Activated microglia may be detrimental to neuronal survival in a number of neurodegenerative diseases. Thus, strategies that reduce microglial neurotoxicity may have therapeutic benefit. Stimulation of group II metabotropic glutamate (mGlu) receptors on rat primary microglia with the specific group II agonist 2S,2ЈR,3ЈR-2-(2Ј,3Ј-dicarboxy-cyclopropyl)glycine for 24 h induced microglial activation and resulted in a neurotoxic microglial phenotype. These effects were attributable to preferential mGlu2 stimulation, because N-acetyl-Laspartyl-L-glutamate, a specific mGlu3 agonist, did not induce microglial activation or neurotoxicity. Stimulation of microglial mGlu2 but not mGlu3 induced caspase-3 activation in cerebellar granule neurons in culture, using microglial-conditioned media as well as cocultures. Stimulation of microglial mGlu2 induced tumor necrosis factor-␣ (TNF␣) release, which contributed to microglial neurotoxicity mediated via neuronal TNF receptor 1 and caspase-3 activation. Stimulation of microglial group I or III mGlu receptors did not induce TNF␣ release. TNF␣ was only neurotoxic in the presence of microglia or microglial-conditioned medium. The toxicity of TNF␣ could be prevented by coexposure of neurons to conditioned medium from microglia stimulated by the specific group III agonist L-2-amino-4-phosphono-butyric acid. The neurotoxicity of TNF␣ derived from mGlu2-stimulated microglia was potentiated by microglial-derived Fas ligand (FasL), the death receptor ligand. FasL was constitutively expressed in microglia and shed after mGlu2 stimulation. Our data suggest that selective and inverse modulation of microglial mGlu2 and mGlu3 may prove a therapeutic target in neuroinflammatory diseases such as Alzheimer's disease and multiple sclerosis.

The lack of formal training is an impediment to the production of useful medical records by ED interns. One solution proposed by both interns and senior personnel was the introduction of the subject into intern education programmes.

Substances that play an important role in the pathogenesis of hepatic encephalopathy (HE) are believed to originate in the gastrointestinal tract, particularly the colon, and to accumulate systemically in liver failure as a consequence of their impaired hepatic removal. Although the ideal goal of treatment for HE is to improve hepatocellular function, traditional therapies, such as lactulose and neomycin, are directed at reducing the systemic accumulation of comagenic substances by decreasing their intestinal absorption or synthesis. Thus these therapies act on the organ that is considered to be the origin of the substances causing the problem (1). An alternative approach is to give a treatment that acts on the target organ, the brain, by reversing neuropathophysiological events that directly contribute to the encephalopathy. That a benzodiazepine receptor (BZR) ligand might be a therapy of this type has been suggested by uncontrolled observations of ameliorations of HE in humans associated with the administration of the BZR antagonist, flumazenil (2-4).In this issue O f HEPATOLOGY, Steindl and her colleagues (5) explore the potential of three different BZR ligands in reversing manifestations of HE in an extensively characterized rat model of fulminant hepatic failure (FHF) (6,7). Is there a rationale for administering a BZR ligand in HE? Specifically, does a BZR-mediated abnormality of neuronal function contribute to HE, and could such an abnormality be amenable to reversal by a BZR ligand? To answer these questions it is first necessary to consider how the central BZR modulates neuronal function. This receptor is an integral component of the GABAA/BZR complex in synaptic neural membranes. The other components of the complex are a receptor for GABA (the GABAA receptor) and a chloride channel. After its release from presynaptic neurons, GABA binds to GABAA receptors on effector postsynaptic neurons. This binding triggers the opening of the chloride channel, which allows passage of chloride ions into the neuron and results in hyperpolarization of the surface membrane. These events are the basis of GABAmediated inhibitory neurotransmission. Gating of the chloride channel by the GABAA receptor is allosterically modulated by the BZR. The BZR may increase or decrease the efficiency of GABA-gated chloride conductance depending on the nature of ligands occupying the Address reprint requests to: E.