title: Assessing neuroprotective P-glycoprotein activity at the blood-brain barrier in killifish (Fundulus heteroclitus) using behavioural profiles.
abstract: The neuroprotective role of P-glycoprotein, a multixenobiotic resistance transporter (ABCB1/MDR1), in the blood-brain barrier in fish was examined using behavioural toxicological assays. P-glycoprotein acts as cellular efflux pump to prevent substrates from accumulating in the brain, including environmental contaminants such as ivermectin, a common aquaculture pesticide and mammalian anti-parasitic drug. The behavioural toxicological assays were developed to determine the neuropathological effect of ivermectin in killifish (Fundulus heteroclitus). P-glycoprotein function and thus blood-brain barrier integrity can be compromised by chemosensitizers that inhibit transport activity. Fish treated with ivermectin and the P-glycoprotein inhibitor cyclosporin A were significantly more sensitive and succumbed more rapidly to tilting, lethargy, slowing of pectoral-fin movement and loss of haptic-reactivity compared to fish treated with ivermectin-only. P-glycoprotein inhibition is associated with significantly earlier onset and increased mortality in ivermectin-exposed fish. Our results suggest that P-glycoprotein confers resistance against ivermectin-induced behavioural neuropathology and mortality in fish. This assay provides us with a non-invasive tool to study P-glycoprotein function in the blood-brain barrier and evaluate the behavioural effects of potential environmental neurotoxins.
authors: Environmental Programmes, Dalhousie University, 1355 Oxford Street, Life Science Centre, Room 820, Halifax, Nova Scotia, Canada B3H 4J1.
authors: Shannon Mala
authors: SM
authors: Bard
authors: Simon
authors: S
authors: Gadbois
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000502:physiology*; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D023781:Fundulidae / Q000502:physiology*; D007559:Ivermectin / Q000494:pharmacology; D008297:Male; D013997:Time Factors; D014874:Water Pollutants, Chemical / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D014874:Water Pollutants, Chemical; D007559:Ivermectin; D016572:Cyclosporine