Intracerebral drug delivery is an emerging treatment strategy aiming to manage seizures in patients with systemic drug-resistant epilepsies. In rat seizure and epilepsy models, the GABAA receptor agonist muscimol has shown powerful antiseizure potential when injected acutely into the subthalamic nucleus (STN), known for its capacity to provide remote control of different seizure types. However, chronic intrasubthalamic muscimol delivery required for long-term seizure suppression has not yet been investigated. We tested the hypothesis that chronic convection-enhanced delivery (CED) of muscimol into the STN produces long-lasting antiseizure effects in the intravenous pentylenetetrazole seizure threshold test in female rats. Acute microinjection was included to verify efficacy of intrasubthalamic muscimol delivery in this seizure model and caused significant antiseizure effects at 30 and 60 ng per hemisphere with a dose-dependent increase of responders and efficacy and only mild adverse effects compared to controls. For the chronic study, muscimol was bilaterally infused into the STN over three weeks at daily doses of 60, 300, or 600 ng per hemisphere using an implantable pump and cannula system. Chronic intrasubthalamic CED of muscimol caused significant long-lasting antiseizure effects for up to three weeks at 300 and 600 ng daily. Drug responder rate increased dose-dependently, as did drug tolerance rates. Transient ataxia and body weight loss were the main adverse effects. Drug distribution was comparable (about 2-3 mm) between acute and chronic delivery. This is the first study providing proof-of-concept that not only acute, but also chronic, continuous CED of muscimol into the STN raises seizure thresholds.
Keywords: Basal ganglia; Epilepsy; Intracerebral drug delivery; Microinjection; Pentylenetetrazole; Pharmacoresistance.
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