NEUROTOXICITY OF GLIA ACTIVATED BY GRAM-POSITIVE BACTERIAL PRODUCTS DEPENDS ON NITRIC-OXIDE PRODUCTION

Thf present study examined the mechanism by which bacterial cell walls from two gram-positive meningeal pathogens, Streptococcus pneumoniae and the group B streptococcus, induced neuronal injury in primary cult ures of rat brain cells, Cell walls from both organisms produced cellu lar injury to similar degrees in pure astrocyte cultures but not in pu re neuronal cultures. Cell walls also induced nitric oxide production in cultures of astrocytes or microglia. When neurons were cultured tog ether with astrocytes or microglia, the cell walls of both organisms b ecame toxic to neurons, L-NAME, a nitric oxide synthase inhibitor, pro tected neurons from cell wall-induced toxicity in mixed cultures with glia, as did dexamethasone. In contrast, an excitatory amino acid anta gonist (MK801) had no effect. Low concentrations of cell walls from ei ther gram-positive pathogen added together dth the excitatory amino ac id glutamate resulted in synergistic neurotoxicity that was inhibited by L-NAME. The induction of nitric oxide production and neurotoxicity bg cell walls was independent of the presence of serum, whereas endoto xin exhibited these effects only in the presence of serum, We conclude that gram-positive cell walls can cause toxicity in neurons bg induci ng the production of nitric oxide in astrocytes and microglia.