Neuroprotection by a caspase inhibitor in acute bacterial meningitis

Nat Med. 1999 Mar;5(3):298-302. doi: 10.1038/6514.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology*
  • Animals
  • Apoptosis
  • CD18 Antigens / immunology
  • Caspase Inhibitors*
  • Cell Line
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Hippocampus / cytology
  • Humans
  • Male
  • Meningitis, Bacterial / immunology
  • Meningitis, Bacterial / pathology*
  • Neurons / cytology
  • Neurons / drug effects
  • Neuroprotective Agents / pharmacology*
  • Pneumococcal Infections / immunology
  • Pneumococcal Infections / pathology*
  • Rabbits


  • Amino Acid Chloromethyl Ketones
  • CD18 Antigens
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Neuroprotective Agents
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone