Authors :
Presenting Author: Hannah Jackson, ME, BS – Massachusetts Institute of Technology
Josue Reyes, DVM – Lab specialist, Pharmacology and Toxicology, University of Utah; Gerald Saunders, BS – Senior lab specialist, Pharmacology and Toxicology, University of Utah; Michael Cima, PhD, BS – Professor of Engineering, Materials Science and Engineering, Massachusetts Institute of Technology; Cameron Metcalf, PhD, BS – Research Assistant Professor in Pharmacology and Toxicology, Pharmacology and Toxicology, University of Utah; Peter West, PhD, BS – Research Assistant Professor in Pharmacology and Toxicology, Pharmacology and Toxicology, University of Utah; Karen Wilcox, PhD, BA – Professor and Chair, Pharmacology and Toxicology, Pharmacology and Toxicology, University of Utah
Rationale:
Focal epilepsy poses significant challenges in treatment, with only a 60% response rate to oral antiseizure medications (ASMs). Existing non-pharmaceutical treatments are limited by invasiveness, associated morbidities, and inaccessibility to seizure foci. Addressing these limitations, our lab has developed a micro-invasive implantable device capable of delivering precise sub-microliter infusions to deep brain structures. Our goal is to adapt the device for chronic implantation, enabling targeted ASM delivery to epileptogenic zones for refractory epilepsy treatment. We hypothesize that direct drug infusion into seizure generating regions of the brain will reduce side effects and improve seizure management. We evaluated the acute suppression of seizure activity by locally delivering nano-doses of phenobarbital (PB) through our device in the intra-hippocampal kainate (IHK) mouse model of temporal lobe epilepsy.
Methods:
Male C57bl/6 mice (n=13) received intrahippocampal injections of kainate, followed by implantation of a bipolar electrode and drug-delivery device in the ipsilateral hippocampus. Seizure-like events (SLEs) in the form of high voltage sharp waves (HVSWs) and hippocampal paroxysmal discharges (HPDs) were assessed six to eight weeks after IHK treatment. Mice (weighing between 22-26 g) were then treated with local infusions through our device of either 105 or 404 ng of PB or vehicle. Volume of injection was varied between 260 nL and 1 uL. The same cohort of animals was used for all treatment conditions, with a washout period between treatments. EEGs were recorded for one hour prior to PB or vehicle administration and continued for one hour following each dose to establish a baseline. SLE numbers and frequency were evaluated for 45 minutes immediately before treatment and reported for the last 45 minutes of recording following treatment (15-60 minutes after injection).
Results:
Local injections of PB at higher injection volumes significantly reduced the number of SLEs compared to baseline, while there was no change in SLEs with vehicle administration. Moreover, animals receiving PB injections exhibited significantly fewer SLEs compared to those receiving vehicle injections regardless of injection volume. No behavioral seizures were observed in animals following injections of PB and animals displayed no overt sedation effects after injections of PB or vehicle compared to baseline.
Conclusions:
We have demonstrated the feasibility of local ASM delivery to suppress seizure activity in a mouse model of temporal lobe epilepsy. The localized drug delivery approach offers the potential for improved seizure control with minimal side effects, as the amount of drug delivered (105 or 404 ng) is significantly lower than systemic administration (25-50 mg/kg). These promising findings warrant further investigation, including testing multiple ASMs with different mechanisms of action and comparing local delivery to systemic methods.
Funding:
Deshpande Center Ignition Grant at MIT