CpG oligodeoxynucleotides induce the expression of the antimicrobial peptide cathelicidin in glial cells.

During bacterial infections, antimicrobial peptides are synthesised as an important part of the innate immune system. However, expression and function in the central nervous system (CNS) need further investigations. The aim of this study was to examine the involvement of the pattern-recognition-receptor toll-like receptor 9 (TLR9) in the expression of the cathelin-related antimicrobial peptide (CRAMP) and to characterise the participating signal transduction pathways. In primary TLR9 deficient and wildtype mice astrocytes as well as microglia cells, the expression of CRAMP after treatment with the TLR9 agonist unmethylated cytosine-guanine oligodeoxynucleotide motifs (CpG-DNA) was examined in vitro. In vivo CRAMP expression after intraventricular infusion of CpG-DNA in TLR9 deficient and wildtype mice as well as in mice with pneumococcal meningitis localised in glial cells was determined. Furthermore, the regulation of different signal transduction pathways involved in CpG-DNA-induced CRAMP expression in glial cells was analysed. An in vitro and in vivo CpG-DNA-induced increase of CRAMP expression in astrocytes and microglia cells using real time RT-PCR and immunofluorescence was demonstrated. Different signal transduction pathways such as mitogen-activated protein kinases and inflammatory mediated pathways are involved in the expression of CRAMP in primary glial cells. Interestingly, TLR9-deficient glial cells showed a reduced but not completely abolished CRAMP mRNA expression and ERK1/2 phosphorylation in response to CpG-DNA treatment. On the other side in vivo, TLR9 deletion did not change CRAMP expression after bacterial infection. In conclusion, our results show that TLR9 can induce the expression of antimicrobial peptides such as CRAMP in response to bacterial DNA motifs in primary glial cells. Additional findings suggest also that CpG-DNA-induced effects are not only mediated by TLR9, but also mediated by other pattern recognition receptors.

Pre-infection physical exercise decreases mortality and stimulates neurogenesis in bacterial meningitis.

Physical exercise has been shown to increase neurogenesis, to decrease neuronal injury and to improve memory in animal models of stroke and head trauma. Therefore, we investigated the effect of voluntary wheel running on survival, neuronal damage and cell proliferation in a mouse model of pneumococcal meningitis. Mice were housed in cages equipped with voluntary running wheels or in standard cages before induction of bacterial meningitis by a subarachnoid injection of a Streptococcus pneumoniae type 3 strain. 24 hours later antibiotic treatment was initiated with ceftriaxone (100 mg/kg twice daily). Experiments were terminated either 30 hours or 4 days (short-term) or 7 weeks (long-term) after infection, and the survival time, inflammatory cytokines and corticosterone levels, neurogenesis in the dentate gyrus of the hippocampal formation and the cognitive function were evaluated in surviving mice. Survival time was significantly increased in running mice compared to control animals (p = 0.0087 in short-term and p = 0.016 in long-term experiments, log-rank test). At the end of the long-term experiment, mortality was lower in trained than in sedentary animals (p = 0.031, Fisher's Exact test). Hippocampal neurogenesis--assessed by the density of doublecortin-, TUC-4- and BrdU + NeuN-colabeled cells--was significantly increased in running mice in comparison to the sedentary group after meningitis. However, Morris water maze performance of both groups 6 weeks after bacterial meningitis did not reveal differences in learning ability. In conclusion, physical exercise prior to infection increased survival in a mouse model of bacterial meningitis and stimulated neurogenesis in the dentate gyrus of the hippocampal formation.

Intrathecal treatment with the anti-phosphorylcholine monoclonal antibody TEPC-15 decreases neuronal damage in experimental pneumococcal meningitis.

