Decompressive craniectomy: technical note.

Decompressive craniectomy is a neurosurgical technique in which a portion of the skull is removed to reduce intracranial pressure. The rationale for this procedure is based on the Monro-Kellie Doctrine; expanding the physical space confining edematous brain tissue after traumatic brain injury will reduce intracranial pressure. There is significant debate over the efficacy of decompressive craniectomy despite its sound rationale and historical significance. Considerable variation in the employment of decompressive craniectomy, particularly for secondary brain injury, explains the inconsistent results and mixed opinions of this potentially valuable technique. One way to address these concerns is to establish a consistent methodology for performing decompressive craniectomies. The purpose of this paper is to begin accomplishing this goal and to emphasize the critical points of the hemicraniectomy and bicoronal (Kjellberg type) craniectomy.

Women at risk for AD show increased parietal activation during a fluency task.

BACKGROUND: Imaging studies have shown disparities in resting metabolism and in functional activation between cognitively normal individuals at high and low risk for AD. A recent study has shown increased parietal activation in high-risk subjects during a paired associates recall task, which the authors postulated might overlap activation typically observed in verbal fluency. OBJECTIVE: To determine whether parietal activation is altered in a letter fluency task in cognitively normal individuals at high risk for AD. METHODS: fMRI was used to compare cortical activation between two groups of cognitively normal women differing in their risk for developing AD. A letter fluency task was used, which activates left frontal and parietal regions. The risk groups differed in family history of AD and APOE allele status but were matched in age, education, and measures of cognitive performance. Average age of the study participants was 53 years. RESULTS: The regional patterns of brain activation were similar between groups and similar to patterns observed by other investigators. However, the high-risk group showed significantly increased activation in the left parietal region despite identical letter fluency performance between risk groups. CONCLUSIONS: Cognitively normal individuals at high risk for AD show increased brain activation in the left parietal region with letter fluency, a region adjacent to that observed by others using a recall task. This convergence of results indicates disruption of functional circuits involving the left parietal lobe in asymptomatic individuals at increased risk for AD.

Inhibition of amyloidosis using low-molecular-weight heparins.

BACKGROUND: Amyloid diseases are characterized by the tissue deposition of extracellular proteinaceous material, which results in organ dysfunction and death. Colocalization of heparan sulfate (HS) proteoglycans to amyloid deposits suggests that they may be an early event in amyloid formation and play an important role in fibril formation. Structural analysis has demonstrated that HS interacts with amyloidogenic proteins resulting in structural changes that allow for an increase in beta-sheet content, possibly enhancing fibrillogenesis. Recent studies have shown that small-molecule anionic sulfonates or sulfates can arrest inflammation-associated (AA) amyloid induction. MATERIALS AND METHODS: In the present study, we examine the effect of low-molecular-weight heparins (LMWHs) on the development of amyloid in the mouse model of AA amyloid. In addition, in vitro fibril formation assays were performed to determine the effect of LMWHs on fibrillogenesis. RESULTS: Injection of mice with clinically relevant doses of LMWHs (enoxaparin and dalteparin) demonstrated a reduction in AA amyloid deposition. These compounds were capable of arresting the progression of AA amyloid and eventually resulting in regression of the amyloid deposits. In vitro analysis indicated that LMWHs prevented AA and Abeta peptide fibril formation by impeding the structural changes necessary for fibril formation. CONCLUSIONS: Our findings suggest that the LMWHs may provide beneficial effects against the development of amyloidoses, including Alzheimer's disease.

Expression of glutathione-S-transferase isozyme in the SY5Y neuroblastoma cell line increases resistance to oxidative stress.

