Meningitis-associated central nervous system complications are mediated by the activation of poly(ADP-ribose) polymerase.

The present study assessed the role of PARP [poly(adenosine diphosphate-ribose) polymerase] activation in experimental pneumococcal meningitis. Mice with a targeted disruption of the PARP 1 gene were protected against meningitis-associated central nervous system complications including blood-brain barrier breaching and increase in intracranial pressure. This beneficial effect was paralleled by a significant reduction in meningeal inflammation, as evidenced by significantly lower cerebrospinal fluid leukocyte counts and interleukin-1beta, -6, and tumor necrosis factor-alpha concentrations in the brain (compared with infected wild-type mice). The reduction in inflammation and central nervous system complications was associated with an improved clinical status of infected, PARP 1-deficient mice. A similar protective effect was achieved by PARP inhibition using 3-aminobenzamide, the pharmacologic efficacy of which was confirmed by a marked attenuation of meningitis-induced poly(ADP)ribose formation. When the rat brain-derived endothelial cell line GP8.3 was cocultured with macrophages, exposure to pneumococci induced endothelial cell death and was paralleled by PARP activation and a reduction in the oxidized form of cellular nicotinamide adenine dinucleotide content. Treatment with 3-aminobenzamide significantly attenuated cellular nicotinamide adenine dinucleotide depletion and pneumococci-induced cytotoxicity. Thus, PARP activation seems to play a crucial role in the development of meningitis-associated central nervous system complications and pneumococci-induced endothelial injury. Inhibitors of PARP activation could provide a potential therapy of acute bacterial meningitis.     

Induced hypothermia in experimental pneumococcal meningitis.

Pneumococcal meningitis resulting from Streptococcus pneumoniae has a death rate of 28% in adults. In severe head injury and stroke, inflammatory changes and intracranial hypertension are improved by induced hypothermia, which also is neuroprotective. We hypothesized that moderate hypothermia ameliorates inflammatory changes in experimental pneumococcal meningitis. Wistar rats were cooled systemically, and meningitis was induced by pneumococcal cell wall components. The increase of regional cerebral blood flow in the meningitis animals was blocked by hypothermia at 6 hours. The reduction of intracranial pressure correlated with temperature. The influx of leukocytes into the cerebrospinal fluid and levels of tumor necrosis factor alpha in the cerebrospinal fluid were decreased. Cooling the animals 2 hours after meningitis induction to 30.5 degrees C was also protective. We conclude that hypothermia is a new adjuvant approach to reduce meningitis-induced changes, in particular intracranial pressure, in the early phase of the disease.     

N(omega) -nitro-L-arginine methyl ester (L-NAME) attenuates the acute inflammatory responses and brain injury during the early phase of experimental Escherichia coli meningitis in the newborn piglet.

We evaluated the anti-inflammatory and neuroprotective effect of nonselective NOS inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), in experimental bacterial meningitis in the newborn piglet. Meningitis was induced by intracisternal injection of 10(8) colony forming units of Escherichia coli. L-NAME 10 mg kg(-1) was given intravenously 30 min before induction of meningitis. L-NAME significantly attenuated the increase in intracranial pressure and decrease in cerebrospinal fluid glucose concentration observed in the meningitis group. Systemic and cerebral perfusion pressure were even higher compared to the control and meningitis groups. However, the meningitis-induced increase in tumor necrosis factor-alpha level, leukocyte numbers and lactate level in the cerebrospinal fluid was not significantly attenuated with L-NAME administration. Reduced cerebral cortical cell membrane Na+, K+ -ATPase activity and increased lipid peroxidation products, indicative of meningitis-induced brain cell membrane dysfunction, were significantly improved with L-NAME treatment. Decreased brain glucose and ATP levels were also significantly improved with L-NAME treatment. These findings suggest that L-NAME was effective in attenuating the acute inflammatory responses and brain injury in neonatal bacterial meningitis.     

