title: Intravenous infusion of docosahexaenoic acid increases serum concentrations in a dose-dependent manner and increases seizure latency in the maximal PTZ model.
abstract: Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (n-3 PUFA) that has been shown to raise seizure thresholds in the maximal pentylenetetrazole model following acute subcutaneous (s.c.) administration in rats. Following s.c. administration, however, the dose-response relationship for DHA has shown an inverted U-pattern. The purposes of the present experiment were as follows: (1) to determine the pattern of serum unesterified concentrations resulting from the intravenous (i.v.) infusions of various doses of DHA, (2) to determine the time course of these concentrations following the discontinuation of the infusions, and (3) to determine whether seizure protection in the maximal PTZ model would correlate with serum unesterified DHA levels. Animals received 5-minute i.v. infusions of saline or 25, 50, 100, or 200mg/kg of DHA via a cannula inserted into one of the tail veins. Blood was collected during and after the infusions by means of a second cannula inserted into the other tail vein (Experiment 1). A separate group of animals received saline or 12.5-, 25-, 50-, 100-, or 200 mg/kg DHA i.v. via a cannula inserted into one of the tail veins and were then seizure-tested in the maximal PTZ model either during infusion or after the discontinuation of the infusions. Slow infusions of DHA increased serum unesterified DHA concentrations in a dose-dependent manner, with the 200-mg/kg dose increasing the concentration approximately 260-fold compared with saline-infused animals. Following discontinuation of the infusions, serum concentrations rapidly dropped toward baseline, with half-lives of approximately 40 and 11s for the 25-mg/kg dose and 100-mg/kg dose, respectively. In the seizure-tested animals, DHA significantly increased latency to seizure onset in a dose-dependent manner. Following the discontinuation of infusion, seizure latency rapidly decreased toward baseline. Overall, our study suggests that i.v. infusion of unesterified DHA results in transient anticonvulsant effects which parallel unesterified DHA serum concentrations.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; University of Toronto Epilepsy Research Program, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Marc-Olivier
authors.initials: MO
authors.lastname: Trépanier
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada; University of Toronto Epilepsy Research Program, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Kei-Man
authors.initials: KM
authors.lastname: Kwong
authors.affiliation: Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Domenichiello
authors.affiliation: Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Chuck T
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; University of Toronto Epilepsy Research Program, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Bazinet
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada; University of Toronto Epilepsy Research Program, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: mac.burnham@utoronto.ca.
authors.forename: W M
authors.initials: WM
authors.lastname: Burnham
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D008297:Male; D010433:Pentylenetetrazole / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000097:blood* / Q000139:chemically induced / Q000188:drug therapy*; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D004281:Docosahexaenoic Acids; D010433:Pentylenetetrazole
keywords: Brain; Docosahexaenoic acid; Intravenous infusion; Omega-3 polyunsaturated fatty acids; Pentylenetetrazole; Seizures