Chronic convection-enhanced muscimol delivery into the subthalamic nucleus produces transient anticonvulsant effects in an acute rat seizure model.

Abstract

Aims : Intracerebral drug delivery is an emerging strategy for the treatment of refractory epilepsies. Recently, the GABA A receptor agonist muscimol was infused into the epileptic focus in drug-resistant epilepsy patients (Heiss et al. 2019 Neurosurgery). In seizure and epilepsy models in rats, muscimol has shown anticonvulsant potential when injected acutely into the subthalamic nucleus (STN). However, continuous administration would be required for the clinical setting. Thus, we hypothesized that chronic convection-enhanced muscimol delivery into the STN produces anticonvulsant effects in an acute rat seizure model. Methods : We examined the effects of intra-STN muscimol following a single microinjection (30 and 60 ng/250 nl) and during continuous administration via a microinfusion pump (60 and 600 ng/day over 3 weeks) on the seizure threshold of female Wistar Unilever rats. Timed intravenous pentylenetetrazole (PTZ) infusion was used as an acute seizure test particularly sensitive to GABA-potentiating manipulations. Results : Acute STN muscimol infusion significantly increased PTZ seizure thresholds compared to vehicle-injected animals. The anticonvulsant effect persisted in the first week during chronic STN inhibition and diminished in the second week, indicating tolerance. Low doses of muscimol were well tolerated and not associated with behavioral adverse effects (e.g., sedation, circling) observed after infusion of higher doses. Evaluation of the spatial distribution of BODIPY-labeled muscimol revealed behavioral adverse effects may be attributable to drug spread into adjacent regions of the STN. Conclusions : These results substantiate the STN as a key region in seizure control and indicate the potential of chronic targeted muscimol delivery for prolonged anticonvulsant effects.

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

“…Again, chronic continuous or discontinuous drug delivery is necessary for long-term seizure suppression. In a chronic transmeningeal drug delivery study, Tang et al [65] showed that discontinuous (50 µL once per day for four consecutive days in each week) epidural muscimol (1 mM) delivery over three weeks maintained antiseizure efficacy without inducing tolerance in rats, which we showed to otherwise occur after about two weeks of continuous intraparenchymal muscimol delivery [57]. In a series of further experiments, Ludvig and colleagues refined their above-described experiments of transmeningeal drug delivery by developing the SPD (see chapter 2).…”

“…Second, a sufficiently long lifespan of the implant to ensure long-term seizure control cannot be reached with polymer-based systems. Third, continuous intracranial drug delivery can be associated with the development of pharmacological tolerance [56,57], favoring techniques that allow discontinuous drug release. For the treatment of brain tumors, polymer-based implants are in further development to allow discontinuous drug release.…”

“…Extensive preclinical and clinical experience exists with CED of drugs to treat brain tumors and neurological diseases such as Parkinson's disease [64] and have helped to establish CED as one of the most promising strategies for the targeted treatment of CNS disorders. CED of drugs is also intensively investigated preclinically by many groups, including ours [13,56,57], and clinically [16], to treat epilepsies. In their clinical safety study, Heiss et al [16] showed that CED of the GABA A receptor agonist muscimol for 12 to 24 h into the epileptic focus of patients with DRE did not damage adjacent brain parenchyma or adversely affect seizure surgery outcome.…”

“…In their clinical safety study, Heiss et al [16] showed that CED of the GABA A receptor agonist muscimol for 12 to 24 h into the epileptic focus of patients with DRE did not damage adjacent brain parenchyma or adversely affect seizure surgery outcome. As mentioned above, continuous intracranial drug delivery can be associated with the development of pharmacological tolerance [56,57], thus favoring techniques, which allow discontinuous drug release [65], such as programmable drug pumps allowing intermittent drug infusion.…”

“…However, efficacy studies of intracranial pharmacotherapy so far did not preselect systemic drug responders and nonresponders, as this is a highly time-consuming procedure. Needs to be elaborated on, intracerebral drug delivery also yields responders and nonresponders as was shown by chronic intrasubthalamic microinfusion of the ASD vigabatrin [56] and the GABA A receptor agonist muscimol [57] by using the ivPTZ-ST fast screening model. It is unknown, if there is an overlap between systemic drug responsiveness and intracerebral drug responsiveness in individual animals.…”