Im Vergleich mit anderen ZNS-Infektionen findet sich bei der Neuroborreliose (NB) im Liquor ein hoher Anteil an B-Lymphozyten (BL) und Plasmazellen. Kürzlich haben wir das B-Lymphozyten anziehende Chemokin CXCL13 in hohen Konzentrationen im Liquor von NB-Patienten entdeckt. Zudem konnten wir zeigen, dass Monozyten nach Kontakt mit Borrelien CXCL13 freisetzen. Somit könnte CXCL13 eine wichtige Rolle für die Immigration von BL in den Liquor von NB-Patienten spielen. Ziel dieser Studie war es, die funktionelle Rolle von CXCL13 bei der akuten NB zu charakterisieren.

Introduction: The plasminogen system is involved in proteolysis in brain injury and inflammation and may also contribute to the pathogenesis of neurodegenerative diseases as has recently been shown in Alzheimers disease and Creutzfeldt-Jacob disease. As yet, there has been little investigation of the role of the plasminogen activator system in amyotrophic lateral sclerosis (ALS).

Urate is largely excluded from the brain under non-inflammatory conditions (concentration gradient serum:CSF about 10:1), but increases markedly in Guillain-Barre Syndrome and bacterial meningitis. The oxidation product allantoin is normally not passively distributed between blood and cerebrospinal fluid (gradient 3:1) and increases 5-fold in CSF of patients with meningitis. Patients with multiple sclerosis had normal levels of urate and allantoin in blood and CSF.

Euro-Neuro '98: First International Update on Neuro-Anaesthesia and Neuro-Intensive Care; Genk, Belgium, 5-7 February 1998

To elucidate the role of bradykinin in the complex pathophysiology of bacterial meningitis we investigated the effect of the bradykinin B2 receptor antagonist Hoe140, incatibant (d-Arg[Hyp3-Thi5-d-Tic7-Oic8]-bradykinin), on pathophysiological alterations in experimental pneumococcal meningitis. Untreated rats injected intracisternally (i.c.) with heat-killed pneumococci developed an increase of regional cerebral blood flow (185.4 ± 27.4%, baseline 100%, mean ± S.D.), brain water content (79.16 ± 0.23%), intracranial pressure (21.4 ± 6.0 mm Hg), and white blood cell count in the cerebrospinal fluid (CSF) (4621 ± 1894 cells/μl) within 6 h after i.c. challenge. Treatment with Hoe140 (0.1 mg/kg i.v. at baseline and 0.05 mg/kg s.c. at 2 h after i.c. challenge) attenuated the increase of brain water content (78.53 ± 0.28%; P < 0.05), intracranial pressure (7.5 ± 2.2 mm Hg; P < 0.05), and regional cerebral blood flow (128.6 ± 23.1%; P < 0.05), and reduced CSF pleocytosis (2690 ± 1898 cells/μl, N.S.). When treatment was started 4 h after i.c. challenge Hoe140 reduced intracranial pressure (P < 0.05), but was no more capable to significantly influence the other pathophysiological parameters. Treatment with lower (0.01 mg/kg i.v. at baseline, followed by 0.005 mg/kg s.c. at 2 h) and higher (2 mg/kg i.v., followed by 1 mg/kg s.c. at 2 h) concentrations of Hoe140 was ineffective. Likewise, i.c. injection of Hoe140, at different dosages (4 nmol, 40 nmol, 400 nmol) did not significantly alter the pathophysiological parameters in pneumococci-induced meningitis, but caused changes in mean arterial blood pressure at dosages greater than 4 nmol. We conclude that bradykinin is involved as an inflammatory mediator of microvascular changes, brain edema, and increased intracranial pressure during the early phase of experimental pneumococcal meningitis.

