title: Astrocytes and manganese neurotoxicity.
abstract: Increasing evidence suggests that astrocytes are the site of early dysfunction and damage in manganese neurotoxicity. Astrocytes accumulate manganese by a high affinity, high capacity, specific transport system. Chronic exposure to manganese leads to increased pallidal signal hyperintensities on T1-weighted magnetic resonance images and selective neuronal loss in basal ganglia structures together with characteristic astrocytic changes known as Alzheimer type II astrocytosis. Manganese is sequestered in mitochondria where it inhibits oxidative phosphorylation. Exposure of astrocytes to manganese results in important changes including (i) decreased uptake of glutamate; (ii) increased densities of binding sites for the "peripheral-type" benzodiazepine receptor (PTBR), a class of receptor localized to mitochondria of astrocytes and involved in oxidative metabolism, mitochondrial proliferation, and neurosteroid synthesis; (iii) increased gene expression and activity of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), known to be associated with apoptosis; (iv) increased uptake of L-arginine, a precursor of nitric oxide, together with increased expression of the inducible form of nitric oxide synthase (iNOS). Potential consequences of these alterations in astrocytic gene expression include failure of energy metabolism, production of reactive oxygen species (ROS), increased extracellular glutamate concentration and excitotoxicity which could play a key role in manganese-induced neuronal cell death as a direct result of impaired astrocytic-neuronal interactions.
authors.affiliation: Department of Medicine, Hôpital Saint-Luc (CHUM), 1058 St.-Denis, Montreal, Que., Canada H2X 3J4. alan.stewart.hazell@umontreal.ca
authors.forename: Alan S
authors.initials: AS
authors.lastname: Hazell
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008345:Manganese / Q000494:pharmacology*
chemical_list: D008345:Manganese