Region-specific enhancement of drug delivery to the brain, without increasing systemic drug dose or actively disrupting the blood-brain barrier, has been sought after for effective pharmacological treatment of various central nervous system disorders. Among different approaches, we propose to enhance the delivery by unbinding the drug from the plasma proteins to increase the local drug concentration that may be transported across the vasculature. The overarching goal of our research is to examine the effects of transcranial focused ultrasound (FUS) on region-specific disruption of plasma protein binding (PPB) with phenytoin (PHT) and to evaluate if the regional increase of parenchymal PHT uptake results in the suppression of temporal lobe epilepsy (TLE) in rodents. First, FUS will be noninvasively applied to an ipsilateral hippocampal area of non- epileptic Sprague-Dawley rats receiving a therapeutic dose of PHT, using varying duty cycles, pulse durations, and intensities of sonication. The parenchymal PHT uptake will be quantified using anti-PHT immunohistochemistry, and the FUS parameter that results in the highest uptake level will be identified. Then, using the parameter, multiple sessions of FUS will be applied to the epileptic brain region of chronic TLE rats receiving daily therapeutic doses of PHT. Electroencephalography (EEG) will be acquired from the animals using a wearable wireless EEG device and the frequency/duration of behavioral seizures and epileptographic EEG will be quantified. These measures will be compared among four combinatorial experimental groups of FUS(+/-) and PHT(+/-) to examine if the increased delivery of PHT, mediated by FUS, will enhance its anti- convulsant effects. The animals, both epileptic and non-epileptic, will be evaluated for potential tissue or vascular damage using histological analysis and for the presence of undesired disruption of the blood-brain barrier. The proposed method of acoustic disruption of PHT-PPB may provide an elegant and unprecedented option for suppressing seizure activity associated with focal epilepsy. Similar FUS protocols may also be applicable to increase regional delivery of a wide range of drugs that have high affinity to plasma proteins.

Public Health Relevance

Pharmacological drug molecules typically bind to the proteins in blood, which limits their therapeutic action by keeping a significant portion of the drug within the bloodstream. We will examine whether noninvasive application of ultrasound to a specific region of the brain through the skull can unbind an antiepileptic drug, phenytoin, from the serum proteins in blood, in order to increase the drug delivery only to the targeted local brain area without elevating the dose systemically. Concurrently, we will also evaluate whether regionally- enhanced delivery of phenytoin, mediated by the application of ultrasound, will result in the suppression of seizures among rats that have chronic focal epilepsy.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZEY1)
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Flanders, Martha C
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Brigham and Women's Hospital
United States
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