Recent studies using a rat model of pneumococcal meningitis have shown that nitric oxide synthase (NOS) inhibitors greatly attenuated microvascular changes and brain edema formation. The site of NO production during bacterial meningitis is unknown. In this study we tested whether primary astrocyte cultures from neonatal rat cortex can be induced to release NO upon stimulation with pneumococci. NO production was assessed by measuring nitrite in the cell culture supernatant using the Griess reaction. Stimulation with heat-killed unencapsulated pneumococci (HKP) increased nitrite concentrations in astrocyte culture supernatants in a dose-dependent fashion. Administration of N-nitro-L-arginine (L-NA), aminoguanidine, L-canavanine, cycloheximide, and dexamethasone prevented the increase in nitrite concentrations. Addition of L-arginine, but not of D-arginine, partially reversed the inhibitory effect of L-NA. Administration of SOD increased nitrite accumulation. Moreover, at 72 h after stimulation with heat-killed pneumococci (10(7) cfu/ml) astrocytes showed an inducible NOS-like immunoreactivity. Accumulation of nitrite was also observed when rat cerebellar neurons and microglia were stimulated with HKP, whereas there was only a slight increase of nitrite in media of rat C6 glioma cells, but no increase of nitrite when the human glioblastoma cell line LN-229 was stimulated with HKP. There was a stronger increase in nitrite levels when astrocytes from Lewis rats were used compared to that from Wistar rats. In conclusion, our study indicates that astrocytes, neurons and microglia are inducible for NO production upon stimulation with pneumococci.

Nitric oxide (NO) is a mediator of haemodynamic changes and cytotoxicity in in vivo models of inflammation such as endotoxaemic shock. The purpose of this study was to investigate whether NO may be involved in the increase of cerebral blood flow (CBF), intracranial pressure (ICP) and brain water content, known to occur in the early phase of pneumococcal meningitis. Rats injected intracisternally with live pneumococci were either untreated or received 5 mg kg-1 i.v. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. Pretreatment with L-NAME prevented the increase in CBF, ICP and brain water content, as seen in untreated animals. CBF tended to return towards baseline when rats were treated with L-NAME 2 h after pneumococcal injection. Whereas none of the untreated and L-NAME-pretreated animals died during the 6 h observation period, 3 out of 9 rats treated with L-NAME and 7 out of 9 rats with simultaneous i.v. injection of L-NAME and L-arginine died. Our results provide preliminary evidence that NO may be involved as a mediator of CBF changes and oedema formation in the early phase of pneumococcal meningitis in the rat. NO inhibition, however, may have detrimental effects of still unidentified cause, as indicated by the increased mortality in treated animals. Further studies with analysis of the causes of mortality, structurally different NO synthase inhibitors and direct evaluation of NO synthase induction are needed to further support this hypothesis.

Previous studies have demonstrated that the radical scavenger superoxide dismutase completely blocked the increase of regional cerebral blood flow (rCBF), intracranial pressure (ICP), and brain water content during the early phase of experimental pneumococcal meningitis in the rat. To obtain information on the nature of the reactive oxygen species involved, the effect of catalase, a hydrogen peroxide scavenger, was tested. Rats injected intracisternally with live pneumococci were either untreated or received intravenous catalase. The increase of rCBF and brain water content in infected untreated rats was significantly attenuated by catalase 6 h after intracisternal challenge. ICP increased in both infected groups, with a trend toward lower ICP with catalase treatment. Cerebrospinal fluid white blood cell counts were not significantly different between infected groups. These results and previous experiments using superoxide dismutase suggest that the increase of rCBF, ICP, and brain water content is mainly caused by superoxide or superoxide reaction products.

Brain edema formation, raised intracranial pressure (ICP) and alterations of the cerebral blood circulation are thought to be of great importance for the outcome of bacterial meningitis (Dodge and Swartz 1965, Swartz 1984, Igarashi et al. 1984). The purpose of our study was to develop an animal model for the evaluation of secondary brain damage during the course of meningitis. This model should permit continuous monitoring of ICP, brain edema and cerebral blood flow during chemical meningitis with carrageenan (CAR). CAR is reported to induce reproducible and fast acting chemical meningitis in the mouse brain (Gamache et al. 1986).