Glutathione-S-transferases (GSTs) are a superfamily of enzymes that function to catalyze the nucleophilic attack of glutathione on electrophilic groups of a second substrate. GSTs are present in many organs and have been implicated in the detoxification of endogenous alpha, beta unsaturated aldehydes, including 4-hydroxynonenal (HNE). Exogenous GST protects hippocampal neurons against HNE in culture. To test the hypothesis that overexpression of GST in cells would increase resistance to exogenous or endogenous HNE induced by oxidative stress, stable transfectants of SY5Y neuroblastoma cells with GST were established. Stable GST transfectants demonstrated enzyme activities 13.7 times (Clone 1) and 30 times (Clone 2) higher than cells transfected with vector alone. GST transfectants (both Clones 1 and 2) demonstrated significantly (p <.05) increased resistance to ferrous sulfate/hydrogen peroxide (20.9% for Clone 1; 46.5% for Clone 2), amyloid beta-peptide (12.2% for Clone 1; 27.5.% for Clone 2), and peroxynitrite (24.3% for Clone 1; 43.9% for Clone 2), but not to exogenous application of HNE in culture medium. GST transfectants treated with 1,1,4-tris (acetyloxy)nonane, a nontoxic derivative of HNE that is degraded to HNE intracellularly, demonstrated a statistically significant (p <.05) increase in viability in a dose-dependent manner compared with SY5Y cells transfected with vector alone. These results suggest that overexpression of GST increases resistance to endogenous HNE induced by oxidative stress or released in the degradation of 1,1,4-tris (acetyloxy)nonane, but not to exogenous application of HNE.

Differences in functional magnetic resonance imaging activation by category in a visual confrontation naming task.

OBJECTIVE: Cortical processing involved in seemingly similar tasks may differ in important ways. The authors mapped cortical regions engaged in a commonly performed picture naming task, seeking differences by semantic category. Functional magnetic resonance imaging was used during presentation of standardized line drawings in 18 healthy right-handed female participants, comparing living versus nonliving entities. During visual naming, across categories there was strong activation of left frontal (BA45/47), bilateral temporo-occipital junction (BA19), and inferior temporal regions (BA36/37). Activation of right inferior temporal cortex (BA19 and BA37) was greater during naming of living versus nonliving category items. No category differences in activation strength in the left temporal lobe were observed. The authors conclude that visual semantic operations may involve visual association cortex in the right temporal lobe in women.

Estrogen receptor alpha, not beta, is a critical link in estradiol-mediated protection against brain injury.

Estradiol protects against brain injury, neurodegeneration, and cognitive decline. Our previous work demonstrates that physiological levels of estradiol protect against stroke injury and that this protection may be mediated through receptor-dependent alterations of gene expression. In this report, we tested the hypothesis that estrogen receptors play a pivotal role in mediating neuroprotective actions of estradiol and dissected the potential biological roles of each estrogen receptor (ER) subtype, ER alpha and ER beta, in the injured brain. To investigate and delineate these mechanisms, we used ER alpha-knockout (ER alpha KO) and ER beta-knockout (ER beta KO) mice in an animal model of stroke. We performed our studies by using a controlled endocrine paradigm, because endogenous levels of estradiol differ dramatically among ER alpha KO, ER beta KO, and wild-type mice. We ovariectomized ER alpha KO, ER beta KO, and the respective wild-type mice and implanted them with capsules filled with oil (vehicle) or a dose of 17 beta-estradiol that produces physiological hormone levels in serum. One week later, mice underwent ischemia. Our results demonstrate that deletion of ER alpha completely abolishes the protective actions of estradiol in all regions of the brain; whereas the ability of estradiol to protect against brain injury is totally preserved in the absence of ER beta. Thus, our results clearly establish that the ER alpha subtype is a critical mechanistic link in mediating the protective effects of physiological levels of estradiol in brain injury. Our discovery that ER alpha mediates protection of the brain carries far-reaching implications for the selective targeting of ERs in the treatment and prevention of neural dysfunction associated with normal aging or brain injury.

Increased serum amyloid a levels reflect colitis severity and precede amyloid formation in IL-2 knockout mice.

