title: Neuronal mdr-1 gene expression after experimental focal hypoxia: a new obstacle for neuroprotection?
abstract: Neuronal damage after stroke-associated brain hypoxia is a leading cause of long-term disability and death. The refractoriness to therapeutic strategies for neuroprotection after 3 h post brain ischemia is poorly understood. P-glycoprotein (P-gp), the multidrug resistance gene (MDR-1) product is normally expressed at blood-brain-barrier. P-gp neuronal expression has been demonstrated in refractory epilepsy and after brain ischemia. In this report we investigated the hypoxia-induced neuronal P-gp expression after local injection of CoCl(2) (1-200 mM) in the fronto-parietal cortex of male adult rats (Bregma -1.30 mm) by stereotaxic surgery. P-gp immunostaining of brain slides was analyzed using specific monoclonal antibodies and double immunolabeling was done with specific astrocytic and neuronal markers. Five days after injection of 1 mM CoCl(2), P-gp expression surrounding the lesion site was observed in neurons, astrocytic end-foot on capillary blood vessels and endothelial cells on blood vessels. Higher CoCl(2) doses (200 mM) resulted in additional P-gp immunostaining of the entire astrocytic and neuronal cytoplasm. Electron microscopy (EM) studies showed alterations in neurons as early as 6 h after the CoCl(2) injection. P-gp expression in hypoxic neurons and astrocytic end-foot could potentially impair of drugs access to the brain parenchyma thus suggesting the presence of two P-gp-based pumping systems (one in astrocytes and other in the hypoxic neurons) that are able to behave as a previously unnoticed obstacle for pharmacological strategies of neuroprotection.
authors: Instituto de Biología Celular y Neurociencias Prof. E. De Robertis, Facultad de Medicina, Universidad de Buenos Aires, Calle Paraguay 2155, 3er piso, (C1121ABG) Buenos Aires, Argentina.
authors: Alberto
authors: A
authors: Lazarowski
authors: Laura
authors: L
authors: Caltana
authors: Amalia
authors: A
authors: Merelli
authors: Maria Dolores
authors: MD
authors: Rubio
authors: Alberto Javier
authors: AJ
authors: Ramos
authors: Alicia
authors: A
authors: Brusco
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016587:Antimutagenic Agents / Q000008:administration & dosage; D003035:Cobalt / Q000008:administration & dosage; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D000860:Hypoxia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010296:Parietal Lobe / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016587:Antimutagenic Agents; D005904:Glial Fibrillary Acidic Protein; D003035:Cobalt; D010751:Phosphopyruvate Hydratase; C018021:cobaltous chloride