Inhibition of glutamine synthetase in rabbit pneumococcal meningitis is associated with neuronal apoptosis in the dentate gyrus

Abstract

Apoptosis of dentate granular cells in the hippocampal formation during bacterial meningitis may be mediated by glutamate toxicity. For this reason, we studied the relationship between glutamine synthetase activity and regional neuronal apoptosis in rabbits with experimental pneumococcal meningitis. The duration of meningitis was 24 h, and the treatment was started 16 h after infection. Significant increases of glutamine synthetase protein concentration (P < 0.05) were found in the frontal cortex of rabbits with meningitis (n = 7) and rabbits with meningitis receiving ceftriaxone treatment (n = 12) as compared to the control animals (n = 14). No significant differences were seen in the hippocampal formation. The enzymatic activity of glutamine synthetase also was elevated in the frontal cortex (P < 0.05), but not in the hippocampal formation of rabbits with meningitis. After intravenous administration of L-methionine sulfoximine (specific inhibitor of glutamine synthetase) in rabbits with meningitis treated with ceftriaxone (n = 10), the concentration of neuron-specific enolase in CSF (P = 0.025) and the density of apoptotic neurons in the dentate gyrus quantified with the in-situ tailing reaction (P = 0.043) were higher than in meningitic animals receiving only ceftriaxone (n = 10). In conclusion, the inability of hippocampal glutamine synthetase to metabolize excess amounts of glutamate may contribute to neuronal apoptosis in the hippocampal formation during meningitis.