Inflammatory neurodegeneration is degeneration of neurons induced by inflammation. Inflammation occurs in most brain pathologies, and there is evidence that this inflammation plays both positive and negative roles in the pathology. For example, long-term use of anti-inflammatory drugs reduces the onset of Alzheimer’s and Parkinson’s diseases. In the brain, inflammation is mainly mediated by glial cells, in particular microglia, and these proliferate, migrate, release pro-inflammatory cytokines and become inflammatory-activated in many brain pathologies. In culture, inflammatory-activated glia kill co-cultured neurons, and this might contribute to neurodegeneration in vivo. We have been investigating mechanisms by which glia become activated and subsequently kill neurons in culture. A variety of inflammatory mediators induce the expression of inducible nitric oxide synthase (iNOS) in microglia and astrocytes and/or activate the microglial NADPH oxidase (NOX), which produces superoxide and hydrogen peroxide. We find that a high level of glial iNOS expression induces neuronal death in synergy with hypoxia, basically by NO inhibition of neuronal respiration resulting in glutamate release and excitotoxicity. This suggests that the inflamed brain may be more sensitive to hypoxic damage. NO also induces glutamate release from astrocytes, but by a different, calcium-dependent mechanism. NO from nNOS can also synergise with hypoxia to induce neuronal death via inhibition of mitochondrial respiration (if glycolysis is blocked). Activation of the microglial NADPH oxidase (by PMA, ATP, arachidonate, IL-1β, Abeta or prion peptide) causes little or no death of co-cultured neurons. However, these agents stimulate microglial proliferation and TNF-alpha release, which is blocked by inhibiting NOX or by removing H2O2 with catalase, and is replicated by adding H2O2. Thus NOX appears to regulate microglial proliferation and activation through H2O2 production, but has little direct effect of neuronal death. However, if we activated NOX (with the above factors) in glia where iNOS had previously been induced there was considerable synergy in inducing death of co-cultured neurons. And this death was prevented either by inhibiting iNOS or NOX, or scavenging peroxynitrite (the neurotoxic product of NO reacting with superoxide). These mechanisms might contribute to neuronal death during neurodegenerative diseases.