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

Abstract

SUMMARYPurpose: 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, Achinduced 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.

Subarachnoid pharmacotherapy for maximizing recovery after cortical ischemic stroke

“…Unlike in rats, in monkeys, the subarachnoid strip or grid can be chronically implanted in the subarachnoid space. We showed that with such a device the epidural pharmacological data obtained in rats can be replicated in primates: subdural/subarachnoid muscimol completely prevented focal, acetylcholine (Ach)-induced neocortical seizures in monkeys in a concentration well tolerated by the animals (Ludvig et al, 2009). Fig.…”

“…Thus, epidurally administered diazepam, pentobarbital and muscimol have been shown to prevent and/or terminate experimentally induced focal neocortical seizures in rats (Collins, 1980;Eder et al, 1997;Stein et al, 2000;Ludvig et al, 2006Ludvig et al, , 2009. Relevant autoradiographic and histological studies have demonstrated the actual intracortical diffusion and spread of water-soluble drugs, such as acetylcholine, N-methyl-D-aspartate and methylene blue (Cornblath and Ferguson, 1976;Ludvig et al, 2008).…”

“…Extensive studies have been devoted to explore the potential of this strategy for the treatment of focal neocortical epilepsy (Ludvig et al, 2006(Ludvig et al, , 2009(Ludvig et al, , 2010aMadhavan et al, 2008), but similar studies have yet to be conducted in the field of stroke research. The concept of subarachnoid pharmacotherapy for maximizing recovery after cortical ischemic stroke ( Fig.…”

“…Second, the physicochemical properties of the cortical pia mater, a single interrupted layer of elongated cells (Lopes and Mair, 1974), allow the diffusion of water-soluble drugs through its layer into the underlying cortical tissue, permitting these molecules to exert neuropharmacological effects in animals, including nonhuman primates (Ludvig et al, , 2009). In fact, the similar permeability of the spinal pia mater (Bernards and Hill, 1990) is exploited in medical practice for intrathecal anesthesia and pain relief: a practice that could certainly be adapted to the localized pharmacological treatment of brain disorders, including stroke.…”

A high-performance transcutaneous battery charger for medical implants

“…Recent advances in biomedical engineering leads the way to many exciting implantable devices for neural signal recording and processing [1]- [4] and drug delivery [5]. As the implantable devices get more complicated to include more functionality, their power requirements also increase.…”