Oxytocin (OT) has broad effects in the brain and plays an important role in cognitive, social, and neuroendocrine function. OT has also been identified as potentially therapeutic in neuropsychiatric disorders such as autism and depression, which are often comorbid with epilepsy, raising the possibility that it might confer protection against the behavioral and seizure phenotypes in epilepsy. Dravet syndrome (DS) is an early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), treatment-resistant afebrile epilepsy, and cognitive and behavioral deficits. De novo loss-of-function mutations in the voltage-gated sodium channel SCN1A are the main cause of DS, while genetic epilepsy with febrile seizures plus (GEFS+), also characterized by early-life FSs and afebrile epilepsy, is typically caused by inherited mutations that alter the biophysical properties of SCN1A. Despite the wide range of available antiepileptic drugs, many patients with SCN1A mutations do not achieve adequate seizure control or the amelioration of associated behavioral comorbidities. In the current study, we demonstrate that nanoparticle encapsulation of OT conferred robust and sustained protection against induced seizures and restored more normal social behavior in a mouse model of Scn1a-derived epilepsy. These results demonstrate the ability of a nanotechnology formulation to significantly enhance the efficacy of OT. This approach will provide a general strategy to enhance the therapeutic potential of additional neuropeptides in epilepsy and other neurological disorders.

De novo loss‐of‐function mutations in SCN1A are the main cause of Dravet syndrome, a catastrophic encephalopathy characterized by recurrent early‐life febrile seizures, a number of other afebrile seizure types that are often refractory to treatment, and behavioral abnormalities including social deficits, motor dysfunction, and cognitive impairment. We previously demonstrated that the reversible acetylcholinesterase inhibitor, Huperzine A, increases seizure resistance in Scn1a mutants. In the present study, we evaluated the therapeutic potential of donepezil, a reversible acetylcholinesterase inhibitor approved by the Food and Drug Administration, in a mouse model of Dravet syndrome (Scn1a^+/−). We found that donepezil conferred robust protection against induced seizures in Scn1a^+/− mutants.

Voltage-gated sodium channel genes are an important family of human epilepsy genes. De novo missense mutations in SCN8A (encoding Na_v1.6) are associated with a spectrum of clinical presentation, including multiple seizure types, movement disorders, intellectual disability, and behavioral abnormalities such as autism. Patients with SCN8A mutations are often treated with multiple antiepileptic drugs, the most common being sodium channel blockers. Cannabidiol (CBD) has been included as a component of treatment regimens for some SCN8A patients; however, to date, there are no clinical trials that have evaluated the therapeutic potential of CBD in patients with SCN8A mutations. In the current manuscript, we demonstrated a dose-dependent increase in seizure resistance following CBD treatment in mice expressing the human SCN8A mutation R1620L (RL/+). We also found that CBD treatment improved social behavior and reduced hyperactivity in the RL/+ mutants. Our findings suggest that CBD may be beneficial in patients with SCN8A-associated disease.