Dexamethasone Increases Hippocampal Neuronal Apoptosis in a Rabbit Model of Escherichia coli Meningitis

Abstract

Mortality and long-term sequelae rates are high among adults and children with acute bacterial meningitis. Adjunctive treatment with dexamethasone has been shown to reduce systemic complications in bacterial meningitis patients, but corticosteroid treatment may have detrimental effects on hippocampal function. We evaluated the effect of dexamethasone treatment in addition to antibiotic therapy in a rabbit model of Escherichia coli meningitis. A moderate anti-inflammatory effect of dexamethasone could be demonstrated with respect to the inflammatory mediator prostaglandin E2, whereas no significant effect of dexamethasone on tumor necrosis factor-␣, cerebrospinal fluid pleocytosis, protein, lactate, indicators of global neuronal damage, or blood gas analysis was found. Dexamethasone, however, increased the rate of apoptotic neurons in the granular layer of the hippocampal dentate gyrus. In view of the proapoptotic effect of adjunctive dexamethasone on hippocampal neuronal cells in animal models of Gram-positive and Gram-negative meningitis, the application of dexamethasone should be considered carefully in those forms of bacterial meningitis for which no evidence-based data of beneficial effect in humans are available, such as neonatal meningitis, bacillary Gram-negative meningitis or nosocomial forms of meningitis (e.g. following neurosurgery).

No Neuroprotective Effect of Erythropoietin Under Clinical Treatment Conditions in a Rabbit Model of Escherichia coli Meningitis

“…In the absence of meningitis, the density of apoptotic neuronal cells/mm 2 in the hippocampal dentate gyrus was found to be approximately 10 apoptotic neurons/mm 2 in previously healthy rabbits killed immediately without longterm anesthesia (19). In uninfected control rabbits subjected to 24 h of urethane long-term anesthesia, antibiotic treatment, and repeated suboccipital punctures the density of apoptotic neuronal cells was approximately 40 apoptotic neurons/mm 2 of the dentate gyrus (14). The greatly increased rate of apoptotic neurons in the hippocampal dentate gyrus of rabbits suffering from meningitis (in the present study: 208 Ϯ 120 apoptotic neurons/mm 2 , mean Ϯ SD) can be attributed to the infection and serves as a parameter for the evaluation of putatively neuroprotective therapeutic agents.…”

“…At 23.5 h post-infection, an arterial blood gas analysis was performed (Radiom-eter ABL 605, Diamond Diagnostics) to determine arterial oxygen (PO 2 ) and carbon dioxide tension (PCO 2 ) and pH. The animals were killed at 24 h post-infection (14).…”

“…NSE in CSF as an indicator of neuronal destruction was quantified at 12 h and 24 h after infection (Table 1) (14). The NSE concentration at 12 h and 24 h post-infection did not differ significantly between rEPOtreated and control animals ( Table 1, p ϭ 0.60 and 0.72, respectively, both U test).…”

“…Neuronal apoptosis was regularly induced by E. coli menin- (14). The rate of apoptotic neurons ranged from 85 to 633/mm 2 (area of the granule cell layer, 208 Ϯ 120, mean Ϯ SD).…”

Adjunctive therapy in bacterial meningitis

“…Aunque diferentes estudios han demostrado que la adición de dexametasona precozcomente en el tratamiento de la meningitis bacteriana disminuye las secuelas auditivas en la meningitis por H. influenzae tipo b en niños, la mejoría de la mortalidad y secuelas en meningitis neumocóccicas no ha sido demostrada concluyentemente (6,(9)(10). Además dexametasona no es una medicación sin riesgos desde que se ha observado que la adición de dexametasona en modelo animal de meningitis bacteriana por S. pneumoniae agrava el daño neuronal incrementado la apoptosis (muerte celular programada) en el hipocampo, estructura cerebral esencial para las funciones de memoria y aprendizaje (11). Recientemente una completa revisión de datos de pacientes individuales que incluyó 2029 sujetos (833 niños) de cinco estudios no ha encontrado ninguna reducción en la muerte o discapacidad neurológica o audiológica en niños, incluso en la meningitis causada por H. influenzae, independientemente del momento de la primera dosis de antibiótico…”