Nω-nitro-L-arginine methyl ester (L-NAME) attenuates the acute inflammatory responses and brain injury during the early phase of experimental Escherichia coli meningitis in the newborn piglet

Abstract

We evaluated the anti-inflammatory and neuroprotective effect of nonselective NOS inhibitor, N^ω-nitro-Larginine methyl ester (L-NAME), in experimental bacterial meningitis in the newborn piglet. Meningitis was induced by intracisternal injection of 10⁸ colony forming units of Escherichia coli. L-NAME 10 mg kg^-1 was given intravenously 30 min before induction of meningitis. L-NAME significantly attenuated the increase in intracranial pressure and decrease in cerebrospinal fluid glucose concentration observed in the meningitis group. Systemic and cerebral perfusion pressure were even higher compared to the control and meningitis groups. However, the meningitis-induced increase in tumor necrosis factor- α level, leukocyte numbers and lactate level in the cerebrospinal fluid was not significantly attenuated with L-NAME administration. Reduced cerebral cortical cell membrane Na⁺ ,K⁺-ATPase activity and increased lipid peroxidation products, indicative of meningitis-induced brain cell membrane dysfunction, were significantly improved with L-NAME treatment. Decreased brain glucose and ATP levels were also significantly improved with L-NAME treatment. These findings suggest that L-NAME was effective in attenuating the acute inflammatory responses and brain injury in neonatal bacterial meningitis. [Neurol Res 2001; 23: 862-868]     

Tumor necrosis factor-alpha, interleukin-1beta and interleukin-6 in the cerebrospinal fluid of newborn with meningitis

OBJECTIVE: To analyze the usefulness of determining the cerebrospinal fluid (CSF) levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) for the early diagnosis and evaluation of the prognosis of neonatal meningitis. METHOD: We studied 54 newborn that underwent lumbar puncture. Thirty patients had meningitis and 24 were the control group. CSF and sera were obtained at the moment of suspicion of meningitis and stored at -70 degrees C. Cytokines were performed by enzyme-linked immunosorbent assay method. RESULTS: CSF cytokines were detected in all the newborn with meningitis. TNF-alpha was detected in the CSF in 63.3% of the neonates, IL-1beta in 73.3% and IL-6 in 96.6%. The CSF levels were significantly higher than serum in neonates with meningitis. There was no correlation between the CSF levels of cytokines and neurologic complications. CONCLUSION: The detection of TNF-alpha, IL-1beta and IL-6 in the CSF is of great value in order to achieve a early diagnosis of neonatal meningitis. Among the three cytokines analyzed, IL-6 was the best indicator of meningeal inflammation.     

Caspase-3 mediates hippocampal apoptosis in pneumococcal meningitis

Bacterial meningitis causes neuronal apoptosis in the hippocampal dentate gyrus, which is associated with learning and memory impairments after cured disease. The execution of the apoptotic program involves pathways that converge on activation of caspase-3, which is required for morphological changes associated with apoptosis. Here, the time course and the role of caspase-3 in neuronal apoptosis was assessed in an infant rat model of pneumococcal meningitis. During clinically asymptotic meningitis (0-12 h after infection), only minor apoptotic damage to the dentate gyrus was observed, while the acute phase (18-24 h) was characterized by a massive increase of apoptotic cells, which peaked at 36 h. In the subacute phase of the disease (36-72 h), the number of apoptotic cells decreased to control levels. Enzymatic caspase-3 activity was significantly increased in hippocampal tissue of infected animals compared to controls at 22 h. The activated enzyme was localized to immature cells of the dentate gyrus, and in vivo activity was evidenced by cleavage of the amyloid-beta precursor protein. Intracisternal administration of the caspase-3-specific inhibitor Ac-DEVD-CHO significantly reduced apoptosis in the hippocampal dentate gyrus. In contrast to a study where the decrease of hippocampal apoptosis after administration of a pan-caspase inhibitor was due to downmodulation of the inflammatory response, our data demonstrate that specific inhibition of caspase-3 did not affect inflammation assessed by TNF-alpha and IL-1beta concentrations in the cerebrospinal fluid space. Taken together, the present results identify caspase-3 as a key effector of neuronal apoptosis in pneumococcal meningitis.     

