Localized transmeningeal muscimol prevents neocortical seizures in rats and nonhuman primates: therapeutic implications.
OBJECTIVE
To determine whether muscimol delivered epidurally or into the subarachnoid space can prevent and/or terminate acetylcholine (Ach)-induced focal neocortical seizures at concentrations not affecting behavior and background electroencephalography (EEG) activity.


METHODS
Rats (n = 12) and squirrel monkeys (n = 3) were chronically implanted with an epidural or subarachnoid drug delivery device, respectively, over the right frontal/parietal cortex, with adjacent EEG electrodes. Recordings were performed in behaving rats and chaired monkeys. Via the implants, either a control solution (artificial cerebrospinal fluid, ACSF) or muscimol (0.25-12.5 mm) was delivered locally as a "pretreatment," followed by the similar delivery of a seizure-inducing concentration of Ach. In five additional rats, the quantities of food-pellets consumed during epidural ACSF and muscimol (2.5 mm) exposures were measured. In a last group of four rats, muscimol (0.8-2.5 mm) was delivered epidurally during the ongoing, Ach-induced EEG seizure.


RESULTS
In contrast to ACSF pretreatments, epidural muscimol pretreatment in rats completely prevented the seizures at and above 2.5 mm. In the monkeys, subarachnoid muscimol pretreatments at 2.5 mm completely prevented the focal-seizure-inducing effect of Ach, whereas similar deliveries of ACSF did not affect the seizures. Furthermore, 2.5 mm epidural muscimol left the eating behavior of rats intact and caused only slight changes in the EEG power spectra. Finally, muscimol delivery during Ach-induced EEG seizures terminated the seizure activity within 1-3 min.


CONCLUSIONS
The results of this study suggest that muscimol is a viable candidate for the transmeningeal pharmacotherapy of intractable focal epilepsy.
Ludvig
Nandor
N
Department of Neurology, Comprehensive Epilepsy Center, NYU Langone Medical Center, School of Medicine, New York, New York, USA. nandor.ludvig@nyumc.org
Baptiste
Shirn L
SL
Tang
Hai M
HM
Medveczky
Geza
G
von Gizycki
Hans
H
Charchaflieh
Jean
J
Devinsky
Orrin
O
Kuzniecky
Ruben I
RI
D000109:Acetylcholine; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods; D004569:Electroencephalography / Q000379:methods; D005247:Feeding Behavior / Q000187:drug effects; D005583:Fourier Analysis; D018755:GABA Agonists / Q000008:administration & dosage*; D008297:Male; D009118:Muscimol / Q000008:administration & dosage*; D019579:Neocortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D020318:Rats, Long-Evans; D012453:Saimiri; D012640:Seizures / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D013346:Subarachnoid Space / Q000187:drug effects / Q000502:physiology*
D018755:GABA Agonists; D009118:Muscimol; D000109:Acetylcholine