achieved when the drug was given during only one of these procedures. Antitumor immunity was long-lasting and, when tested in the 4T1 model, 48% of mice were resistant to a second challenge of lethal tumor cells. Tumor-free immune mice that were given indomethacin for more than 300 days remained healthy with normal white blood cell counts and normal spleen size. Cells isolated from immune mice were able to kill tumor cells in culture after in vitro activation by interleukin-2, in a manner similar to cells from naive normal control mice. In addition, the mitogenic response of their T cells was as high as that of the control naive mice. While indomethacin was able to induce antitumor immunity to 4T1 and 3LL murine carcinoma cells, both of which contain a high concentration of endogenic prostaglandin E(2) (PGE2), no such immunity was achieved to murine tumor cells with a low concentration of endogenic PGE2. These results suggest a correlation between PGE2 concentration and the ability of indomethacin to induce antitumor immunity. We therefore suggest that an immunotherapy protocol with long-term dispensation of a tolerable dose of an immunomodulator, given together with irradiated autologous tumor cells, may stimulate antitumor responses to tumors containing high concentrations of endogenic PGE2.

Adjuvants, Immunologic↗

PubMed2000

Susceptibility of transgenic mice expressing human apolipoprotein E to closed head injury: the allele E3 is neuroprotective whereas E4 increases fatalities.

Apolipoprotein E, the major brain lipid-binding protein, is expressed in humans as three common isoforms (E2, E3 and E4). Previous studies revealed that the allele apolipoprotein E4 is a major genetic risk factor of Alzheimer's disease and that traumatic brain injury is associated with increased risk for developing this disease. Furthermore, it has been suggested that the effects of traumatic head injury and apolipoprotein E4 in Alzheimer's disease are synergistic. To test the hypothesis that the apolipoprotein E genotype affects susceptibility to brain injury, we subjected transgenic mice, expressing either human apolipoprotein E3 or human apolipoprotein E4 on a null mouse apolipoprotein E background and apolipoprotein E-deficient knockouts, to closed head injury and compared mortality, neurological recovery and the extent of brain damage of the survivors. More than 50% of the transgenic mice expressing human apolipoprotein E4 died following closed head injury, whereas only half as many of the transgenic mice expressing human apolipoprotein E3, and of the control and apolipoprotein E-deficient mice died during this period (P<0.02). A neurological severity score used for clinical assessment of the surviving mice up to 11 days after closed head injury revealed that the four mouse groups displayed similar severity of damage at 1h following injury. At three and 11 days post-injury, however, the neurological severity scores of the transgenic mice expressing human apolipoprotein E3 were significantly lower than those of the other three groups whose scores were similar, indicating better recovery of the transgenic mice expressing human apolipoprotein E3. Histopathological examination of the mice performed 11 days post-injury revealed, consistent with the above neurological results, that the size of the damaged brain area of the transgenic mice expressing human apolipoprotein E3 was smaller than that of the other head-injured groups. These findings show that transgenic mice expressing human apolipoprotein E4 are more susceptible than those expressing apolipoprotein E3 to closed head injury. We suggest that this effect is due to both a protective effect of apolipoprotein E3 and an apolipoprotein E4-related pathological function.

Alleles↗

PubMed2000

Increased levels of intracellular iron in the brains of ApoE-deficient mice with closed head injury.