Plasminogen activator inhibitor-1 influences cerebrovascular complications and death in pneumococcal meningitis

Cerebrovascular complications are common in pneumococcal meningitis and are a main determinant of unfavourable outcome and death. We hypothesized that plasminogen activator inhibitor-1 (PAI-1) is a major contributor to cerebrovascular complications and death in pneumococcal meningitis. In a nationwide prospective cohort study we evaluated the effect of the 4G/5G polymorphism (rs1799889) in SERPINE1 (coding for PAI-1) on cerebrovascular complications and outcome in adults with pneumococcal meningitis proven by cerebrospinal fluid (CSF) culture. From 2006 to 2011, a total of 991 adult patients with community-acquired bacterial meningitis were included in the cohort and 712 had pneumococcal meningitis. The rs1799889 5G/5G genotype was associated with an increased risk of unfavourable outcome [odds ratio (OR) 1.69, 95 % confidence interval (CI) 1.03–2.78] and mortality (OR 2.20, 95 % CI 1.02–4.86) in white adults with pneumococcal meningitis. rs1799889 was associated with CSF PAI-1 concentrations (P = 0.048), and white patients homozygous for the low PAI-1 producing genotype (5G/5G) had a significantly higher risk for cerebral infarctions (P = 0.015) and haemorrhages (P = 0.005). Subsequently, we assessed the functionality of PAI-1 in a pneumococcal meningitis mouse model, using Serpine1 knockout mice. Consistent with the human data, Serpine1-deficient mice had increased mortality and cerebral haemorrhages compared to wild-type mice. We conclude PAI-1 is protective for death in humans and mice with pneumococcal meningitis by reducing cerebrovascular complications.     

Inhibition of the kynurenine-NAD+ pathway leads to energy failure and exacerbates apoptosis in pneumococcal meningitis

Pneumococcal meningitis causes neurological sequelae, including learning and memory deficits in up to half of the survivors. In both humans and in animal models of the disease, there is apoptotic cell death in the hippocampus, a brain region involved in learning and memory function. We previously demonstrated that in an infant rat model of pneumococcal meningitis, there is activation of the kynurenine (KYN) pathway in the hippocampus, and that there was a positive correlation between the concentration of 3-hydroxykynurenine and the extent of hippocampal apoptosis. To clarify the role of the KYN pathway in the pathogenesis of hippocampal apoptosis in pneumococcal meningitis, we specifically inhibited 2 key enzymes of the KYN pathway and assessed hippocampal apoptosis, KYN pathway metabolites, and nicotinamide adenine dinucleotide (NAD) concentrations by high-performance liquid chromatography. Pharmacological inhibition of kynurenine 3-hydroxylase and kynureninase led to decreased cellular NAD levels and increased apoptosis in the hippocampus. The cerebrospinal fluid levels of tumor necrosis factor and interleukin-1α and -β were not affected. Our data suggest that activation of the KYN pathway in pneumococcal meningitis is neuroprotective by compensating for an increased NAD demand caused by infection and inflammation;this mechanism may prevent energy failure and apoptosis in the hippocampus.     

Interleukin-1beta,tumor necrosis factor-alpha,and nitrite levels in febrile seizures

Proinflammatory cytokines (such as interleukin-1beta, tumor necrosis factor-alpha) and nitric oxide are known to have both direct and indirect modulating effects on neurons and neurotoxic neurotransmitters released during excitation or inflammation. We measured interleukin-1beta, tumor necrosis factor-alpha, and nitrite levels in the peripheral blood and cerebrospinal fluid of children with febrile seizures and compared our results with those of children with febrile illnesses without seizures. Twenty-nine children with febrile seizure and 15 controls were studied. The mean concentrations of interleukin-1beta and nitrite were significantly increased in the cerebrospinal fluid (P < .01) of the children with febrile seizure. There were no significant changes in serum interleukin-1beta, tumor necrosis factor-alpha, nitrite, and cerebrospinal fluid tumor necrosis factor-alpha levels. Our data support the hypothesis that increased production of interleukin-1beta in the central nervous system or increased diffusion of interleukin-1beta through the blood-brain barrier is involved in the pathogenesis of febrile seizures.     

