Tumour necrosis factor alpha induces only minor inflammatory changes in the central nervous system, but augments experimental meningitis.
Although tumour necrosis factor alpha is said to play a key role in bacterial meningitis and other CNS diseases, the effects of this pro-inflammatory cytokine have only been studied in part and are incompletely understood. In a rat model, we investigated the effect of intracisternal injection of recombinant rat-specific tumour necrosis factor alpha (5, 35, 70 and 280 microg tumour necrosis factor alpha) (i) alone, (ii) combined with pneumococcal cell wall components, on regional cerebral blood flow, intracranial pressure, white blood cell count in the cerebrospinal fluid, and brain water content. Tumour necrosis factor a dose-dependently caused an increase in regional cerebral blood flow (up to 221 +/- 43% of baseline values) over the six hour observation period and mild cerebrospinal fluid leukocytosis; intracranial pressure and brain water content were unchanged. Hypothesizing that regional cerebral blood flow changes are dependent on nitric oxide, tumour necrosis factor alpha-induced regional cerebral blood flow increase was abolished by Aminoguanidine, a selective inhibitor of inducible nitric oxide synthase. Combination of the lowest tumour necrosis factor alpha dose and a low dose pneumococcal cell wall preparation magnified the inflammatory effect of both. We conclude that intrathecally injected tumour necrosis factor alpha alone results in only minor inflammatory changes, whereas it dramatically augments experimental meningitis.
Angstwurm
K
K
Department of Neurology, Charité, Humboldt-University, Berlin, Germany.
Freyer
D
D
Dirnagl
U
U
Hanisch
U K
UK
Schumann
R R
RR
Einhäupl
K M
KM
Weber
J R
JR
D000818:Animals; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology*; D002473:Cell Wall; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology*; D007427:Intracranial Pressure / Q000187:drug effects / Q000502:physiology; D007958:Leukocyte Count; D008297:Male; D008586:Meningitis, Pneumococcal / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D013296:Streptococcus pneumoniae; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology
D006146:Guanidines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C004479:pimagedine