BACKGROUND: Neuronal injury in pneumococcal meningitis is a consequence of microglial activation and direct toxicity by bacterial products and systemic inflammation. METHODS: The treatment effect of the TEPC-15 antibody recognizing teichoic and lipoteichoic acids was investigated in murine microglial cells and in a rabbit model of pneumococcal meningitis. RESULTS: In vitro, the TEPC-15 antibody recognizing teichoic and lipoteichoic acids increased Streptococcus pneumoniae phagocytosis by murine microglial cells. In rabbit ceftriaxone-treated S. pneumoniae meningitis, intracisternal TEPC-15 reduced the density of apoptotic neurons in the hippocampal dentate gyrus (116 ± 70 vs. 221 ± 132/mm(2); p = 0.03). Cerebrospinal fluid inflammatory parameters (protein, lactate, leukocytes, prostaglandins) were not reduced in TEPC-15-treated rabbits. CONCLUSION: Intracisternal treatment with the TEPC-15 antibody reduced neuronal damage probably by promoting rapid phagocytosis of bacterial products.

Feasibility of prehospital teleconsultation in acute stroke--a pilot study in clinical routine.

BACKGROUND: Inter-hospital teleconsultation improves stroke care. To transfer this concept into the emergency medical service (EMS), the feasibility and effects of prehospital teleconsultation were investigated. METHODOLOGY/PRINCIPAL FINDINGS: Teleconsultation enabling audio communication, real-time video streaming, vital data and still picture transmission was conducted between an ambulance and a teleconsultation center. Pre-notification of the hospital was carried out with a 14-item stroke history checklist via e-mail-to-fax. Beside technical assessments possible influences on prehospital and initial in-hospital time intervals, prehospital diagnostic accuracy and the transfer of stroke specific data were investigated by comparing telemedically assisted prehospital care (telemedicine group) with local regular EMS care (control group). All prehospital stroke patients over a 5-month period were included during weekdays (7.30 a.m.-4.00 p.m.). In 3 of 18 missions partial dropouts of the system occurred; neurological co-evaluation via video transmission was conducted in 12 cases. The stroke checklist was transmitted in 14 cases (78%). Telemedicine group (n = 18) vs. control group (n = 47): Prehospital time intervals were comparable, but in both groups the door to brain imaging times were longer than recommended (median 59.5 vs. 57.5 min, p = 0.6447). The prehospital stroke diagnosis was confirmed in 61% vs. 67%, p = 0.8451. Medians of 14 (IQR 9) vs. 5 (IQR 2) stroke specific items were transferred in written form to the in-hospital setting, p<0.0001. In 3 of 10 vs. 5 of 27 patients with cerebral ischemia thrombolytics were administered, p = 0.655. CONCLUSIONS: Teleconsultation was feasible but technical performance and reliability have to be improved. The approach led to better stroke specific information; however, a superiority over regular EMS care was not found and in-hospital time intervals were unacceptably long in both groups. The feasibility of prehospital tele-stroke consultation has future potential to improve emergency care especially when no highly trained personnel are on-scene. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register (ISRCTN) ISRCTN83270177.

The use of S100B and Tau protein concentrations in the cerebrospinal fluid for the differential diagnosis of bacterial meningitis: a retrospective analysis.

BACKGROUND: Patients with meningitis are often difficult to classify into bacterial (BM) or benign viral (VM) meningitis. To facilitate the differential diagnosis, S100B and Tau protein in the cerebrospinal fluid (CSF) were measured and compared with standard laboratory parameters. METHODS: S100B(CSF), Tau(CSF), and routine parameters (CSF leukocyte count, protein(CSF), lactate(CSF), serum C-reactive protein, blood leukocyte count and body temperature) were analyzed in 33 patients with microbiologically confirmed BM and in 19 with VM. Their classification accuracy, sensitivity and specificity were studied by receiver operating characteristic (ROC) curves. RESULTS: S100B(CSF) concentrations were higher in BM than in VM patients (p = 0.03) and showed a promising accuracy (90%) for the differential diagnosis of BM versus VM. Its discriminative properties were comparable to routine parameters. Of all parameters, S100B(CSF) showed the highest specificity (100%) with an optimal cut-off of 3.1 ng/ml. Tau(CSF) concentrations were useless for the discrimination (p = 0.64). CONCLUSIONS: In contrast to Tau(CSF), S100B(CSF) concentrations ≥3.1 ng/ml are promising to discriminate bacterial from viral meningitis.