3-Aminobenzamide,a poly (ADP-ribose) synthetase inhibitor,attenuates the acute inflammatory responses and brain injury in experimental Escherichia coli meningitis in the newborn piglet

Abstract

The aim of the present study was to evaluate the anti-inflammatory and neuroprotective effects of a poly (ADP-ribose) synthetase inhibitor 3-aminobenzamide during the early phase of experimental bacterial meningitis in the newborn piglet. Meningitis was induced by intracisternal injection of 10⁸ colony forming units of Escherichia coli in 100 μl of saline. 3-Aminobenzamide, given 30 mg kg^–1 as a bolus i.v. injection 30 min before induction of meningitis, significantly attenuated the meningitis-induced acute inflammatory responses such as increased cerebrospinal fluid (CSF) lactate concentration, CSF leukocytosis and increased CSF tumor necrosis factor-α level. However, meningitis-induced increase in intracranial pressure and decrease in CSF glucose level were not significantly improved. Increased cerebral cortical cell membrane lipid peroxidation products (conjugated dienes) and decreased brain ATP/phosphocreatine levels observed in the meningitis group were also significantly improved with 3-aminobenzamide treatment. However, the improvement of reduced Na⁺,K⁺-ATPase activity did not reach a statistical significance (p = 0.06). In summary, 3-aminobenzamide significantly attenuated the acute inflammatory responses and the ensuing brain injury during the early phase of neonatal bacterial meningitis. These findings suggest that poly (ADP-ribose) synthetase inhibitors such as 3-aminobenzamide might be a promising novel anti-inflammatory and neuroprotective adjuvant therapy in neonatal bacterial meningitis.     

Cerebrospinal Fluid TNF-α, IL-6, and IL-8 in Children With Bacterial Meningitis

ObjectiveWe evaluated the levels of cerebrospinal fluid concentrations of tumor necrosis factor-α, interleukin-6, and interleukin-8 in bacterial meningitis in children.MethodsThe study included children up to 14 years of age admitted to a pediatric ward with fever, headache, vomiting, and seizures. The diagnosis of bacterial meningitis was based on clinical features: physical examination, blood and cerebrospinal fluid cytochemical findings, Gram stain, and bacterial culture. The cerebrospinal fluid levels of tumor necrosis factor-α, interleukin-6, and interleukin-8 were measured in 57 children with bacterial meningitis, 15 with viral meningitis, and 15 controls by enzyme-linked immunosorbent assay methods.ResultsThe mean concentrations of cerebrospinal fluid, tumor necrosis factor-α, interleukin-6, and interleukin-8 were 1108 ± 183, 652 ± 287, and 442 ± 120 pg/mL, respectively, in children with bacterial meningitis and were significantly increased in those in the viral meningitis group (tumor necrosis factor-α : 711 ± 105, IL-6 : 272 ± 161, IL-8 : 175 ± 62 pg/mL; P < 0.001) or control (390 ± 37, 59 ± 17, 19 ± 13 pg/mL, respectively, P < 0.001). At optimum cutoff level based on the receiver operating characteristic curve, cerebrospinal fluid cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-8) showed sensitivity and specificity of 100% for the diagnosis of bacterial meningitis. For differentiation of bacterial from viral meningitis, cerebrospinal fluid level of tumor necrosis factor-α, IL-6, and IL-8 showed sensitivity and specificity of 94.7% and 86.7%, 80.7% and 53.3%, and 89.5% and 86.7%, respectively.ConclusionThe increased concentration of cerebrospinal fluid tumor necrosis factor-α, interleukin-6, and interleukin-8 in children with meningitis suggests a role in the pathogenesis of bacterial meningitis and these levels might prove to be useful in children whose diagnosis is in question.     

Triptans reduce the inflammatory response in bacterial meningitis.