The lack of sensitive and relatively non-invasive measures has hampered monitoring the clinical course of spontaneously developing colitis in IL-2-deficient (-/-) mice. We selected (i) to study the correlation of the acute phase plasma proteins serum amyloid A (SAA) and serum amyloid P component (SAP) levels with colonic disease and (ii) to characterize the amyloidosis in the IL-2(-/-)animals. IL-2(-/-)mice exhibited increasing severity of gross intestinal inflammation with age, confined to the distal colon. Histologically, the colonic disease score increased serially in IL-2(-/-)animals. Wild-type mice showed no activity, while 16-week-old IL-2(+/-)animals had minimal colitis with small ulcers and lamina propria inflammatory infiltrate. Periportal hepatitis was present and positive Congo red staining indicated amyloidosis of the liver and spleen in 16 week IL-2(-/-)mice. SAA immunostaining in the liver and spleen was increased in the 8 week and 16 week IL-2(-/-)and 16 week IL-2(+/-)animals indicating AA amyloid deposits. Plasma SAA and SAP levels were markedly elevated, and generally preceded the onset of colitis and reflected its severity. Northern analysis showed markedly increased SAA expression in the liver and intestine of IL-2(-/-)and intestine of IL-2(+/-)16-week-old animals. Increased intestinal expression of SAA3 (lamina propria macrophages) indicates local inflammation in IL-2(+/-)animals at 16 weeks. Treatment of 3-week-old animals with systemic IL-2 or IL-1 receptor antagonist (IL-1ra) delayed inflammation, postponed the increase in SAA levels and minimized disease onset. These results further demonstrate that IL-2 plays a significant role in normal immune responses in the body and that plasma SAA levels both reflect colonic disease severity and may indicate subclinical disease in both IL-2(-/-)and IL-2(+/-)mice. Furthermore. The mechanism of IL-2-deficient induced colitis appears to be mediated in part through the increase in IL-1. In addition, the IL-2(-/-)mouse of spontaneous enterocolitis may provide a unique system for studying spontaneously developing AA amyloidosis.

Expression of mouse acute-phase (SAA1.1) and constitutive (SAA4) serum amyloid A isotypes: influence on lipoprotein profiles.

The serum amyloid A (SAA) family of proteins consists of inducible acute-phase members and a constitutive member that are minor apolipoproteins of normal high density lipoprotein (HDL). During inflammation, HDL cholesterol and apolipoprotein A-I (apoA-I) protein are decreased, and these changes are thought to be partly related to the increase in acute-phase SAA proteins that associate with the HDL particle to become the major apolipoprotein species. To determine the specific role of SAA in the alteration of HDL in the absence of a generalized acute-phase response, acute-phase Saa1.1 transgene expression was directed via an inducible mouse metallothionein promoter. Elevated levels of SAA1.1 (28+/-9 mg/dL) comparable to a moderate acute-phase response were achieved over a 5-day period. SAA association with the HDL particles at this concentration did not significantly alter the apoA-I or HDL cholesterol levels or change the lipoprotein profiles in the transgenic mice compared with wild-type mice. In addition, we used adenoviral vectors to increase the SAA expression to levels seen in a major acute-phase response. Injection of adenovirus expressing the mouse SAA1.1 protein resulted in high-level expression (72+/-8 mg/dL) but did not alter apoA-I levels. However, the SAA associated with the HDL particle gave rise to significantly larger HDL particles ( approximately 10%). Adenoviral expression of the constitutive SAA4 protein resulted in an increase in HDL size ( approximately 10%) and an increase in very low density lipoprotein levels (20-fold) and triglyceride levels (1.7-fold). These studies suggest that increases in acute-phase SAA proteins alone are insufficient to alter HDL cholesterol or apoA-I levels during inflammation. A role for constitutive SAA4 in HDL-very low density lipoprotein interactions should be considered.

Amyloid formation in the rat: adenoviral expression of mouse serum amyloid A proteins.

Serum amyloid A (SAA) proteins are acute-phase apolipoproteins that are associated with high-density lipoprotein (HDL) particles: SAA proteins are precursors to secondary amyloid fibril proteins and under certain conditions of chronic or recurrent inflammation these proteins are deposited as amyloid fibrils. Of two isotypes found in mouse, SAA1.1 and SAA2.1, only SAA1.1 is deposited into amyloid. The CE/J mouse is unique, in that the only isoform identified is a hybrid between SAA1.1 and SAA2.1 and the mouse does not show amyloid deposition. In the rat, a deletion in the SAA1/SAA2 gene is associated with the absence of protein in the plasma and subsequently no amyloid deposition is detected. We have generated adenoviral vectors to study the expression of SAA proteins on HDL metabolism and amyloid formation. Injection of SAA viruses into rats resulted in expression of the mouse SAA proteins in the plasma with specific association of the SAA with HDL particles. The induction of SAA proteins was comparable to that seen in mice presented with the inflammatory agent, bacterial lipopolysaccharide (LPS). Adenoviral induced SAA levels were maintained for up to several weeks without a significant decrease in SAA expression. Injection of rats with the mouse SAA1.1 adenoviral vector, followed by amyloid enhancing factor (AEF) and silver nitrate resulted in the deposition of amyloid fibrils in the spleen. After 2 weeks, amyloid could be detected in other tissues, including the heart, liver, kidneys and lungs. When animals were injected with null or the SAA2.2 virus no amyloid was detected. These studies demonstrate that the inability of the rat to develop AA amyloid is due to the lack of synthesizing an amyloidogenic SAA protein. Furthermore, the expression of the adenoviral SAA protein from the liver and incorporation onto HDL particles further supports the hypothesis that AA amyloid is derived from circulating SAA protein. The ease of use of the adenoviral vectors and the rat provide an excellent model to study the function of SAA proteins.

