Localized transmeningeal muscimol prevents neocortical seizures in rats and nonhuman primates: Therapeutic implications
Article first published online: 4 DEC 2008
Wiley Periodicals, Inc. © 2008 International League Against Epilepsy
Volume 50, Issue 4, pages 678–693, April 2009
How to Cite
Ludvig, N., Baptiste, S. L., Tang, H. M., Medveczky, G., Von Gizycki, H., Charchaflieh, J., Devinsky, O. and Kuzniecky, R. I. (2009), Localized transmeningeal muscimol prevents neocortical seizures in rats and nonhuman primates: Therapeutic implications. Epilepsia, 50: 678–693. doi: 10.1111/j.1528-1167.2008.01914.x
- Issue published online: 3 APR 2009
- Article first published online: 4 DEC 2008
- Accepted September 16, 2008; Early View publication December 4, 2008.
- Dura mater;
- Pia mater;
- Neocortical seizures
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 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.