Previous studies have revealed that apolipoprotein E (apoE)-deficient mice have distinct memory deficits and neurochemical derangements and are oxidatively stressed prior to and following closed head injury. The objective of this study was to evaluate the possibility that the enhanced susceptibility of apoE-deficient mice to closed head injury is related to impairments in their antioxidative iron-chelating mechanisms. ApoE-deficient and control mice were subjected to closed had injury, after which the extent of brain-damage and the level of iron-containing cells were assessed. Examination of the brain-damaged areas in the injured mice revealed that, by Day 3 post injury, animals of both groups were maximally and similarly affected. While the size of the damaged area of the injured control mice diminished significantly by Day 7, however recovery was not observed in injured apoE-deficient mice up to at least 14 days post-injury. Histopathologically, the decrease in the damaged areas in the control mice was interpreted as related to decreased edema. Numbers of iron-containing cells at Days 3 and 7 after injury were greater in the brains of control mice than in the apoE-deficient mice. Whereas the number of iron-containing cells in injured control mice decreased at days 9 and 14-post injury, that of the injured apoE-deficient mice plateaued by Day 9 at a level more than two-fold higher than the maximal level seen for controls. The size of the damaged areas and the number of iron-containing cells were correlated (P < 0.03) for both mouse groups at days 9 and 14 after injury. The data suggest that the increased susceptibility of apoE-deficient mice to closed head injury may be due, at least in part, to impaired iron scavenging and sustained oxidative stress.

Animals↗

PubMed2000

Increased hepatic lipid soluble antioxidant capacity as compared to other organs of streptozotocin-induced diabetic rats: a cyclic voltammetry study.

It has been suggested that oxidative stress plays an important role in the chronic complications of diabetes. The experimental findings regarding the changes in tissue antioxidant enzymes and lipid peroxidation of diabetic tissues have been inconsistent. Previous studies in our laboratory demonstrated that the reducing power of a specific tissue correlates with its low molecular weight antioxidant (LMWA) capacity. In the present study, the overall LMWA capacity (reducing equivalents) of plasma and tissues of streptozotocin (STZ)-induced diabetic rats (1-4 weeks) and insulin treated diabetic rats were measured by cyclic voltammetry. Levels of water and lipid soluble LMWA capacity progressively decreased in the diabetic plasma, kidney, heart and brain, while the diabetic liver, at 2, 3 and 4 weeks after STZ injection, showed a significant increase in the overall lipid soluble LMWA capacity (p < 0.001). Subsequently, analysis of specific components by high pressure liquid chromatography (electrochemical detection) showed decreased levels of ascorbic acid in plasma, kidney, heart and brain of diabetic animals. The alpha-tocopherol level dropped in all tissues, except for the liver in which there was a significant increase (p < 0.01 and p < 0.001 at 2-4 weeks). Lipid peroxidation was assessed by conjugated diene levels, which increased significantly in all diabetic tissues except the liver. Insulin treatment that was started after 3 weeks of diabetes and continued for 3 weeks showed no change in the conjugated dienes and in the overall LMWA capacity in all organs. Our results suggest a unique behavior of the liver in the STZ-induced diabetic rats to the stress and indicate its higher capacity to cope with oxidative stress as compared to other organs.

Animals↗

PubMed2000

Neurological recovery from closed head injury is impaired in diabetic rats.

Diabetes mellitus is a metabolic disorder associated with central nervous system impairments. Recent studies implicate oxidative stress mediated by reactive oxygen species (ROS) in the pathogenesis of diabetic complications. ROS have been shown to play role in the pathophysiology of brain injury. In the present study, closed head injury (CHI) was induced in diabetic rats to test the hypothesis that chronic oxidative stress exacerbates brain damage following CHI. Neurological recovery, edema, levels of low molecular weight antioxidants (LMWA), and markers of lipid peroxidation were determined at different intervals after injury. Diabetic rats (4 weeks after induction with streptozotocin) were subjected to CHI. Brain edema (percent water) and clinical status (neurological severity score) were assessed during 7 days. Brain LMWA were determined using cyclic voltammetry (CV) and HPLC-EC. In addition, conjugated dienes and thiobarbituric acid reactive substances (TBARS) were measured. Diabetic-CHI rats exhibited a lower rate of recovery and greater and more sustained edema (p < 0.01), as compared with the controls. At all times diabetic rats had higher levels of TBARS and conjugated dienes and lower concentrations of LMWA, and of vitamins C and E, suggesting chronic oxidative stress. At 5 min of CHI, the amounts of LMWA in control-CHI brains decreased (approximately 50%, p < 0.01) and returned to normal by 48 h and 7 days. In the diabetic-CHI brain only one class of LMWA slightly declined but remained low for 7 days. The present results support the hypothesis that diabetic rats are under chronic oxidative stress, and suffer greater neurological dysfunction, associated with further lipid peroxidation following CHI.