Amyloid beta-peptide effects on synaptosomes from apolipoprotein E-deficient mice.

Apolipoprotein E (apoE) is present in the brain and may contribute to neurophysiologic or neuropathologic events, depending on environmental and genetic influences. Recent studies indicate a role for apoE in synaptic plasticity and maintenance of synaptic membrane symmetry, suggesting that apoE may be involved in regulating synaptic homeostasis. In the present study, cerebrocortical synaptosomes were prepared from transgenic mice lacking apoE (apoE KO) to analyze the possible contribution of apoE toward maintaining homeostasis in synaptosomes. Synaptosomal preparations from apoE KO and wild-type mice exhibited similar basal levels of reactive oxygen species, mitochondrial function, and caspase activity; however, following application of amyloid beta-peptide [Abeta(1-40)], apoE KO synaptosomes displayed increased levels of oxidative stress, mitochondrial dysfunction, and caspase activation compared with synaptosomes from wild-type mice. Synaptosomal membranes from apoE KO mice were more fluid than wild-type synaptosomes and contained higher levels of thiobarbituric acid-reactive substances, consistent with elevated levels of lipid peroxidation occurring in the synapses of apoE KO mice. Together, these data are consistent with a role for apoE in maintaining homeostasis by attenuating oxidative stress, caspase activation, and mitochondrial homeostasis in synapses.

ALS-linked Cu/Zn-SOD mutation impairs cerebral synaptic glucose and glutamate transport and exacerbates ischemic brain injury.

Although degeneration of lower motor neurons is the most striking abnormality in amyotrophic lateral sclerosis (ALS), more subtle alterations may occur in the brain. Mutations in copper/zinc superoxide dismutase (Cu/Zn-SOD) are responsible for some cases of inherited ALS, and expression of mutant Cu/Zn-SOD in transgenic mice results in progressive motor neuron loss and a clinical phenotype similar to that of ALS patients. It is now reported that Cu/Zn-SOD mutant mice exhibit increased vulnerability to focal ischemic brain injury after transient occlusion of the middle cerebral artery. Levels of glucose and glutamate transport in cerebral cortex synaptic terminals were markedly decreased, and levels of membrane lipid peroxidation were increased in Cu/Zn-SOD mutant mice compared to nontransgenic mice. These findings demonstrate that mutant Cu/Zn-SOD may endanger brain neurons by a mechanism involving impairment of glucose and glutamate transporters. Moreover, our data demonstrate a direct adverse effect of the mutant enzyme on synaptic function.

Oxidized high-density lipoprotein induces neuron death.

High-density lipoprotein (HDL) exists within the brain and is highly vulnerable to oxidative modifications. The focus of the present study was to determine the effect of HDL and oxidized HDL (oxHDL) upon neurons, astrocytes, and microglia. Administration of highly oxidized HDL, but not native, minimally, or moderately modified HDL resulted in a dose- and time-dependent increase in oxidative stress and death of cultured rat embryonic neurons. Astrocyte and microglia cultures treated with highly oxidized HDL displayed increased reactive oxygen species formation but no toxicity. Application of oxHDL exacerbated oxidative stress and neuron death induced by beta-amyloid peptide. Studies using pharmacological inhibitors implicate the involvement of calcium and reactive oxygen species in oxHDL-induced neuronal loss. Neural cells expressing increased levels of BCL-2 had decreased levels of oxidative stress and neuron death following exposure to oxHDL. Together, these data demonstrate that oxHDL increases oxidative stress in neurons, astrocytes, and microglia which ultimately culminate in neuron death.

Presenilin-1 mutation increases neuronal vulnerability to focal ischemia in vivo and to hypoxia and glucose deprivation in cell culture: involvement of perturbed calcium homeostasis.

Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Studies of cultured neural cells suggest that PS1 mutations result in perturbed cellular calcium homeostasis and may thereby render neurons vulnerable to apoptosis. In light of evidence that metabolic impairment plays a role in AD, that cerebral ischemia may be a risk factor for AD, and that individuals with AD have increased morbidity and mortality after stroke, we examined the impact of a PS1 mutation on neuronal vulnerability to ischemic injury. We report that the extent of brain injury after focal cerebral ischemia reperfusion is increased, and behavioral outcome is worsened, in PS1 mutant knock-in mice compared to wild-type mice. Cultured cortical neurons from PS1 mutant mice exhibit increased vulnerability to glucose deprivation and chemical hypoxia compared to their wild-type counterparts. Calcium imaging studies demonstrated enhanced elevation of intracellular calcium levels after glucose deprivation and chemical hypoxia in neurons from PS1 mutant mice. Agents that block calcium release from IP(3)- and ryanodine-sensitive stores (xestospongin and dantrolene, respectively) protected against the endangering action of the PS1 mutation. Our data suggest that presenilin mutations may promote neuronal degeneration in AD by increasing the sensitivity of neurons to age-related ischemia-like conditions. The data further suggest that drugs that stabilize endoplasmic reticulum calcium homeostasis may prove effective in suppressing the neurodegenerative process in AD patients.

Expression of mouse apolipoprotein SAA1.1 in CE/J mice: isoform-specific effects on amyloidogenesis.

Amyloid A (AA) amyloid deposition in mice is dependent upon isoform-specific effects of the serum amyloid A (SAA) protein. In type A mice, SAA1.1 and SAA2.1 are the major apolipoprotein-SAA isoforms found on high-density lipoproteins. During inflammation, both isoforms are increased 1000-fold, but only SAA1.1 is selectively deposited into amyloid fibrils. Previous studies showed that the CE/J mouse strain is resistant to amyloid induction. This resistance is not due to a deficiency in SAA synthesis, but is probably related to the unusual SAA isoform present. The CE/J mouse has a single acute-phase SAA protein (SAA2.2), which is a composite of the SAA1.1 and SAA2.1, with an amino terminus similar to the nonamyloidogenic SAA2.1. Recently, genetic experiments suggested that the SAA2.2 isoform might provide protection from amyloid deposition. To determine the amyloidogenic potential of the CE/J mouse, we generated SAA adenoviral vectors to express the various isoforms in vitro and in vivo. Purified recombinant SAA proteins demonstrated that SAA1.1 was fibrillogenic in vitro, whereas SAA2.2 was unable to form fibrils. Incubation of increasing concentrations of the nonamyloidogenic SAA2.2 protein with the amyloidogenic SAA1.1 did not inhibit the fibrillogenic nature of SAA1.1, or alter its ability to form extensive fibrils. Injection of the mouse SAA1.1 or SAA2.2 adenoviral vectors into mice resulted in isoform-specific expression of the SAA proteins. Amyloid induction after viral expression of the SAA1.1 protein resulted in the deposition of amyloid fibrils in the CE/J mouse, whereas SAA2.2 expression had no effect. Similar expression of the SAA2.2 protein in C57BL/6 mice did not alter amyloid deposition. These data demonstrate that the failure of the CE/J mouse to deposit amyloid is due to the structural inability of the SAA2.2 to form amyloid fibrils. This mouse provides a unique system to test the amyloidogenic potential of altered SAA proteins and to determine the important structural features of the protein.

Lack of the p50 subunit of nuclear factor-kappaB increases the vulnerability of hippocampal neurons to excitotoxic injury.

Nuclear factor-kappaB (NF-kappaB) is activated in brain cells after various insults, including cerebral ischemia and epileptic seizures. Although cell culture studies have suggested that the activation of NF-kappaB can prevent neuronal apoptosis, the role of this transcription factor in neuronal injury in vivo is unclear, and the specific kappaB subunits involved are unknown. We now report that mice lacking the p50 subunit of NF-kappaB exhibit increased damage to hippocampal pyramidal neurons after administration of the excitotoxin kainate. Gel-shift analyses showed that p50 is required for the majority of kappaB DNA-binding activity in hippocampus. Intraventricular administration of kappaB decoy DNA before kainate administration in wild-type mice resulted in an enhancement of damage to hippocampal pyramidal neurons, indicating that reduced NF-kappaB activity was sufficient to account for the enhanced excitotoxic neuronal injury in p50(-/-) mice. Cultured hippocampal neurons from p50(-/-) mice exhibited enhanced elevations of intracellular calcium levels and increased levels of oxidative stress after exposure to glutamate and were more vulnerable to excitotoxicity than were neurons from p50(+/+) and p50(+/-) mice. Collectively, our data demonstrate an important role for the p50 subunit of NF-kappaB in protecting neurons against excitotoxic cell death.