Mechanisms of injury in bacterial meningitis.

PURPOSE OF REVIEW: This review describes the pathophysiology of cellular and axonal injury in bacterial meningitis. RECENT FINDINGS: Toll-like receptors have been recognized as important mediators for the initiation of the immune response within the central nervous system. Activation of microglial cells by bacterial products through these receptors increases their ability to phagocytose bacteria, but can also lead to destruction of neurons. The cholesterol-binding hemolysin pneumolysin has a direct toxic effect on neuronal cells. Adjuvant therapy with corticosteroids and glycerol improved the outcome of bacterial meningitis in clinical studies. SUMMARY: Brain damage in bacterial meningitis leading to long-term neurologic sequelae and death is caused by several mechanisms. Bacterial invasion and the release of bacterial compounds promote inflammation, invasion of leukocytes and stimulation of microglia. Leukocytes, macrophages and microglia release free radicals, proteases, cytokines and excitatory amino acids, finally leading to energy failure and cell death. Vasculitis, focal ischemia and brain edema subsequent to an increase in cerebrospinal fluid outflow resistance, breakdown of the blood-brain barrier and swelling of necrotic cells cause secondary brain damage.

Recurrent systemic infections with Streptococcus pneumoniae do not aggravate the course of experimental neurodegenerative diseases.

Neurological symptoms of patients suffering from neurodegenerative diseases such as Alzheimer's dementia (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) often worsen during infections. We assessed the disease-modulating effects of recurrent systemic infections with the most frequent respiratory pathogen, Streptococcus pneumoniae, on the course of AD, PD, and ALS in mouse models of these neurodegenerative diseases [transgenic Tg2576 mice, (Thy1)-[A30P]alpha SYN mice, and Tg(SOD1-G93A) mice]. Mice were repeatedly challenged intraperitoneally with live S. pneumoniae type 3 and treated with ceftriaxone for 3 days. Infection caused an increase of interleukin-6 concentrations in brain homogenates. The clinical status of (Thy1)-[A30P]alpha SYN mice and Tg(SOD1-G93A) mice was monitored by repeated assessment with a clinical score. Motor performance was controlled by the tightrope test and the rotarod test. In Tg2576 mice, spatial memory and learning deficits were assessed in the Morris water maze. In none of the three mouse models onset or course of the disease as evaluated by the clinical tests was affected by the recurrent systemic infections performed. Levels of alpha-synuclein in brains of (Thy1)-[A30P]alpha SYN mice did not differ between infected animals and control animals. Plaque sizes and concentrations of A beta 1-40 and A beta 1-42 were not significantly different in brains of infected and uninfected Tg2576 mice. In conclusion, onset and course of disease in mouse models of three common neurodegenerative disorders were not influenced by repeated systemic infections with S. pneumoniae, indicating that the effect of moderately severe acute infections on the course of neurodegenerative diseases may be less pronounced than suspected.

Stimulation of Toll-like receptor 9 by chronic intraventricular unmethylated cytosine-guanine DNA infusion causes neuroinflammation and impaired spatial memory.

Bacterial DNA contains a high frequency of unmethylated cytosine-guanine (CpG) motifs that have strong immunostimulatory properties; they are recognized by mammalian Toll-like receptor 9 (TLR9). Because accumulating data suggest that chronic inflammatory processes are involved in the pathogenesis of neurodegenerative diseases, we hypothesized that inflammatory responses stimulated by CpG DNA might contribute to neurodegeneration and brain dysfunction. To assess the effects of continuous CpG DNA exposure in the brain, C57BL/6 (n = 21) and TLR9-deficient mice (n = 15) were given intracerebroventricular infusions of CpG DNA or saline for 28 days. Spatial memory assessed weekly by Morris water maze demonstrated impairment in CpG-treated wild-type mice but not in TLR9-deficient or control-treated mice. Motor function was not affected. Immunohistochemical analysis revealed marked microglial activation and acute axonal damage surrounding the ventricles, ependymal disruption, and reactive astrogliosis within the hippocampal formation in the CpG-treated wild-type but not TLR9-deficient mice or saline-infused controls. These results suggest that the unfavorable effects of CpG DNA are dependent on TLR9 signaling and that exposure to bacterial DNA may contribute to impaired neural function, neuroinflammation, and subsequent neurodegeneration.

