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.
Hoffmann
Olaf
O
Department of Neurology, University Hospital Charité, Humboldt University, Berlin, Germany.
Keilwerth
Nikolas
N
Bille
Margarethe Bastholm
MB
Reuter
Uwe
U
Angstwurm
Klemens
K
Schumann
Ralf R
RR
Dirnagl
Ulrich
U
Weber
Joerg R
JR
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000134:cerebrospinal fluid / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004388:Dura Mater / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D017078:Laser-Doppler Flowmetry; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D008586:Meningitis, Pneumococcal / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D010069:Oxadiazoles / Q000494:pharmacology; D023303:Oxazolidinones / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D013373:Substance P / Q000378:metabolism; D015996:Survival Rate; D014363:Tryptamines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; C470302:HTR1B protein, human; D007211:Indoles; C108531:N-(3-(2-dimethylamino)ethoxy-4-methoxyphenyl)-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; D010069:Oxadiazoles; D023303:Oxazolidinones; D010880:Piperidines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; C106783:naratriptan