Abstracts

Rationale: As a part of our systematic effort, in animals, as well as in epileptic patients in neurosurgical setting, to identify the ideal seizure-preventing agent for transmeningeal pharmacotherapy to treat intractable focal epilepsy (e.g., Ludvig et al., 2006, Epilepsia, 47:1792-1802; Madhavan et al., 2008, Epilepsy Res.78:235-239), the present study was designed to test the viability of muscimol, a GABA-A receptor agonist. Methods: Rats (n = 17) were chronically implanted with an epidural cup placed over the right frontal/parietal cortex, with bipolar epidural electrodes positioned adjacent to the cup and the contralateral neocortex. In 5 rats, used solely for behavioral studies, only the epidural cup was implanted. In addition, a novel, subdural drug delivery device was chronically implanted in the right frontal cortical subdural/subarachnoid space in squirrel monkeys (Saimiri sciureus; n = 3), with similar epidural electrode placements as in rats. After a 2-10-day recovery period, EEG recordings were performed in the rats during free behavior and in the monkeys while seated, awake, in a primate chair. Through the epidural cup in the rats, and the subdural device in the monkeys, either a control solution (artificial cerebrospinal fluid; ACSF) or muscimol (0.25 - 12.5 mM) was delivered at the 5th recording minute (as a “pre-treatment”), followed by the similar delivery of acetylcholine (Ach) 3 min later at the seizure-inducing concentration of 548 mM. The behavioral study in the rats consisted of monitoring the quantity of food pellets their consumed in a test chamber during exposures to epidurally delivered ACSF and 2.5 mM muscimol. Results: In the rats, epidural muscimol pre-treatment significantly reduced the severity of focal Ach-induced seizures at and above 0.25 mM and completely prevented the seizures at and above 2.5 mM. Such a concentration-dependent seizure-preventing effect was absent following epidural ACSF pre-treatment. In the monkeys, subdural muscimol deliveries at 2.5 mM completely prevented the focal seizure-inducing effect of Ach, while similar ACSF deliveries did not alter the seizure-inducing potential of Ach. The behavioral study in the rats revealed that the quantities of food-pellets consumed by the rats following the epidural delivery of 2.5 mM muscimol and the similar delivery of ACSF were not different statistically. Conclusions: Considering the robust seizure-preventing action of relatively low concentrations of transmeningeally delivered muscimol in this study, in both rodents and non-human primates, and appreciating the facts that muscimol is water-soluble at pH = 7.4 and retains its pharmacological efficacy in solution for several months, we conclude that muscimol is a promising agent for the localized subdural treatment of focal epilepsy with hybrid neuroprosthetic implants. (Supported by NYU/FACES).