Increased neurogenesis after hypoxic-ischemic encephalopathy in humans is age related.

The leading cause of morbidity and mortality after successful resuscitation is hypoxic-ischemic encephalopathy (HIE), which results in neuronal loss within the neocortex and the hippocampal formation. This study focuses on the impact of HIE on adult neurogenesis in the human hippocampal dentate gyrus as a potential intrinsic regenerative mechanism in response to neuronal damage. Brain sections of 22 autopsy cases with HIE and of 19 age-matched controls without neuropathological abnormalities were investigated by means of immunohistochemistry. The densities of immature granule cells during axon guidance and outgrowth (assessed by TUC-4 immunohistochemistry) and of young calretinin-expressing postmitotic neurons were increased in the granule cell layer of cases who had suffered from HIE (P = 0.0002 and P = 0.0001, respectively). Similarly, the density of apoptotic granule cells, as detected by in situ tailing and morphological criteria, was increased in HIE (P = 0.014). In cases with HIE, the increase in the density of TUC-4-labeled cells inversely correlated with age (P = 0.027). In contrast, neither the density of proliferating nor that of apoptotic cells was substantially influenced by age within the control group. Taken together, both an increase in adult neurogenesis and in neuronal apoptosis was observed in the human dentate gyrus in response to HIE. The data suggest a decrease of adult neurogenesis in older-aged cases. Whether neurogenesis can contribute to recovery after HIE remains to be determined. The stimulation of adult neurogenesis may be less efficient in older victims of HIE.

TAT-Bcl-x(L) improves survival of neuronal precursor cells in the lesioned striatum after focal cerebral ischemia.

Cerebral ischemia activates endogenous neurogenesis in the subventricular zone (SVZ) and the dentate gyrus. Consecutively, SVZ-derived neural precursors migrate towards ischemic lesions. However, functional relevance of activated neurogenesis is limited by poor survival of new-born precursors. We therefore employed the HI-virus-derived fusion protein TAT-Bcl-x(L) to study the effects of acute anti-apoptotic treatment on endogenous neurogenesis and functional outcome after transient cerebral ischemia in mice. TAT-Bcl-x(L) treatment led to significantly reduced acute ischemic cell death (128+/-23 vs. 305+/-65 TUNEL+ cells/mm(2) in controls) and infarct volumes resulting in less motor deficits and improved spatial learning. It significantly increased survival of doublecortin (Dcx)-positive neuronal precursors (389+/-96 vs. 213+/-97 Dcx+ cells in controls) but did not enhance overall post-ischemic cell proliferation or lesion-specific neuronal differentiation 28 days after ischemia. Our data demonstrate that post-stroke TAT-Bcl-x(L)-treatment results in acute neuroprotection, improved functional outcome, and enhanced survival of lesion-specific neuronal precursor cells after cerebral ischemia in mice.

Enriched environment fails to increase meningitis-induced neurogenesis and spatial memory in a mouse model of pneumococcal meningitis.