Animals↗

PubMed2000

Experimental closed head injury: analysis of neurological outcome, blood-brain barrier dysfunction, intracranial neutrophil infiltration, and neuronal cell death in mice deficient in genes for pro-inflammatory cytokines.

Cytokines are important mediators of intracranial inflammation following traumatic brain injury (TBI). In the present study, the neurological impairment and mortality, blood-brain barrier (BBB) function, intracranial polymorphonuclear leukocyte (PMN) accumulation, and posttraumatic neuronal cell death were monitored in mice lacking the genes for tumor necrosis factor (TNF)/lymphotoxin-alpha (LT-alpha) (TNF/LT-alpha-/-) and interleukin-6 (IL-6) and in wild-type (WT) littermates subjected to experimental closed head injury (total n = 107). The posttraumatic mortality was significantly increased in TNF/LT-alpha-/- mice (40%; P < 0.02) compared with WT animals (10%). The IL-6-/- mice also showed a higher mortality (17%) than their WT littermates (5.6%), but the difference was not statistically significant (P > 0.05). The neurological severity score was similar among all groups from 1 to 72 hours after trauma, whereas at 7 days, the TNF/LT-alpha-/- mice showed a tendency toward better neurological recovery than their WT littermates. Interestingly, neither the degree of BBB dysfunction nor the number of infiltrating PMNs in the injured hemisphere was different between WT and cytokine-deficient mice. Furthermore, the analysis of brain sections by in situ DNA nick end labeling (TUNEL histochemistry) at 24 hours and 7 days after head injury revealed a similar extent of posttraumatic intracranial cell death in all animals. These results show that the pathophysiological sequelae of TBI are not significantly altered in mice lacking the genes for the proinflammatory cytokines TNF, LT-alpha, and IL-6. Nevertheless, the increased posttraumatic mortality in TNF/LT-alpha-deficient mice suggests a protective effect of these cytokines by mechanisms that have not been elucidated yet.

Animals↗

PubMed2000

Selective antagonism of endothelin-A-receptors improves outcome in both head trauma and focal stroke in rat.

Increased levels of endothelin (ET) have been demonstrated in the ischemic brain, and ET receptor antagonism has been shown to improve outcome in cerebral ischemia. However, no previous work has been carried out evaluating the role of ET and its antagonism in brain trauma as compared to experimental stroke. In this study, we evaluated changes in brain ET levels following closed head injury (CHI) and the effects of SB 234551, an endothelin-A- (ET(A)) selective antagonist, and SB 209670, a mixed endothelin-A- and -B- (ET(A)/ET(B)) antagonist, on outcome in CHI and focal stroke. Male Sabra rats were subjected to CHI (weight drop model). Male Sprague Dawley rats were subjected to focal stroke (intraluminal suture model). Motor function(s) were assessed and immunoreactive ET (irET) and the degree of cerebral edema were measured for 24 h after CHI. Brain swelling (edema), neurological deficits and forebrain infarct volumes were measured 24 h after focal stroke. Antagonists (total doses of 7.5, 15, 30 or 60 mg/kg) were administered intravenously for 6-24 h (beginning 15 min after injury). Control rats were infused with vehicle. CHI resulted in increased ET levels in the directly contused hemisphere at 12 and 24 h. In addition, SB 234551 significantly reduced neurological deficits (decreased 30%) and brain edema (decreased 40%) following CHI (p < 0.05 at 60 mg/kg dose). SB 209670 had no effects on CHI outcome. Focal stroke studies yielded similar results. SB 234551 reduced focal stroke-induced neurological deficits by 50%, brain swelling by 54% and the degree of infarction by 36% (p < 0.05 at 30 mg/kg). SB 209670 did not provide any neuroprotection in focal stroke. These data indicate that ET plays a significant role in the pathophysiology of CHI, and that selectively targeting ET(A)-receptors similarly in both CHI and stroke might be a therapeutic opportunity.

