Acetylcholine receptor agonist effect on seizure activity and GABAergic mechanisms involved in prolonged febrile seizure development in an animal model

摘要

Febrile seizures are a paediatric condition which affects 2-5 % of children worldwide with prolonged febrile seizures (PFS) being found to cause long-term complications and predispose patients to other neurological conditions later in life. Febrile seizures occur due to an imbalance between the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA. alpha 7-nicotinic acetylcholine receptors (alpha 7-nAchRs) have been found to mediate GABA release as well as its neurotransmission. In this study, alpha 7-nAchRs were activated by using PNU-282,987 (PNU), a selective alpha 7-nAchR agonist, in order to evaluate their effect in seizure threshold as well as GABAergic parameters in a PFS rat model. PFS was induced on 14-day old Sprague-Dawley rat pups by administration of lipopolysaccharide (217 ug/kg, i.p) followed 2.5 h later by kainic acid (KA) (1.83 mg/kg, i.p). PNU was given prior to KA administration and Methyllycaconitine (MLA), an alpha 7-nAchR antagonist, was given following KA injection. Seizure activity was recorded and monitored for one hour following seizure induction. Glutamate decarboxylase (GAD)1 and GAD 2 expression, as well as GABA concentration in the hippocampus, were assessed. Our results show that activating alpha 7-nAchRs delays PFS progression and this delay was attenuated by the antagonist, MLA. Exposure to PFS reduced the expression of GAD1 and GABA concentration while PNU injection prevented this decrease. This suggests that specific nicotinic acetylcholine receptors may be used as therapeutic targets in the maintenance of adequate hippocampal GABA concentration for the prevention of PFS development.