Transcranial focused ultrasound-mediated unbinding of phenytoin from plasma proteins for suppression of chronic temporal lobe epilepsy in a rodent model

Abstract

The efficacy of many anti-epileptic drugs, including phenytoin (PHT), is reduced by plasma protein binding (PPB) that sequesters therapeutically active drug molecules within the bloodstream. An increase in systemic dose elevates the risk of drug side effects, which demands an alternative technique to increase the unbound concentration of PHT in a region-specific manner. We present a low-intensity focused ultrasound (FUS) technique that locally enhances the efficacy of PHT by transiently disrupting its binding to albumin. We first identified the acoustic parameters that yielded the highest PHT unbinding from albumin among evaluated parameter sets using equilibrium dialysis. Then, rats with chronic mesial temporal lobe epilepsy (mTLE) received four sessions of PHT injection, each followed by 30 min of FUS delivered to the ictal region, across 2 weeks. Two additional groups of mTLE rats underwent the same procedure, but without receiving PHT or FUS. Assessment of electrographic seizure activities revealed that FUS accompanying administration of PHT effectively reduced the number and mean duration of ictal events compared to other conditions, without damaging brain tissue or the blood–brain barrier. Our results demonstrated that the FUS technique enhanced the anti-epileptic efficacy of PHT in a chronic mTLE rodent model by region-specific PPB disruption.