Animals↗

PubMed2000

Tumor necrosis factor and reactive oxygen species cooperative cytotoxicity is mediated via inhibition of NF-kappaB.

BACKGROUND: Tumor necrosis factor alpha (TNFalpha) plays a key role in pathogenesis of brain injury. However, TNFalpha exhibits no cytotoxicity in primary cultures of brain cells. This discrepancy suggests that other pathogenic stimuli that exist in the setting of brain injury precipitate TNFalpha cytotoxicity. The hypothesis was tested that reactive oxygen species (ROS), that are released early after brain injury, act synergistically with TNFalpha in causing cell death. MATERIALS AND METHODS: Cultured human and rat brain capillary endothelial cells (RBEC), and cortical astrocytes were treated with TNFalpha alone or together with different doses of H2O2, and apoptotic cell death and DNA fragmentation were measured by means of 3'-OH-terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Hoechst fluorescence assay, respectively. The effect of H2O2 on TNFalpha-induced activation of nuclear factor kappa B (NF-kappaB) was measured by Western blots of cytoplasmic and nuclear extracts of RBEC using anti-inhibitor of NF-kappaB (IkappaB) and anti-p65 subunit of NF-kappaB antibodies. Nuclear translocation of NF-kappaB was investigated by immunofluorescent staining of RBEC with anti-p65 antibodies. RESULTS: TNFalpha alone had no cytotoxic effect in brain endothelial cells and astrocytes at concentrations up to 100 ng/ml. Co-treatment with 5-10 microM of H2O2 caused a two-fold increase in the number of apoptotic cells 24 hr later. Similar doses (1-3 microM) of H2O2 initiated early DNA fragmentation. H2O2 inhibited TNFalpha-induced accumulation of p65 in the nucleus, although it had no effect on degradation of the IkappaB in cytoplasm. Immunostaining confirmed that H2O2 inhibited p65 transport to the nucleus. CONCLUSIONS: Reactive oxygen species could act synergistically with TNFalpha in causing cytotoxicity via inhibition of a cytoprotective branch of TNFalpha signaling pathways, which starts with NF-kappaB activation.

Animals↗

PubMed1999

Rasagiline, a monoamine oxidase-B inhibitor, protects NGF-differentiated PC12 cells against oxygen-glucose deprivation.

In our in vitro model, rasagiline a selective irreversible monoamine oxidase-B (MAO-B) inhibitor, protected nerve growth factor (NGF)-differentiated PC12 cells from cell death under oxygen and glucose deprivation (OGD). The severity of the OGD insult, as expressed by cell death, was time-dependent. Exposure of the cells to OGD for 3 hr followed by 18 hr of reoxygenation caused about 30-40% cell death. Under these conditions, the neuroprotective effect of rasagiline was dose-dependent: rasagiline reducing OGD-induced cell death by 68% and 80% at 100 nM and 1 microM, respectively. The neuroprotective effect of rasagiline was also observed when added after the OGD insult (55% reduction in cell death). Under rasagiline treatment, there was a lesser decrease in ATP content in cultures exposed to OGD compared with that in untreated cultures. OGD followed by reoxygenation resulted in a several fold increase in PGE(2) release into the extracellular medium. Rasagiline (100 nM-1 microM) markedly inhibited OGD-induced PGE(2) release. Clorgyline, a monoamine oxidase-A (MAO-A) inhibitor, did not protect NGF-differentiated PC12 cells against OGD-induced cell death. As NGF-differentiated PC12 cells contain exclusively MAO type A, these data suggest that the neuroprotective effect of rasagiline under OGD conditions is independent of MAO inhibition.