Severe headache and meningism provide clear evidence for the activation of trigeminal neurotransmission in meningitis. The authors assessed the antiinflammatory potential of 5HT1B/D/F receptor agonists (triptans), which inhibit the release of proinflammatory neuropeptides from perivascular nerve fibers. In a 6-hour rat model of pneumococcal meningitis, zolmitriptan and naratriptan reduced the influx of leukocytes into the cerebrospinal fluid, and attenuated the increase of regional cerebral blood flow. Elevated intracranial pressure as well as the brain water content at 6 hours was reduced by triptans. These effects were partially reversed by a specific 5HT1D as well as by a specific 5HT1B receptor antagonist. Meningitis caused a depletion of calcitonin gene-related peptide (CGRP) and substance P from meningeal nerve fibers, which was prevented by zolmitriptan and naratriptan. In line with these findings, patients with bacterial meningitis had significantly elevated CGRP levels in the cerebrospinal fluid. In a mouse model of pneumococcal meningitis, survival and clinical score at 24 hours were significantly improved by triptan treatment. The findings suggest that, besides mediating meningeal nociception, meningeal nerve fibers contribute to the inflammatory cascade in the early phase of bacterial meningitis. Adjunctive treatment with triptans may open a new therapeutic approach in the acute phase of bacterial meningitis.     

Differential regulation of blood-brain barrier permeability in brain trauma and pneumococcal meningitis-role of Src kinases

Increased vascular permeability causing vasogenic brain edema is characteristic for many acute neurological diseases such as stroke, brain trauma, and meningitis. Src family kinases, especially c-Src, play an important role in regulating blood-brain barrier permeability in response to VEGF, but also mediate leukocyte function and cytokine signalling. Here we demonstrate that pharmacological inhibition of Src or c-Src deficiency does not influence cerebrospinal fluid (CSF) pleocytosis, brain edema formation, and bacterial outgrowth during experimental pneumococcal meningitis despite the increased cerebral expression of inflammatory chemokines, such as IL-6, CCL-9, CXCL-1, CXCL-2 and G-CSF as determined by protein array analysis. In contrast, inhibition of Src significantly reduced brain edema formation, lesion volume, and clinical worsening in cold-induced brain injury without decreasing cytokine/chemokine expression. While brain trauma was associated with increased cerebral VEGF formation, VEGF levels significantly declined during pneumococcal meningitis. Therefore, we conclude that in brain trauma blood-brain barrier tightness is regulated by the VEGF/Src pathway whereas c-Src does not influence brain edema formation and leukocyte function during bacterial meningitis.     

Experimental pneumococcal meningitis. Effects of neuraminidase and other pneumococcal constituents on cerebrospinal fluid in the intact dog.

The intracisternal administration of a Type I pneumococcus to mongrel dogs resulted in spinal fluid abnormalities and clinical course and outcome similar to those of meningitis in humans. In order to define the pathogenic role of pneumococcal neuraminidase and other pneumococcal extracts in experimental meningitis, the following preparations were derived from the same Type I pneumococcus: crude neuraminidase, partially purified neuraminidase, heat-inactivated crude neuraminidase, and heat-killed pneumococci. These preparations were administered intracisternally daily for 5 days to a series of mongrel dogs. These substances did not produce clinical morbity similar to that observed in infected animals, even though there was significant decrease in the NANA content of cortical brain subcellular structures in the neuraminidase-treated dogs. It was concluded that the substances investigated were not responsible for morbidity and mortality in experimental pneumococcal meningitis. Both heat-killed pneumococci and the crude neuraminidase preparation elicited significant alterations in spinal fluid glucose and protein concentrations which were similar to those recorded in infected animals; however these abnormalities were not associated with significant morbidity. It is proposed that spinal fluid glucose and protein abnormalities may not be directly linked to brain damage or dysfunction in this experimental model, or in man.     

