title: Transmeningeal delivery of GABA to control neocortical seizures in rats.
abstract: Transmeningeal drug delivery, using an implanted hybrid neuroprosthesis, has been proposed as a novel therapy for intractable focal epilepsy. As part of a systematic effort to identify the optimal compounds and protocols for such a therapy, this study aimed to determine whether transmeningeal gamma-aminobutyric acid (GABA) delivery can terminate and/or prevent neocortical seizures in rats. Rats were chronically implanted with an epidural cup and an adjacent EEG electrode in the right parietal cortex. While the rat was behaving freely, a seizure-inducing concentration of acetylcholine (Ach) was applied into the cup. In a seizure termination study, either artificial cerebrospinal fluid (ACSF) or GABA (0.25, 2.5, 25 or 50mM) was delivered into the exposed neocortical area during an ongoing seizure. In a seizure prevention study, either ACSF or 50mM GABA was delivered into the epidural cup before the application of Ach. Epidural delivery of 50mM GABA completely terminated ongoing Ach-induced EEG seizures and convulsions within 17-437s after its delivery. ACSF and lower concentrations of GABA did not produce this effect, but 25mM GABA reduced seizure severity. However, the used GABA concentration could not prevent the development, or affect the severity, of Ach-induced EEG seizures and convulsions. This study indicates that transmeningeal GABA delivery can be used for terminating neocortical seizures, but to achieve seizure prevention via this route either a more efficient GABA delivery method needs to be developed or other neurotransmitters/pharmaceuticals should be employed for this purpose.
authors.affiliation: Comprehensive Epilepsy Center, Department of Neurology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Jenine E
authors.initials: JE
authors.lastname: John
authors.forename: Shirn L
authors.initials: SL
authors.lastname: Baptiste
authors.forename: Lynette G
authors.initials: LG
authors.lastname: Sheffield
authors.forename: Hans
authors.initials: H
authors.lastname: von Gizycki
authors.forename: Ruben I
authors.initials: RI
authors.lastname: Kuzniecky
authors.forename: Orrin
authors.initials: O
authors.lastname: Devinsky
authors.forename: Nandor
authors.initials: N
authors.lastname: Ludvig
mesh_terms: D000109:Acetylcholine; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D004569:Electroencephalography; D005583:Fourier Analysis; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D019579:Neocortex / Q000187:drug effects*; D051381:Rats; D020318:Rats, Long-Evans; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage*
chemical_list: D000927:Anticonvulsants; D005904:Glial Fibrillary Acidic Protein; D005680:gamma-Aminobutyric Acid; D000109:Acetylcholine