Tumor Necrosis Factor‐α Contributes to Apoptosis in Hippocampal Neurons during Experimental Group B Streptococcal Meningitis

Abstract

To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) in neuronal injury in experimental group B streptococcal meningitis, infected neonatal rats were treated with a monoclonal antibody against TNF-alpha (20 mg/kg intraperitoneally) or saline given at the time of infection. Histopathology after 24 h showed necrosis in the cortex and apoptosis in the hippocampal dentate gyrus. Treated animals had significantly less hippocampal injury than did controls (P < .001) but had similar cortical injury and cerebrospinal fluid (CSF) inflammation. The antibody was then administered directly intracisternally (170 microg) to test whether higher CSF concentrations reduced inflammation or cortical injury. Again, hippocampal apoptosis was significantly reduced (P < .01), while cortical injury and inflammation were not. Thus, TNF-alpha played a critical role in neuronal apoptosis in the hippocampus, while it was not essential for the development of inflammation and cortical injury in this model.

Group B streptococcal β-hemolysin/cytolysin activates neutrophil signaling pathways in brain endothelium and contributes to development of meningitis

“…Our findings that HBMEC do not produce TNF-α or IL-1 in response to an acute GBS infection suggests that cells other than the brain endothelium, including astrocytes, microglial cells, and recruited leukocytes, may be the main source of these cytokines during disease progression. In fact, TNF-α induction may be more significant to the latter stages of meningitis, because it contributes to apoptosis of hippocampal neurons (32) and further breakdown of BBB integrity (33).…”

Intracisternally Localized Bacterial DNA Containing CpG Motifs Induces Meningitis

“…Inhibition of TNF-␣ release by ␣-MSH decreased the incidence and score of inflammatory cell infiltrate triggered by CpG ODN. It has been demonstrated that TNF-␣ can initiate meningeal inflammation (7), resulting in breach of the blood-brain barrier leading to brain edema and increased intracranial pressure (2); and it plays a critical role in neuronal apoptosis in the hippocampus (57). Nitrite levels are usually significantly elevated in CSF of patients with bacterial meningitis and in experimental meningitis (34,58).…”

Reduction of Potassium Currents and Phosphatidylinositol 3-Kinase-Dependent Akt Phosphorylation by Tumor Necrosis Factor-α Rescues Axotomized Retinal Ganglion Cells from Retrograde Cell DeathIn Vivo

“…In vivo studies have demonstrated damaging effects in cerebral ischemia (Dawson et al, 1996;Barone et al, 1997;Meistrell et al, 1997;Nawashiro et al, 1997), experimental autoimmune encephalomyelitis (Klinkert et al, 1997) and head injury models (Shohami et al, 1996(Shohami et al, , 1997. Furthermore, TNF-␣ contributes to apoptosis in rat hippocampal neurons during experimental meningitis (Bogdan et al, 1997). On the other hand, TNF-␣ seems to protect primary hippocampal neurons against hypoxia or nitric oxideinduced injury (Tamatani et al, 1998) or cultured mesencephalic neurons against glutamate neurotoxicity (Shinpo et al, 1999).…”