The proinflammagen lipopolysaccharide (LPS) was infused chronically (37 days) into the basal forebrain of rats. The current study determined whether the chronic administration of either a non-competitive N-methyl-D-aspartate- (NMDA-) sensitive receptor antagonist, memantine, or a selective cyclooxygenase-2 (COX2)/lipoxygenase inhibitor, CI987, could provide significant neuroprotection from the cytotoxic effects of LPS-induced neuroinflammation. Chronic LPS infusions decreased cortical choline acetyltransferase activity, which paralleled a decline in the number of choline-acetyltransferase-immunoreactive-cells within the basal forebrain as well as the number of activated resident microglia. The infusions appeared to be selective for cholinergic neurons. Peripheral administration of memantine (i.p.) or CI987 (s.c.) significantly attenuated the cytotoxic effects of the chronic inflammatory processes upon cholinergic cells within the basal forebrain. However, only CI987 attenuated the neuroinflammation produced by LPS and the subsequent changes in microglial activation. These results indicate that the cytotoxic effects of chronic neuroinflammation may involve prostanoid synthesis and may operate through NMDA receptors, and that the effects of prostaglandins occur upstream to NMDA-receptor activation.