Adenosine Triphosphate↗

PubMed1999

Antioxidant mechanisms in apolipoprotein E deficient mice prior to and following closed head injury.

Apolipoprotein E deficient mice have distinct memory deficits and neurochemical derangements and their recovery from closed head injury is impaired. In the present study, we examined the possibility that the neuronal derangements of apolipoprotein E deficient mice are associated with oxidative stress, which in turn affects their ability to recover from close head injury. It was found that brain phospholipid levels in apolipoprotein E deficient mice are lower than those of the controls (55+/-15% of control, P<0. 01), that the cholesterol levels of the two mice groups are similar and that the levels of conjugated dienes of the apolipoprotein E deficient mice are higher than those of control mice (132+/-15% of P<0.01). Brains of apolipoprotein E deficient mice had higher Mn-superoxide dismutase (134+/-7%), catalase (122+/-8%) and glutathione reductase (167+/-7%) activities than control (P<0.01), whereas glutathione peroxidase activity and the levels of reduced glutathione and ascorbic acid were similar in the two mouse groups. Closed head injury increased catalase and glutathione peroxidase activities in both mouse groups, whereas glutathione reductase increased only in control mice. The superoxide dismutase activity was unaffected in both groups. These findings suggest that the antioxidative metabolism of apolipoprotein E deficient mice is altered both prior to and following head injury and that antioxidative mechanisms may play a role in mediating the neuronal maintenance and repair derangements of the apolipoprotein E deficient mice.

Animals↗

PubMed1999

Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse.

UNLABELLED: The potential neuroprotective effects of rasagiline, N-propargyl-1R-aminoindan, a selective monoamine oxidase-B inhibitor and its inactive enantiomer TVP 1022, N-propargyl-1S-aminoindan were assessed against the sequelae of closed head injury in the mouse. Injury was induced in the left hemisphere under ether anaesthesia. Rasagiline (0.2 and 1 mg/kg) or TVP1022 (1 and 2 mg/kg) injected 5 min after injury accelerated the recovery of motor function and spatial memory and reduced the cerebral oedema by about 40-50%, (P < 0.01). The neuroprotective effects on motor function and spatial memory, but not on cerebral oedema, were prevented by scopolamine (0.2 mg/kg). Daily injection of rasagiline (1 mg/kg) from day 3 after injury accelerated the recovery of spatial memory but not motor function. CONCLUSIONS: Early administration of rasagiline or TVP1022 can reduce the immediate sequelae of brain injury. The mechanism of action does not appear to involve monoamine oxidase-B inhibition but could be mediated by the maintenance of cholinergic transmission in brain neurons.

Animals↗

PubMed1999

Dexanabinol; a novel neuroprotective drug in experimental focal cerebral ischemia.

The permanent middle cerebral artery occlusion (PMCAO) model was used to investigate the cerebroprotective effects of the synthetic cannabinoid, dexanabinol (HU-211). Dexanabinol is a noncompetitive N-methyl-D-aspartate antagonist, with antioxidant and anti-TNFalpha properties. Twenty hypertensive rats were subjected to PMCAO. Eight were given 4 mg/kg dexanabinol, i.v., 1 h after PMCAO, eight received vehicle and four were not injected Five rats underwent sham surgery. Infarct volumes were assessed, as well as TNFalpha concentrations and NOS activity in brain homogenates. Dexanabinol significantly decreased infarct volumes. It also significantly lowered TNFalpha levels in the ipsilateral hemisphere although not to the level of sham operated rats. No effect could be demonstrated on NOS activity. In conclusion, dexanabinol may be a pluripotent cerebroprotective agent.

Animals↗

PubMed1999

Serum-mediated osteogenic effects of head injury on cultured rat marrow stromal cells.