An increase in adult neurogenesis was observed after exposure to enriched environment (EE) and during reconvalescence from experimental pneumococcal meningitis. This study investigated neurogenesis and spatial learning performance 5 weeks after bacterial meningitis and exposure to EE. C57BL/6 mice were infected by intracerebral injection of Streptococcus pneumoniae and treated with ceftriaxone for 5 days. Forty-eight hours after infection, one group (n = 22) was exposed to EE and the other group (n = 23) housed under standard conditions. Another set of mice was kept under either enriched (n = 16) or standard (n = 15) conditions without bacterial meningitis. Five weeks later, the Morris water maze was performed, and neurogenesis was evaluated by means of immunohistochemistry. Mice housed in EE without prior bacterial infection displayed both increased neurogenesis and improved water maze performance in comparison with uninfected control animals. Bacterial meningitis stimulated neurogenesis in the granular cell layer of the dentate gyrus: with standard housing conditions, we observed a higher density of BrdU-immunolabeled and TUC-4-expressing cells 5 weeks after induction of bacterial meningitis than in the noninfected control group. EE did not further increase progenitor cell proliferation and neuronal differentiation in the subgranular cell layer of the dentate gyrus after bacterial meningitis in comparison with infected mice housed under standard conditions. Moreover, the Morris water maze showed no significant differences between survivors of meningitis exposed to EE and animals kept in standard housing. In summary, exposure to EE after pneumococcal meningitis did not further increase meningitis-induced neurogenesis or improve spatial learning.

Rapid microtubule bundling and stabilization by the Streptococcus pneumoniae neurotoxin pneumolysin in a cholesterol-dependent, non-lytic and Src-kinase dependent manner inhibits intracellular trafficking.

Streptococcus pneumoniae is the most frequent cause of bacterial meningitis, leading to permanent neurological damage in 30% and lethal outcome in 25% of patients. The cholesterol-dependent cytolysin pneumolysin is a major virulence factor of S. pneumoniae. It produces rapid cell lysis at higher concentrations or apoptosis at lower concentrations. Here, we show that sublytic amounts of pneumolysin produce rapid bundling and increased acetylation of microtubules (signs of excessive microtubule stabilization) in various types of cells--neuroblastoma cells, fibroblasts and primary astrocytes. The bundling started perinuclearly and extended peripherally towards the membrane. The effect was not connected to pneumolysin's capacity to mediate calcium influx, macropore formation, apoptosis, or RhoA and Rac1 activation. Cellular cholesterol depletion and neutralization of the toxin by pre-incubation with cholesterol completely inhibited the microtubule phenotype. Pharmacological inhibition of Src-family kinases diminished microtubule bundling, suggesting their involvement in the process. The relevance of microtubule stabilization to meningitis was confirmed in an experimental pneumococcal meningitis animal model, where increased acetylation was observed. Live imaging experiments demonstrated a decrease in organelle motility after toxin challenge in a manner comparable to the microtubule-stabilizing agent taxol, thus proposing a possible pathogenic mechanism that might contribute to the CNS damage in pneumococcal meningitis.

No long-term effect two years after intrauterine exposure to dexamethasone on dentate gyrus volume, neuronal proliferation and differentiation in common marmoset monkeys.

Glucocorticoids are prenatally administered to promote the maturation of the lungs. They, however, can affect neuronal proliferation and differentiation. In newborn marmoset monkeys, intrauterine hyperexposure to dexamethasone (DEX) resulted in a significantly decreased proliferation rate in the hippocampal dentate gyrus without affecting neuronal differentiation. In this study, marmoset monkeys received 5 mg/kg body weight DEX either during early (days 42-48) or late (days 90-96) pregnancy. The volume of the dentate granule cell layer as well as the proliferation and neuronal differentiation in the dentate gyrus of their 2-year-old offspring were investigated. The density of proliferating cells (Ki-67), apoptotic cells (in situ tailing) and cells differentiating to neurons (double cortin, TUC-4 and calretinin) were determined immunohistochemically. Analysis of the dentate granule cell layer volume showed no significant differences between early or late DEX-exposed marmosets and untreated control animals. Similarly, proliferation and neuronal differentiation in DEX-treated animals was not significantly different in comparison with controls. In summary, the decreased proliferation rate observed in newborn marmosets after intrauterine exposure to DEX was no longer detectable in their 2-year-old siblings suggesting no long-lasting effect of prenatal hyperexposure to DEX on neuronal proliferation and differentiation in the dentate gyrus of marmoset monkeys.

