Translational potential of the ghrelin receptor agonist macimorelin for seizure suppression in pharmacoresistant epilepsy.

Current drugs for epilepsy affect seizures, but no antiepileptogenic or disease-modifying drugs are available that prevent or slow down epileptogenesis, which is characterized by neuronal cell loss, inflammation and aberrant network formation. Ghrelin and ghrelin receptor (ghrelin-R) agonists were previously found to exert anticonvulsant, neuroprotective and anti-inflammatory effects in seizure models and immediately after status epilepticus (SE). Therefore, the aim of this study was to assess whether the ghrelin-R agonist macimorelin is antiepileptogenic in the pharmacoresistant intrahippocampal kainic acid (IHKA) mouse model. SE was induced in C57BL/6 mice by unilateral IHKA injection. Starting 24 h after SE, mice were treated intraperitoneally with macimorelin (5 mg/kg) or saline twice daily for 2 weeks, followed by a 2-week wash-out. Mice were continuously electroencephalogram-monitored, and at the end of the experiment neuroprotection and gliosis were assessed. Macimorelin significantly decreased the number and duration of seizures during the treatment period, but had no antiepileptogenic or disease-modifying effect in this dose regimen. While macimorelin did not significantly affect food intake or body weight over a 2-week treatment period, its acute orexigenic effect was preserved in epileptic mice but not in sham mice. While the full ghrelin-R agonist macimorelin was not significantly antiepileptogenic nor disease-modifying, this is the first study to demonstrate its anticonvulsant effects in the IHKA model of drug-refractory temporal lobe epilepsy. These findings highlight the potential use of macimorelin as a novel treatment option for seizure suppression in pharmacoresistant epilepsy.