benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and Meningitis--Bacterial

Bacterial meningitis causes persisting neurofunctional sequelae. Theoccurrence of apoptotic cell death in the hippocampal subgranular zone of the dentate gyrus characterizes the disease in patients and relates to deficits in learning and memory in corresponding experimental models. Here, we investigated why neurogenesis fails to regenerate the damage in the hippocampus associated with the persistence of neurofunctional deficits. In an infant rat model of bacterial meningitis, the capacity of hippocampal-derived cells to multiply and form neurospheres was significantly impaired comparedto that in uninfected littermates. In an in vitro model of differentiating hippocampal cells, challenges characteristic of bacterial meningitis (i.e. bacterial components, tumor necrosis factor [20 ng/mL], or growth factor deprivation) caused significantly more apoptosis in stem/progenitor cells and immature neurons than in mature neurons. These results demonstrate that bacterial meningitis injures hippocampal stem and progenitor cells, a finding that may explain the persistence of neurofunctional deficits after bacterial meningitis.

Topics: Amino Acid Chloromethyl Ketones; Analysis of Variance; Animals; Animals, Newborn; Annexin A5; Apoptosis; Cell Differentiation; Cells, Cultured; Collagen; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Intercellular Signaling Peptides and Proteins; Meningitis, Bacterial; Nerve Tissue Proteins; Neural Stem Cells; Neurogenesis; Neurons; Neuroprotective Agents; Rats; Rats, Wistar; Time Factors; Tumor Necrosis Factor-alpha

Half of the survivors of bacterial meningitis experience motor deficits, seizures, hearing loss or cognitive impairment, despite adequate bacterial killing by antibiotics. We demonstrate that the broad-spectrum caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone (z-VAD-fmk) prevented hippocampal neuronal cell death and white blood cell influx into the cerebrospinal fluid compartment in experimental pneumococcal meningitis. Hippocampal neuronal death was due to apoptosis derived from the inflammatory response in the cerebrospinal fluid. Apoptosis was induced in vitro in human neurons by inflamed cerebrospinal fluid and was blocked by z-VAD-fmk. As apoptosis drives neuronal loss in pneumococcal meningitis, caspase inhibitors might provide a new therapeutic option directed specifically at reducing brain damage.

Topics: Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Caspase Inhibitors; CD18 Antigens; Cell Line; Cysteine Proteinase Inhibitors; Hippocampus; Humans; Male; Meningitis, Bacterial; Neurons; Neuroprotective Agents; Pneumococcal Infections; Rabbits