Pharmacologic interference with NF-kappaB activation attenuates central nervous system complications in experimental Pneumococcal meningitis.
This study assessed the effects of 2 different inhibitors of NF-kappaB activation on central nervous system complications and clinical symptoms in an advanced stage of experimental pneumococcal meningitis: the calpain inhibitor I N-acetyl-leucinyl-leucinyl-norleucinal (ALLN), which interferes with IkappaB proteolysis, and BAY 11-7085, which inhibits IkappaB phosphorylation. Pneumococcal meningitis was associated with an increase in NF-kappaB activity, as determined by immunohistochemistry and Western blot analysis of rat brains 24 h after infection. Treatment with ALLN or BAY 11-7085 improved the clinical scores of infected rats, compared with those of untreated infected rats. This beneficial effect was parallelled by a significant reduction of the increase in intracranial pressure, blood-brain barrier permeability (as measured by the Evans blue-extravasation technique), cerebrospinal fluid (CSF) pleocytosis, CSF interleukin-6 levels, and impairment of cerebrovascular CO(2) reactivity and autoregulation. Thus, pharmacologic interference with NF-kappaB activation might be a possible target for adjunctive therapy in bacterial meningitis.
Koedel
U
U
Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University of Munich, Munich, Germany.
Bayerlein
I
I
Paul
R
R
Sporer
B
B
Pfister
H W
HW
D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D006023:Glycoproteins / Q000627:therapeutic use*; D007427:Intracranial Pressure / Q000187:drug effects; D008297:Male; D008586:Meningitis, Pneumococcal / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D009570:Nitriles; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones
D000890:Anti-Infective Agents; C416282:BAY 11-7085; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; C039304:calpain inhibitors