Glial cells couple inflammation to glutamate neurodegeration: Let's cut it there

New information indicates that the glia is an active participant of synaptic transmission and brain circuitry. Astrocytes respond to synaptic neurotransmitters, by releasing chemical transmitter (glutamate) themselves and inducing neuromodulation. These cells possess a Ca²⁺-dependent transmitter release mechanism resembling in many aspects regulated neuronal exocytosis. However, astrocyte release is in response to ligand-activated calcium elevations, not to electrical signals. Here, prostaglandins (PGs) play a key role, by supporting a major component of the calcium rise that triggers glutamate release. Indeed, typical nonsteroidal antiinflammatory agents (NSAIDs) such as aspirin and indomethacin act to reduce PG-dependent calcium elevations and glutamate release from astrocytes. It is well established that PGs levels increase during inflammatory processes, and this occurs also in parenchymal brain inflammation, sustained by the astrocytes and microglia. Pro-inflammatory cytokines, such as IL-1β and TNFα, enhance expression of inducible cyclooxygenase (COX-2) and production of PGs in these cells. As a consequence, higher glial calcium elevations and glutamate release are expected, with potential toxic consequences for the surrounding brain cells, particularly neurons and oligodendrocytes that are vulnerable to high glutamate concentrations. This scenario might apply to a number of brain pathologies with an inflammatory component and account for progression of brain damage, particularly in Alzheimer's disease, where amyloid plaques are tightly surrounded by inflammatory glia and COX-2 overexpression is thought to worsen neuropathology, and to AIDS-related neuropathology, where an excitotoxic glia-dependent cascade is apparently the primary cause of neurodegeneration. The above findings encourage therapeutic strategies aimed at blocking inflammation-neurodegeneration coupling at the glial cell level.