Inflammatory response during bacterial meningitis is unchanged in Fas- and Fas ligand-deficient mice

Fas (CD95) and Fas ligand (FasL, CD95L) have been implicated to be involved in the acute inflammatory response by attracting neutrophils and regulating their survival. Increased levels of soluble Fas and FasL are found in cerebrospinal fluid (CSF) samples of patients with bacterial meningitis but not in controls. Functional FasL (gld)- or Fas (lpr)-deficient mice were used to assess their role in the pathophysiology of pneumococcal meningitis. Induction of meningitis in wild-type (WT) mice caused an increase in CSF white blood cell (WBC) count, intracranial pressure (ICP), and vessel permeability, paralleled by a worse clinical status at 24 h. The inflammatory response was accompanied by elevated levels of IL-1beta, MMP-2, and MMP-9 in the brain. Neither gld- nor lpr-mice showed significant differences in the above-mentioned pneumococci-induced pathophysiological alterations. These results indicate that Fas and FasL are not essential in the regulation of the acute inflammatory response during pneumococcal meningitis.     

Concentration of interleukin-18, interleukin-1beta, soluble receptor for interleukin-1 (sIL-1RII) and C-reactive protein in patients with neuroborreliosis

BACKGROUND AND PURPOSE: The aim of the present study was to determine the role of interleukin-18 (IL-18), interleukin-1beta (IL-1beta) and its soluble receptor sIL-1RII in the pathogenesis of neuroborreliosis as well as the usefulness of C-reactive protein (CRP) determination in the diagnosis and monitoring of treatment of Lyme neuroborreliosis. MATERIAL AND METHODS: The study group consisted of 20 patients with Lyme meningitis (age range 16-72 years, mean age 42.6 years). For measurements of IL-18, IL-1beta and sIL-1RII levels in serum and cerebrospinal fluid (CSF) the control group consisted of 10 healthy volunteers and 10 patients with infection of the central nervous system ruled out, respectively. Cytokines and sIL-1RII levels in serum and CSF were measured twice, before and after the 30-day treatment period. Serum and CSF levels of IL-18, IL-1beta and sIL-1RII were measured using ELISA, and CRP serum levels were measured using the immunoturbidimetric method. RESULTS: Before the treatment the concentration of IL-18, IL-1beta and sIL-1RII in serum as well as in CSF was significantly higher as compared to the controls. After the treatment end the level of IL-18, IL-1beta and sIL-1RII was reduced but the serum level of sIL-1RII and CSF level of IL-18 and sIL-1RII remained significantly higher than in the control group. The serum level of CRP was increased only in 15% of patients and after the treatment CRP concentration returned to a basal level (except one patient in whom CRP was slightly higher than in the control group). No correlation between CRP and IL-18, IL-1beta and sIL-1RII was observed. CONCLUSIONS: Our results confirm the involvement of IL-18, IL-1beta and sIL-1RII in the pathogenesis of neuroborreliosis and uselessness of CRP determination in the diagnosis of Lyme meningitis.     

Levels of soluble delta-like ligand 1 in the serum and cerebrospinal fluid of tuberculous meningitis patients

In this study,the levels of soluble delta-like ligand 1 in cerebrospinal fluid and serum of 50 patients with tuberculous meningitis,30 patients with viral meningitis,20 patients with purulent meningitis and 40 subjects without central nervous system disease were determined using an enzyme-linked immunosorbent assay.The mean levels of soluble delta-like ligand 1 in both cerebrospinal fluid and serum from patients with tuberculous meningitis were significantly higher compared with those from patients with viral meningitis or purulent meningitis or from subjects without central nervous system disease.Meanwhile,the level of soluble delta-like ligand 1 gradually decreased as tuberculous meningitis patients recovered.If patients deteriorated after treatment,the level of soluble delta-like ligand 1 in cerebrospinal fluid gradually increased.There was no correlation between the level of soluble delta-like ligand 1 and the protein level/cell number in cerebrospinal fluid.Our findings indicate that the levels of soluble delta-like ligand 1 in cerebrospinal fluid and serum are reliable markers for the diagnosis of tuberculous meningitis and for monitoring treatment progress.At the same time,this index is not influenced by protein levels or cell numbers in cerebrospinal fluid.     

Interleukin-1beta, interleukin-1 receptor antagonist levels in patients with subacute sclerosing panencephalitis and the effects of different treatment protocols.

