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Tumor necrosis factor-α (TNF-α) is critically involved in inflammation and may participate in hippocampal injury in bacterial meningitis. In a mouse model of ceftriaxone-treated pneumococcal meningitis, spatial memory and motor performance of TNF-α-deficient (n = 57) and control mice (n = 55) were investigated. After infection, therapy was initiated with ceftriaxone (100 mg/kg twice daily for 5 days). Sixty-three percent TNF-α-deficient mice and 40% control animals died within 6 days (Fisher's exact test: P = 0.02). TNF-α-deficient mice surviving pneumococcal meningitis took substantially longer to reach the hidden platform than controls, and the distance of swim tracks was longer (P = 0.02). The swim speed in both groups was similar (P = 0.59). The proliferation of dentate granule cells was lower in TNF-α-deficient than in wild-type mice (P = 0.03). In pneumococcal meningitis, TNF-α deficiency caused increased mortality and stronger deficits in spatial memory possibly due to impaired neurogenesis.