Nanoparticle-encapsulated neuropeptide Y provides robust seizure protection in SCN1A-derived epilepsy.

Abstract

OBJECTIVE: Neuropeptides have garnered great interest as potential treatments for epilepsy due to their impact on neuronal excitability through modulation of ion channels and neurotransmitter receptor activity. Neuropeptide Y (NPY) is a 36-amino acid neuropeptide that is expressed primarily by γ-aminobutyric acidergic (GABAergic) interneurons. NPY has widespread effects on the brain, at both the cellular (e.g., reducing excitatory glutamatergic transmission) and circuit levels (e.g., increasing food intake, improving learning and memory, increasing seizure resistance). Previous studies have demonstrated antiseizure effects of NPY following invasive brain delivery methods or gene therapy approaches to increase the expression of NPY or its receptor activity. However, these routes of administration pose challenges for translation into clinical practice. METHODS: To overcome these obstacles, we generated a nanoparticle formulation to encapsulate neuropeptides. In the current study, we evaluated the ability of nanoparticle-encapsulated NPY (NP-NPY) to increase resistance to 6 Hz-, pentylenetetrazole-, and hyperthermia-induced seizures in mouse models of SCN1A-derived epilepsy. We also examined the ability of NP-NPY treatment to protect against spontaneous seizures in Scn1amutant mice, a model of Dravet syndrome. Quantitative reverse transcription polymerase chain reaction was performed to compare expression levels of NPY and its receptors in hippocampi from Scn1amutants and wild-type littermates. RESULTS: We found that intranasal NP-NPY administration was able to provide robust protection against induced seizures in two mouse models of SCN1A-derived epilepsy and reduce spontaneous seizure frequency in Scn1amutant mice. SIGNIFICANCE: These results provide support for further evaluation of NP-NPY as a treatment for SCN1A-derived epilepsy and possibly other epilepsy subtypes.