Localized transmeningeal muscimol prevents neocortical seizures in rats and nonhuman primates: Therapeutic implications

Purpose:   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 m m ) 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 m m ) exposures were measured. In a last group of four rats, muscimol (0.8–2.5 m m ) 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 m m . In the monkeys, subarachnoid muscimol pretreatments at 2.5 m m completely prevented the focal-seizure–inducing effect of Ach, whereas similar deliveries of ACSF did not affect the seizures. Furthermore, 2.5 m m 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.