Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate-induced excito-neurotoxicity likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases. Microglial clearance of dying neurons and associated debris is essential to maintain healthy neural networks in the central nervous system. In fact, the functions of microglia are regulated by various signaling molecules that are produced as neurons degenerate. Here, we show that the soluble CX3C chemokine fractalkine (sFKN), which is secreted from neurons that have been damaged by glutamate, promotes microglial phagocytosis of neuronal debris through release of milk fat globule-EGF factor 8, a mediator of apoptotic cell clearance. In addition, sFKN induces the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in microglia in the absence of neurotoxic molecule production, including NO, TNF, and glutamate. sFKN treatment of primary neuron-microglia co-cultures significantly attenuated glutamate-induced neuronal cell death. Using several specific MAPK inhibitors, we found that sFKN-induced heme oxygenase-1 expression was primarily mediated by activation of JNK and nuclear factor erythroid 2-related factor 2. These results suggest that sFKN secreted from glutamate-damaged neurons provides both phagocytotic and neuroprotective signals.
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PMID:Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression. 2737 64

Microglia play a crucial role in the development of inflammatory demyelinating lesions in multiple sclerosis (MS). Microglia act on inflammatory lymphocytes as antigen presenting cells, and produce inflammatory cytokines, glutamate, and reactive oxygen species (ROS). Neurodegeneration, which is observed in the demyelinating lesions, affects the prognosis in MS. Neuritic beading, focal bead-like swellings of the dendrites and axons, is a neuropathological sign in the early phase of neurodegeneration in MS. Microglia-derived glutamate and ROS initiate beading formation. Microglia can exert neuroprotective effect by deprivation of dead cells and induction of neurotrophic factors, anti-inflammatory cytokines, and anti-oxidant enzyme in MS. Neurons are thought to be not merely passive targets of microglia but rather control microglial activity through various signals including cytokines and chemokines. Soluble fractalkine (sFKN), which is secreted from damaged neurons by glutamate, promotes microglial phagocytosis of neuronal debris, and induces the antioxidant enzyme heme oxygenase-1 in microglia. IL-34 secreted from neurons also induces microglial neuroprotection. Astrocytes exert neuroprotective effect. However, toll-like receptor ligands induce neurotoxic molecules in astrocytes. IL-33 produced by astrocytes induces microglial activation. Thus, disruption of beneficial interaction between glia and neurons is crucial for the pathogenesis of MS.
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PMID:[Disruption of interactions between immunocytes, glia and neurons in demyelinating diseases: a view from neuroscience]. 2227 7