Role of CD200 in neuron-glia intercommunication during inflammation

Neuroinflammation, characterized by the presence of activated microglia, may underlie the progression of many age-related neurodegenerative diseases. The failure of glia to convert spontaneously from a pro-inflammatory to an anti-inflammatory activation state, resulting in inappropriate activation of microglia and increases levels of cytokines and free radicals, may be one of the main pathogenetic processes of neuroinflammation, leading to neuronal injury and cell loss. Neuroinflammation can be induced by chronic lipopolysaccharide (LPS) infusion into the 4th ventricle of young rats resulting in region-selective microglia activation, increased glutamate release, and enhanced NMDA-dependent signalling. Memantine, a low-moderate affinity open channel uncompetitive NMDA receptor antagonist, can reduce OX6-immunolabeling for activated microglia. In this study rats were chronically infused via osmotic minipump into the 4th ventricle for 1, 4 or 8 weeks with LPS alone, vehicle alone, or LPS for two weeks followed by two weeks with memantine given by an osmotic minipump subcutaneously (15 mg/kg/day). Microglia activation and the expression of a negative regulator of microglia activation, CD200, were investigated in each experimental group. Within the hippocampus, LPS increased the number of activated microglia, reduced the number of cells expressing CD200 protein and increased immunoreactive expression of cytoplasmic calbindin. Memantine at low doses, reduced the number of activated microglia even when it was administered after the neuroinflammatory processes were fully developed and restored to normal the expression patterns CD200 and calbindin. Our results indicate that in the presence of memantine neurons are able to produce and release CD200 in order to communicate with microglia to reduce their expression of MHCII and become quiescent. Therefore, therapeutically relevant doses of memantine delivered at any stage in the progression of neuroinflammation-influenced diseases may confer neuroprotection.