Localized transmeningeal muscimol prevents neocortical seizures in rats and nonhuman primates: Therapeutic implications |
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Authors: | Nandor Ludvig,Shirn L. Baptiste,Hai M. Tang,Geza Medveczky,&dagger Hans von Gizycki,&Dagger Jean Charchaflieh,Orrin Devinsky, Ruben I. Kuzniecky |
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Affiliation: | Department of Neurology, Comprehensive Epilepsy Center, NYU Langone Medical Center, School of Medicine, New York, New York, U.S.A.;;Scientific Computing Center, SUNY Downstate Medical Center, Brooklyn, New York, U.S.A.;;and Department of Anesthesiology, SUNY Downstate Medical Center, Brooklyn, New York, U.S.A. |
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Abstract: | 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. |
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Keywords: | Muscimol Acetylcholine Dura mater Pia mater Neocortical seizures |
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