Contribution of capsular and clonal types and beta-lactam resistance to the severity of experimental pneumococcal meningitis.

We used a rabbit model to assess the effects of capsular serotype, genetic background and beta-lactam resistance on the course and severity of experimental meningitis. Meningitis was induced by five pneumococcal strains belonging to five different clones with known invasive potential: two serotype 3 strains (ST260(3) and Netherlands(3)-31 clones) and three serotype 23F strains with different beta-lactam susceptibility patterns (Spain(23F)-1 clone, Tennessee(23F)-4 clone and a double locus variant of the Tennessee(23F)-4 clone). Major differences in secondary bacteremia and mortality rates were observed between serotypes 3 and 23F, as were divergences in the CSF lactate, protein and lipoteichoic-teichoic acid concentrations. Minor differences in the CSF-induced inflammatory response were found among strains belonging to the same serotype. Our results suggest that capsular serotype might be the main factor determining the course and severity of pneumococcal meningitis and genetic background contributes to a lesser extent. The acquisition of beta-lactam resistance does not reduce the virulence of the invasive clones. Since five strains belonging to two serotypes were studied, our findings have to be confirmed with other pneumococcal serotypes.

No neuroprotective effect of erythropoietin under clinical treatment conditions in a rabbit model of Escherichia coli meningitis.

Despite effective antibiotic treatment, neuronal injury is frequent among children and adults with bacterial meningitis resulting in a high rate of death and neurologic sequelae. The hematopoietic cytokine erythropoietin (EPO) provides neuroprotection in models of acute and chronic neurologic diseases. We studied whether recombinant EPO (rEPO) reduces neuronal damage in a rabbit model of Escherichia coli meningitis. Inflammation within the central nervous system (CNS) was monitored by measurement of bacterial load, pleocytosis, protein, and lactate in the cerebrospinal fluid (CSF). Neuronal damage was measured by quantification of the density of apoptotic neurons in the hippocampal dentate gyrus and the concentration of the global neuronal destruction marker neuron-specific enolase (NSE) in CSF. To increase clinical relevance, rEPO was applied as adjunctive therapy from the beginning of antibiotic therapy 12 h after infection. EPO treatment applied as an intravenous injection at a dose of 1000 IU/kg body weight resulted in plasma concentrations of 6993 +/- 1406 mIU/mL, CSF concentrations of 1291 +/- 568 mIU/mL, and a CSF-to-plasma ratio of 0.18 +/- 0.07 (mean +/- SD) 6 h after injection. Under these treatment conditions, no anti-inflammatory or neuroprotective effect of EPO was observed. "

Systemic infections in multiple sclerosis and experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). It has been suggested that viral and bacterial infections contribute to the pathogenesis of MS. This review will give an overview about the influence of viral and bacterial infections on MS and experimental autoimmune encephalomyelitis (EAE). It will focus on bacterial infections and will also emphasise therapeutic consequences such as the impact of antibiotic treatment on the course of EAE. In summary, a growing body of evidence suggests that systemic infections are a risk factor for the initiation of autoimmune processes including the induction of acute events in MS. Experimental and clinical data strongly suggest early treatment of bacterial infections in MS patients to avoid aggravation and relapse.

Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation.

Axonal destruction and neuronal loss occur early during multiple sclerosis, an autoimmune inflammatory CNS disease that frequently manifests with acute optic neuritis. Available therapies mainly target the inflammatory component of the disease but fail to prevent neurodegeneration. To investigate the effect of minocycline on the survival of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve, we used a rat model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis. Optic neuritis in this model was diagnosed by recording visual evoked potentials and RGC function was monitored by measuring electroretinograms. Functional and histopathological data of RGCs and optic nerves revealed neuronal and axonal protection when minocycline treatment was started on the day of immunization. Furthermore, we demonstrate that minocycline-induced neuroprotection is related to a direct antagonism of multiple mechanisms leading to neuronal cell death such as the induction of anti-apoptotic intracellular signalling pathways and a decrease in glutamate excitotoxicity. From these observations, we conclude that minocycline exerts neuroprotective effects independent of its anti-inflammatory properties. This hypothesis was confirmed in a non-inflammatory disease model leading to degeneration of RGCs, the surgical transection of the optic nerve.

