piperidines and Meningitis--Pneumococcal

Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperid inepropanol (RO 25-6981). Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28) or 3.75 mg (150 mg/kg; n = 15) every 3 h or an equal volume of sterile saline (250 microl; n = 40) starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus.. Treatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P < 0.05 for all RO 25-6981 treated animals combined). The extent of apoptosis was not affected by low or high doses of RO 25-6981. Number of apoptotic cells (median [range]) was 12.76 [3.16-25.3] in animals treated with low dose RO 25-6981 (control animals 13.8 [2.60-31.8]; (P = NS) and 9.8 [1.7-27.3] (controls: 10.5 [2.4-21.75]) in animals treated with high dose RO 25-6981 (P = NS).. Treatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures.

Topics: Animals; Animals, Suckling; Apoptosis; Cell Count; Cerebrospinal Fluid; Dentate Gyrus; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Meningitis, Pneumococcal; Neurons; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Survival Rate; Treatment Outcome

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.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzamides; Calcitonin Gene-Related Peptide; Cerebrovascular Circulation; Dura Mater; Humans; Indoles; Laser-Doppler Flowmetry; Leukocytes; Male; Meningitis, Pneumococcal; Mice; Mice, Inbred Strains; Oxadiazoles; Oxazolidinones; Piperidines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Substance P; Survival Rate; Tryptamines

Study investigates the role of endothelin (ET) receptors in mediating early changes in cerebral blood flow--as measured by laser Doppler flowmetry (CBFLDF)--during experimental pneumococcal meningitis. Meningitis was induced with heat-killed pneumococci and confirmed by a significant increase in CBFLDF (baseline 100%; 225.3 +/- 21.8% after 6 hours; mean +/- SD), intracranial pressure (ICP), brain water content, and white blood cell count in the CSF. Intravenous administration of the selective endothelin B (ETB) receptor antagonist BQ-788 immediately before pneumococcal challenge (but not 4 hours afterward) significantly attenuated these pathophysiologic alterations (e.g., CBFLDF 6 hours after pneumococcal challenge: 116.7 +/- 17.4%). Pretreatment with BQ-123, a selective endothelin A receptor antagonist, had no significant effect on ICP and brain water content, but augmented the increase in CBFLDF and CSF white blood cell count. Since ET is known to trigger the release of nitric oxide (NO) by ETB receptor activation, we examined specific ET-NO interactions in primary rat cerebromicrovascular endothelial cells after stimulation with heat-killed pneumococci. Pneumococci induced a significant increase in both ET and NO concentrations in endothelial cell culture medium. Treatment with phosphoramidon, an inhibitor of the endothelin-converting enzyme, prevented the production of endothelin and markedly reduced NO generation. Our data provide evidence that ET is involved as a mediator in early pneumococcal meningitis in the rat and contributes to the increase in CBFLDF, ICP, brain water content, and CSF pleocytosis, presumably through ETB receptor-mediated NO production.

Topics: Animals; Cerebrovascular Circulation; Endothelin Receptor Antagonists; Endothelins; Male; Meningitis, Pneumococcal; Oligopeptides; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin B; Receptors, Endothelin