Neuronal injury in bacterial meningitis: mechanisms and implications for therapy.
In bacterial meningitis, long-term neurological sequelae and death are caused jointly by several factors: (1) the systemic inflammatory response of the host, leading to leukocyte extravasation into the subarachnoid space, vasculitis, brain edema and secondary ischemia; (2) stimulation of resident microglia within the CNS by bacterial compounds; and (3) possible direct toxicity of bacterial compounds on neurons. Neuronal injury is mediated by the release of reactive oxygen intermediates, proteases, cytokines and excitatory amino acids, and is executed by the activation of transcription factors, caspases and other proteases. In experimental meningitis, dexamethasone as an adjunct to antibiotic treatment leads to an aggravation of neuronal damage in the hippocampal formation, suggesting that corticosteroids might not be the ideal adjunctive therapy. Several approaches that interfere selectively with the mechanisms of neuronal injury are effective in animal models, including the use of nonbacteriolytic protein synthesis-inhibiting antibiotics, antioxidants and inhibitors of transcription factors, matrix metalloproteinases, and caspases.
Nau
Roland
R
Dept of Neurology, University of Göttingen, University Hospital, Robert-Koch-Str. 40, D-37075, Göttingen, Germany. rnau@gwdg.de
Brück
Wolfgang
W
D000818:Animals; D001419:Bacteria / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000276:immunology / Q000378:metabolism; D002545:Brain Ischemia / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004660:Encephalitis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D018846:Excitatory Amino Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D016920:Meningitis, Bacterial / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism
D001427:Bacterial Toxins; D061945:Caspase Inhibitors; D018846:Excitatory Amino Acids; D017382:Reactive Oxygen Species; D020169:Caspases