Minocycline delays but does not attenuate the course of experimental autoimmune encephalomyelitis in Streptococcus pneumoniae-infected mice.

OBJECTIVES: Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), can be aggravated by a mild Streptococcus pneumoniae infection. This study was performed to assess whether treatment with antibiotics inhibiting bacterial protein synthesis reduces the detrimental effect of infection on the course of EAE. METHODS: In vitro, release of proinflammatory pneumococcal products was studied by enzyme immunoassay and western blot. Seven days after induction of EAE (prior to the onset of symptoms) mice were infected intraperitoneally with S. pneumoniae and treated either with the inhibitors of bacterial protein synthesis minocycline or rifampicin, or with the beta-lactam ceftriaxone. RESULTS: During bacterial killing in vitro, minocycline and rifampicin released lower quantities of proinflammatory bacterial products from S. pneumoniae than ceftriaxone. Mice treated with minocycline developed symptoms of EAE 1 day later than mice treated with ceftriaxone. Neither minocycline nor rifampicin therapy, however, reduced the severity of EAE in comparison with ceftriaxone treatment. CONCLUSIONS: Although statistically significant (P = 0.04), a delay of 1 day in the onset of symptoms of EAE after minocycline treatment is of minor clinical relevance. These data do not support the hypothesis of superiority of a bacterial protein synthesis inhibitor over a beta-lactam antibiotic for the treatment of concomitant infections during the latent phase of EAE or MS.

Antiinflammatory but no neuroprotective effects of melatonin under clinical treatment conditions in rabbit models of bacterial meningitis.

Neuronal injury is frequent in bacterial meningitis, resulting in a high rate of death and neurological sequelae. In a search of potential neuroprotective strategies for treatment of bacterial meningitis, the antioxidant melatonin was neuroprotective in cell culture experiments and in a rabbit Streptococcus pneumoniae meningitis model, when treatment was started at the time of infection. In the present study, adjunctive melatonin treatment applied from the beginning of antibiotic therapy 12 hr after infection at a dose of 1.67 mg/kg/hr resulted in plasma concentrations of 451 +/- 198 ng/ml, cerebrospinal fluid (CSF) concentrations of 154 +/- 57 ng/ml and a CSF-to-plasma ratio of 0.38 +/- 0.19 (mean +/- SD). Melatonin therapy had antiinflammatory effects but did not reduce neuronal injury in either a rabbit model of gram-positive Streptococcus pneumoniae or gram-negative Escherichia coli meningitis.

Intrauterine exposure to dexamethasone impairs proliferation but not neuronal differentiation in the dentate gyrus of newborn common marmoset monkeys.

Glucocorticoids applied prenatally alter birth weight and the maturation of the lungs. Moreover, glucocorticoids impair neuronal proliferation and differentiation in the hippocampal dentate gyrus. In the present study proliferation and neuronal differentiation in the dentate gyrus were studied in newborn common marmoset monkeys which were intrauterinely exposed to the synthetic glucocorticoid dexamethasone (DEX). Pregnant marmoset monkeys received DEX (5 mg/kg body weight) daily either during early (days 42-48) or late (days 90-96) pregnancy. In the hippocampi of newborn monkeys immunohistochemistry was performed with markers of proliferation (Ki-67), apoptosis (in situ tailing) as well as early and late neuronal differentiation (calretinin and calbindin). Both after early and late intrauterine exposure to DEX, proliferation of dentate gyrus cells was significantly decreased (P < 0.05). The density of apoptotic neurons was not altered by DEX treatment. Quantification of calretinin- and calbindin-immunoreactive neurons showed no significant differences between DEX-exposed and control animals. In conclusion, the proliferation of putative precursor cells but not the differentiation into mature cells was impaired in the dentate gyrus of newborn marmosets exposed intrauterinely to DEX.