Altered brain activation in cognitively intact individuals at high risk for Alzheimer's disease.

OBJECTIVE: To determine whether brain function is altered in cognitively normal individuals at high risk for AD several years before the typical age at onset for this illness. BACKGROUND: Neuropathologic alterations in AD precede cognitive impairment by several years. It is unknown whether functional alterations in neural circuitry accompany these neuropathologic changes, and if so, whether they may be detectable before onset of symptoms. METHODS: We used functional MRI to compare cortical activation between two groups of cognitively normal women differing only in their risk for developing AD. Visual naming and letter fluency tasks were used to activate brain areas subserving object and face recognition, previously described sites of hypometabolism and neuropathologic alteration in AD. The risk groups differed in family history of AD and apolipoprotein E allele status, but were matched in age, education, and measures of cognitive performance. Average age of the study participants was 52 years. RESULTS: The regional patterns of brain activation were similar between groups. However, the high risk group showed areas of significantly reduced activation in the mid- and posterior inferotemporal regions bilaterally during both tasks despite identical naming and letter fluency performance. CONCLUSIONS: Cognitively normal individuals at high risk for AD demonstrate decreased brain activation in key areas engaged during naming and fluency tasks. Decreased activation in the high risk group may be a consequence of the presence of subclinical neuropathology in the inferotemporal region or in the inputs to that region. If so, these findings provide evidence of a window of opportunity for disease-modifying treatment before the onset of symptomatic AD.

Arachidonic acid and leukotriene C4: role in transient cerebral ischemia of gerbils.

Accumulation of arachidonic acid (AA) is greatest in brain regions most sensitive to transient ischemia. Free AA released after ischemia is either: 1) reincorporated into the membrane phospholipids, or 2) oxidized during reperfusion by lipoxygenases and cyclooxygenases, producing leukotrienes (LT), prostaglandins, thromboxanes and oxygen radicals. AA, its metabolite LTC4 and lipid peroxides (generated during AA metabolism) have been implicated in the blood-brain barrier (BBB) dysfunction, edema and neuronal death after ischemia/reperfusion. This report describes the time course of AA release, LTC4 accumulation and association with the physiological outcome during transient cerebral ischemia of gerbils. Significant amount of AA was detected immediately after 10 min ischemia (0 min reperfusion) which returned to sham levels within 30 min reperfusion. A later release of AA occurred after 1 d. LTC4 levels were elevated at 0-6 h and 1 d after ischemia. Increased lipid peroxidation due to AA metabolism was observed between 2-6 h. BBB dysfunction occurred at 6 h. Significant edema developed at 1 and 2 d after ischemia and reached maximum at 3 d. Ischemia resulted in approximately 80% neuronal death in the CA1 hippocampal region. Pretreatment with a 5-lipoxygenase inhibitor, AA861 resulted in significant attenuation of LTC4 levels (Baskaya et al. 1996. J. Neurosurg. 85: 112-116) and CA1 neuronal death. Accumulation of AA and LTC4, together with highly reactive oxygen radicals and lipid peroxides, may alter membrane permeability, resulting in BBB dysfunction, edema and ultimately to neuronal death.

Oxidized lipoproteins increase reactive oxygen species formation in microglia and astrocyte cell lines.

Lipoproteins exist in the central nervous system and surrounding vasculature possibly mediating effects upon cells in the brain during times of oxidative stress or compromised blood-brain barrier. The focus of the present study was to determine the effect of unmodified and oxidatively modified lipoproteins on astrocytes and microglia. Application of oxidized low-density lipoprotein resulted in an increase in DCF fluorescence, which was inhibited by pretreatment with antioxidants, consistent with the formation of reactive oxygen species (ROS). Low-density at concentrations below 20 microg/ml likewise increased ROS formation. Because ROS are associated with numerous astrocyte and microglia activities including proliferation, activation, and cytokine production it is possible that lipoproteins may mediate such effects on glial cells in the central nervous system.

Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor.

Ischemic and excitotoxic insults to the brain induce rapid production of tumor necrosis factor-alpha (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.