Epidural Pentobarbital Delivery Can Prevent Locally Induced Neocortical Seizures in Rats: The Prospect of Transmeningeal Pharmacotherapy for Intractable Focal Epilepsy

Abstract

Summary:Purpose: To determine whether epidural pentobarbital (PB) delivery can prevent and/or terminate neocortical seizures induced by locally administered acetylcholine (Ach) in freely moving rats.Methods: Rats were implanted permanently with an epidural cup placed over the right parietal cortex with intact dura mater. Epidural screw-electrodes, secured to the cup, recorded local neocortical EEG activity. In the seizure-termination study, Ach was delivered into the epidural cup, and after the development of electrographic and behavioral seizures, the Ach solution was replaced with either PB or artificial cerebrospinal fluid (aCSF; control solution). In the seizure-prevention study, the epidural Ach delivery was preceded by a 10-min exposure of the delivery site to PB or aCSF. Raw EEG recordings, EEG power spectra, and behavioral events were analyzed.Results: Ach-induced EEG seizures associated with convulsions, which were unaffected by epidural aCSF applications, were terminated by epidurally delivered PB within 2-2.5 min. Epidural deliveries of PB before Ach applications completely prevented the development of electrographic and behavioral seizures, whereas similar deliveries of aCSF exerted no influence on the seizure-generating potential of Ach.Conclusions: This study showed for the first time that epidural AED delivery can prevent, as well as terminate, locally induced neocortical seizures. The findings support the viability of transmeningeal pharmacotherapy for the treatment of intractable neocortical epilepsy.

Convection-Enhanced Delivery in the Treatment of Epilepsy

“…Since diffusible agents rapidly dissipate from the injection site, they must be infused continuously to obtain the sustained tissue concentrations necessary for chronic seizure protection. Antiseizure agents can also be applied to the brain surface via the epidural or subdural spaces, so that delivery occurs by the transmeningeal route 6-8. This mode of delivery, which is particularly applicable for neocortical epilepsies, requires therapeutic molecules that can penetrate the meninges and diffuse into the underlying neocortex to at least a limited extent.…”

Subarachnoid pharmacodialysis for central nervous system disorders

“…(This experiment also demonstrated the therapeutic effect of a single subarachnoid muscimol administration in stopping ongoing ACh-seizures (C, I) during saline treatment). [19][20][21] and intracerebral infusion of neurotrophic factors promotes neurogenesis after stroke [22], whereas clinically, localized postoperative chemotherapy is beneficial for glioma [23]. These and other studies of intracranial drug delivery have used pumps for convection-enhanced delivery (CED) via narrow-lumen intraparenchymal cannulae [21,[23][24][25], as well as drug-releasing polymers or micro-electro-mechanical-system (MEMS) microchips [26][27][28].…”

“…At least a subgroup of this patient population could benefit from localized pharmacodialysis treatment. Administration of antiepileptic drugs directly into the seizure focus has been proposed by many groups [19][20][21]24,26,27]. Complementing this pharmacotherapy through drainage of proconvulsant Fig.…”

Subarachnoid pharmacotherapy for maximizing recovery after cortical ischemic stroke

“…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.…”