title: Increases in seizure latencies induced by subcutaneous docosahexaenoic acid are lost at higher doses.
abstract: Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid (PUFA) which has been found to have anticonvulsant properties. Our group has previously reported in a pilot study that the acute administration of subcutaneous (s.c.) DHA increases seizure latencies in the maximal pentylenetetrazole (PTZ) seizure test, however it loses its effect at higher doses. The purpose of the present experiments was (1) to confirm that DHA loses its effect at higher doses, (2) to correlate the anticonvulsant properties of DHA with DHA levels in the different lipid pools of serum and (3) to evaluate whether an anticonvulsant dose of DHA resulted in an increase in DHA release from the brain phospholipids following induction of seizure. In the first experiment, male Wistar rats were injected s.c. with 200, 300, 400 or 600 mg/kg of DHA, or 400mg/kg oleic acid (OA, isocaloric control), and seizure tested with the maximal PTZ test 1h post injection (Experiment 1). In a second experiment, subjects received either: (1) an effective dose of DHA (400mg/kg), (2) a higher, non-effective dose (600 mg/kg; based on the findings of Experiment 1), or (3) OA (400mg/kg). Subjects were sacrificed 1h post injection and blood was collected for fatty acid analysis (Experiment 2). In the third experiment, subjects were injected with either the effective dose of DHA (400mg/kg) or OA (400mg/kg). One hour post lipid injection, animals received either PTZ or saline, and animals were euthanized via microwave fixation. Brain were extracted and unesterified fatty acid concentrations were measured (Experiment 3). Experiment 1 confirmed that DHA loses its effects at higher doses in the maximal PTZ test. The 400mg/kg dose was maximally effective but effects were lost at 600 mg/kg. Experiment 2 showed that only the unesterified DHA pool in serum was statistically increased by an acute injection of s.c. DHA (P<0.05, as compared to OA), whereas esterified DHA pools were unchanged (P>0.05). Curiously, unesterified DHA levels were similar in both the 400mg/kg and 600 mg/kg dosage groups. Experiment 3 showed that an anticonvulsant dose of DHA (400mg/kg) did not increase DHA release from brain phospholipids following seizure induction (P>0.05). In conclusion, DHA has anticonvulsant properties when injected s.c., but these properties are lost at higher doses. The anticonvulsant effects of DHA are accompanied by increased levels of unesterified DHA in the serum, but not in increased DHA release from brain phospholipids.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Marc-Olivier
authors.initials: MO
authors.lastname: Trépanier
authors.forename: Ameer Y
authors.initials: AY
authors.lastname: Taha
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Mantha
authors.forename: Flaviu A
authors.initials: FA
authors.lastname: Ciobanu
authors.forename: Qiudi H
authors.initials: QH
authors.lastname: Zeng
authors.forename: George M
authors.initials: GM
authors.lastname: Tchkhartichvili
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Domenichiello
authors.forename: Richard P
authors.initials: RP
authors.lastname: Bazinet
authors.forename: W M
authors.initials: WM
authors.lastname: Burnham
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D004281:Docosahexaenoic Acids / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D004281:Docosahexaenoic Acids