Subacute sclerosing panencephalitis is a rare progressive inflammatory disease of the central nervous system caused by a persistent aberrant measles virus infection. Cytokines are polypeptides that regulate immune responses and inflammatory reactions. Interleukin-1beta has been implicated as a central mediator of tissue damage and destruction in a number of central nervous system diseases. Interleukin-1 receptor antagonist could function as an important anti-inflammatory cytokine. We studied interleukin-1beta and interleukin-1 receptor antagonist levels in the cerebrospinal fluids of patients with subacute sclerosing panencephalitis and evaluated the effects of different treatment protocols on these cytokines. Interleukin-1beta and interleukin-1 receptor antagonist levels were measured in 15 patients who had a recent diagnosis of subacute sclerosing panencephalitis (group 1), 6 patients who had been treated with isoprinosine (group 2), 5 patients with intraventricular interferon-alpha (group 3), and 6 patients with interferon-beta (group 4). The results were compared within the groups and also with the results of 10 patients with other neurologic disease (group 5).The interleukin-1beta concentrations in cerebrospinal fluid and sera were all below the detection limits (3.9 pg/mL). Interleukin-1 receptor antagonist levels were not statistically different, except for the group treated with intraventricular interferon-alpha. Interleukin-1 receptor antagonist levels were 170 +/- 52, 175 +/- 58, 1605 +/- 518, 77.5 +/- 24, and 108 +/- 18 pg/mL in groups 1 to 5, respectively. Interleukin-1 receptor antagonist levels and cerebrospinal fluid serum ratios were significantly increased during interferon-alpha treatment. In conclusion, interleukin-1 and interleukin-1 receptor antagonist levels were not elevated in the patients with subacute sclerosing panencephalitis. The only treatment protocol that affects interleukin-1 receptor antagonist levels in cerebrospinal fluid was intraventricular interferon-alpha. Further studies on higher numbers of patients may better document the immunologic status of patients with subacute sclerosing panencephalitis and the effects of different treatment modes.     

3-Aminobenzamide, a poly (ADP-ribose) synthetase inhibitor, attenuates the acute inflammatory responses and brain injury in experimental Escherichia coli meningitis in the newborn piglet.

The aim of the present study was to evaluate the anti-inflammatory and neuroprotective effects of a poly (ADP-ribose) synthetase inhibitor 3-aminobenzamide during the early phase of experimental bacterial meningitis in the newborn piglet. Meningitis was induced by intracisternal injection of 10(8) colony forming units of Escherichia coli in 100 microl of saline. 3-Aminobenzamide, given 30 mg kg(-1) as a bolus i.v. injection 30 min before induction of meningitis, significantly attenuated the meningitis-induced acute inflammatory responses such as increased cerebrospinal fluid (CSF) lactate concentration, CSF leukocytosis and increased CSF tumor necrosis factor-alpha level. However, meningitis-induced increase in intracranial pressure and decrease in CSF glucose level were not significantly improved. Increased cerebral cortical cell membrane lipid peroxidation products (conjugated dienes) and decreased brain ATP/phosphocreatine levels observed in the meningitis group were also significantly improved with 3-aminobenzamide treatment. However, the improvement of reduced Na+, K+-ATPase activity did not reach a statistical significance (p = 0.06). In summary, 3-aminobenzamide significantly attenuated the acute inflammatory responses and the ensuing brain injury during the early phase of neonatal bacterial meningitis. These findings suggest that poly (ADP-ribose) synthetase inhibitors such as 3-aminobenzamide might be a promising novel anti-inflammatory and neuroprotective adjuvant therapy in neonatal bacterial meningitis.     

Fibrin degradation products in the cerebrospinal fluid of patients with pneumococcal meningitis.

Raised levels of fibrin degradation products were found in the cerebrospinal fluid of nearly all of 35 patients with pneumococcal meningitis. The mean level was higher in patients who died subsequently than in those who survived. Cerebrospinal fluid from patients with pneumococcal meningitis showed increased fibrinolytic activity as assessed by clot lysis, suggesting local production of fibrin degradation products within the subarachnoid space.