Transmeningeal muscimol can prevent focal EEG seizures in the rat neocortex without stopping multineuronal activity in the treated area

Ludvig, Nándor; Tang, Hai; Artan, N. Sertac; Mirowski, Piotr; Medveczky, Geza; Baptiste, Shirn L.; Darisi, Sindhu; Kuzniecky, Ruben; Devinsky, Orrin; French, Jacqueline A.

doi:10.1016/j.brainres.2011.02.038

Cited by 7 publications

(7 citation statements)

References 38 publications

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“…In a comparative study with epidural cup delivery of drugs at a fixed concentration of 1 mM aiming to prevent disturbance of physiological osmolarity of CSF and brain extracellular fluid, it was shown that only muscimol, but not lidocaine, midazolam, pentobarbital, and GABA, exerted anticonvulsant effects in this rat model [108]. Furthermore, local physiological multineuronal activity may be undisturbed at least by short-term transmeningeal muscimol treatment [112].…”

Section: Acute Transmeningeal Drug Delivery In Animal Models Of Seizumentioning

confidence: 93%

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Gernert¹,

Feja²

2020

Pharmaceutics

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Epilepsies are common chronic neurological diseases characterized by recurrent unprovoked seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiseizure drugs (ASDs). Systemic pharmacotherapies for epilepsies are facing two main challenges. First, adverse effects from (often life-long) systemic drug treatment are common, and second, about one-third of patients with epilepsy have seizures refractory to systemic pharmacotherapy. Especially the drug resistance in epilepsies remains an unmet clinical need despite the recent introduction of new ASDs. Apart from other hypotheses, epilepsy-induced alterations of the blood–brain barrier (BBB) are thought to prevent ASDs from entering the brain parenchyma in necessary amounts, thereby being involved in causing drug-resistant epilepsy. Although an invasive procedure, bypassing the BBB by targeted intracranial drug delivery is an attractive approach to circumvent BBB-associated drug resistance mechanisms and to lower the risk of systemic and neurologic adverse effects. Additionally, it offers the possibility of reaching higher local drug concentrations in appropriate target regions while minimizing them in other brain or peripheral areas, as well as using otherwise toxic drugs not suitable for systemic administration. In our review, we give an overview of experimental and clinical studies conducted on direct intracranial drug delivery in epilepsies. We also discuss challenges associated with intracranial pharmacotherapy for epilepsies.

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Section: Acute Transmeningeal Drug Delivery In Animal Models Of Seizumentioning

confidence: 93%

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Gernert¹,

Feja²

2020

Pharmaceutics

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“…[6] There have been several clinical trials of focal electrical stimulation that have shown marginal benefit, even though some preclinical studies had shown promise. [78910] There have been a number of preclinical reports about the potential benefits of various focal drug infusions or recently,[111213] focal transfection with a light-activated protein,[14] but no clinical trials have been reported with this approach. Animal stimulation studies have also had quite variable results.…”

Section: Electrophysiology In the Future: Defining Targets For Directmentioning

confidence: 99%

Electrophysiology in epilepsy surgery: Roles and limitations

Bertram

2014

Ann Indian Acad Neurol

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Successful epilepsy surgery depends on the localization of the seizure onset zone in an area of the brain that can be safely resected. Defining these zones uses multiple diagnostic approaches, which include different types of electroencephalography (EEG) and imaging, and the results are best when all of the tests point to the same region. Although EEG obtained with scalp recordings is often sufficient for the purposes of localization, there are times when intracranial recordings directly from the brain are needed; but the planning, use, value, and interpretation of the these recordings are not standardized, in part because the questions that are to be answered vary considerably across many patients and their heterogenous types of epilepsy that are investigated. Furthermore, there is a desire to use the opportunity of direct brain recordings to understand the pathophysiology of epilepsy, as these recordings are viewed as an opportunity to answer questions that cannot be otherwise answered. In this review, we examine the situations that may require intracranial electrodes and discuss the broad issues that this powerful diagnostic tool can help address, for identifying the seizure focus and for understanding the large scale circuits of the seizures.

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“…In contrast to systemic administration, when delivered transmeningeally in experimental animals, muscimol has antiepileptic effects, without the adverse effects associated with systemic delivery [12][13][14][15]. Direct injection of muscimol into the brain is orders-ofmagnitude more effective than intravenous injection.…”

Section: Introductionmentioning

confidence: 99%

An On-Demand Drug Delivery System for Control of Epileptiform Seizures

et al. 2022

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Drug delivery systems have the potential to deliver high concentrations of drug to target areas on demand, while elsewhere and at other times encapsulating the drug, to limit unwanted actions. Here we show proof of concept in vivo and ex vivo tests of a novel drug delivery system based on hollow-gold nanoparticles tethered to liposomes (HGN-liposomes), which become transiently permeable when activated by optical or acoustic stimulation. We show that laser or ultrasound simulation of HGN-liposomes loaded with the GABAA receptor agonist, muscimol, triggers rapid and repeatable release in a sufficient concentration to inhibit neurons and suppress seizure activity. In particular, laser-stimulated release of muscimol from previously injected HGN-liposomes caused subsecond hyperpolarizations of the membrane potential of hippocampal pyramidal neurons, measured by whole cell intracellular recordings with patch electrodes. In hippocampal slices and hippocampal–entorhinal cortical wedges, seizure activity was immediately suppressed by muscimol release from HGN-liposomes triggered by laser or ultrasound pulses. After intravenous injection of HGN-liposomes in whole anesthetized rats, ultrasound stimulation applied to the brain through the dura attenuated the seizure activity induced by pentylenetetrazol. Ultrasound alone, or HGN-liposomes without ultrasound stimulation, had no effect. Intracerebrally-injected HGN-liposomes containing kainic acid retained their contents for at least one week, without damage to surrounding tissue. Thus, we demonstrate the feasibility of precise temporal control over exposure of neurons to the drug, potentially enabling therapeutic effects without continuous exposure. For future application, studies on the pharmacokinetics, pharmacodynamics, and toxicity of HGN-liposomes and their constituents, together with improved methods of targeting, are needed, to determine the utility and safety of the technology in humans.

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Transmeningeal muscimol can prevent focal EEG seizures in the rat neocortex without stopping multineuronal activity in the treated area

Cited by 7 publications

References 38 publications

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Electrophysiology in epilepsy surgery: Roles and limitations

An On-Demand Drug Delivery System for Control of Epileptiform Seizures

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