No neuroprotective effect of erythropoietin under clinical treatment conditions in a rabbit model of Escherichia coli meningitis.

Despite effective antibiotic treatment, neuronal injury is frequent among children and adults with bacterial meningitis resulting in a high rate of death and neurologic sequelae. The hematopoietic cytokine erythropoietin (EPO) provides neuroprotection in models of acute and chronic neurologic diseases. We studied whether recombinant EPO (rEPO) reduces neuronal damage in a rabbit model of Escherichia coli meningitis. Inflammation within the central nervous system (CNS) was monitored by measurement of bacterial load, pleocytosis, protein, and lactate in the cerebrospinal fluid (CSF). Neuronal damage was measured by quantification of the density of apoptotic neurons in the hippocampal dentate gyrus and the concentration of the global neuronal destruction marker neuron-specific enolase (NSE) in CSF. To increase clinical relevance, rEPO was applied as adjunctive therapy from the beginning of antibiotic therapy 12 h after infection. EPO treatment applied as an intravenous injection at a dose of 1000 IU/kg body weight resulted in plasma concentrations of 6993 +/- 1406 mIU/mL, CSF concentrations of 1291 +/- 568 mIU/mL, and a CSF-to-plasma ratio of 0.18 +/- 0.07 (mean +/- SD) 6 h after injection. Under these treatment conditions, no anti-inflammatory or neuroprotective effect of EPO was observed. "

Antiinflammatory but no neuroprotective effects of melatonin under clinical treatment conditions in rabbit models of bacterial meningitis.

Neuronal injury is frequent in bacterial meningitis, resulting in a high rate of death and neurological sequelae. In a search of potential neuroprotective strategies for treatment of bacterial meningitis, the antioxidant melatonin was neuroprotective in cell culture experiments and in a rabbit Streptococcus pneumoniae meningitis model, when treatment was started at the time of infection. In the present study, adjunctive melatonin treatment applied from the beginning of antibiotic therapy 12 hr after infection at a dose of 1.67 mg/kg/hr resulted in plasma concentrations of 451 +/- 198 ng/ml, cerebrospinal fluid (CSF) concentrations of 154 +/- 57 ng/ml and a CSF-to-plasma ratio of 0.38 +/- 0.19 (mean +/- SD). Melatonin therapy had antiinflammatory effects but did not reduce neuronal injury in either a rabbit model of gram-positive Streptococcus pneumoniae or gram-negative Escherichia coli meningitis.

Dexamethasone increases hippocampal neuronal apoptosis in a rabbit model of Escherichia coli meningitis.

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-alpha, 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).