Central nervous system (CNS) injuries in humans are frequently associated with heterotopic ossification (HO) and with enhanced fracture healing. In search for an experimental HO model we tested sera, from an established rat model of closed head injury (CHI), for their osteogenic effects on rat marrow stromal cells. Most normal rat sera increased cell proliferation not discriminating between osteoprogenitors and other stromal cells. Rats followed longitudinally by sequential blood sampling were bled 24 hours before and 24 hours, 48 hours, and 7 days after CHI. Sera obtained 24 and 48 hours after CHI progressively decreased cell proliferation and specific alkaline phosphatase (ALP) activity compared with pre-CHI sera of the same rats. Sera obtained from these rats, 7 days post-CHI, partially recovered proliferation induction, more than recovering induction of specific ALP activity. A positive correlation between day 11 ALP activity and day 21 mineralization was found under stimulation by pre-CHI sera. However, no correlation was found on stimulation with sera obtained 48 hours after CHI. Correlation between ALP and mineralization partially recovered in cultures exposed to sera obtained 7 days after CHI. In cross-sectional experiments where rats were subjected to single blood sampling, sera of 24 hours and 7 days post-CHI induced proliferation, whereas sera of 48 hours and 14 days post-CHI did not. The results indicate that 48 hours post-CHI, the mitogenicity of sera decreased in both cross-sectional and longitudinal blood sampling. In addition, 48 hours post-CHI, the specific ALP activity increases in cultured marrow stromal cells. Thus, changes in bone-seeking factors, causing serum-mediated osteogenic activity in rats, are expected close on 48 hour post-CNS injury.

Alkaline Phosphatase↗

PubMed1999

Dual role of tumor necrosis factor alpha in brain injury.

Brain injury (ischemia, trauma) is among the leading cause of mortality and disability in the western world. It induces increased production of tumor necrosis factor (TNF alpha) by brain resident cells. There is conflicting evidence on the role of this response in the injured brain, showing its potential effect in both processes of repair and of damage. This review presents data from clinical and experimental studies on the stimulation of TNF alpha production in brain injury and on the deleterious consequence of this acute response. Its inhibition by pharmacologic agents, neutralizing antibodies or soluble receptors has protective effects. In contrast, there are reports (from in-vitro studies or knock-out mice) on the beneficial effects of TNF alpha. To reconcile these apparently conflicting reports, the exact timing and extent of TNF alpha activation must be taken into account, as well as the presence of other mediators such as reactive oxygen species. It is suggested that the appropriate context of mediators, at any given time after brain injury may well determine whether the effect of TNF alpha is protective or toxic.

Animals↗

PubMed1999

Antioxidants attenuate acute toxicity of tumor necrosis factor-alpha induced by brain injury in rat.

Tumor necrosis factor-alpha alpha (TNF-alpha) and reactive oxygen species (ROS) are produced in the brain after traumatic injury and have deleterious effects. In a rat model of closed head injury (CHI), the synthetic antioxidant from the nitroxide family, Tempol, improved recovery and protected the blood-brain barrier. Similar protection was found after CHI in heat-acclimated rats, in which the endogenous antioxidants have been shown to be elevated after CHI. The present study examined the relationship between TNF-alpha and ROS after CHI, namely, whether after CHI, antioxidants that afforded cerebroprotection also attenuated brain levels of TNF-alpha. Three groups of rats were subjected to CHI: (1) control, nontreated, (2) Tempol-treated, and (3) heat-acclimated (30 days at 34 degrees C). Four hours after injury (time for peak production of TNF-alpha), the activity of TNF-alpha was measured. Although clinical recovery was facilitated in rats of the two treated groups, TNF-alpha activity was as high as in the traumatized, untreated rats. Moreover, direct injection of TNF-alpha into mouse brain induced disruption of the blood-brain barrier, indicating its acute harmful effect. This toxic effect was attenuated by before and after treatment with Tempol. Our results support the hypothesis that in vivo antioxidants neutralize TNF-alpha toxicity, probably by interfering with activation of the transcription factor NF-kappa-B.

Analysis of Variance↗