Abstracts

This abstract has been invited to present during the Basic Science Poster Highlights poster session

Rationale: Neuropeptide Y (NPY) is a well characterized, 36 amino acid neuropeptide that plays an important role in a number of physiological processes. NPY is released in response to high frequency stimulation and can reduce excitatory glutamatergic transmission. In animal models, reduced expression of NPY is associated with increased seizure susceptibility, while overexpression of NPY protects against seizures. Furthermore, exogenous administration of NPY has been shown to be seizure protective. Overall, this suggests NPY may be a potential treatment for epilepsy. However, there are several challenges associated with neuropeptide-based treatments. For example, when neuropeptides are administered peripherally, they have poor blood brain barrier penetrance and are rapidly degraded. One strategy to overcome these challenges is to package neuropeptides in nanoparticles. Nanoparticles can protect the protein from degradation and facilitate crossing of the blood brain barrier. We previously showed that nanoparticle encapsulation of oxytocin confers sustained seizure protection and improved treatment efficacy when compared to unencapsulated oxytocin. Therefore, nanoparticle encapsulation may similarly improve the efficacy of NPY as a treatment for epilepsy.

Methods: Full-length NPY or a cleaved version of NPY (amino acids 13-36) were packaged in a BSA-based nanoparticle formulation conjugated with rabies-virus glycoprotein (NP-NPY). Adult CF1 mice were intranasally administered NP-NPY (either the full-length or cleaved version). In addition, to test our preparation in a genetic model of epilepsy, Scn1a knockout (Scn1a^+/-) mice were also treated with NP-NPY (full-length). Mice were tested for seizure susceptibility using the 6 Hz seizure induction paradigm and induced seizures were scored using a modified Racine scale (a score of 0 indicates no seizure activity; 1 indicates temporary immobility, 2 indicates head bobbing or forelimb clonus, and 3 indicates rearing and falling or loss of posture). NP-NPY is also being tested in additional acute seizure induction paradigms. _x000D_
Results: Both preparations of NP-NPY (full-length or cleaved) reduced the average Racine score of CF1 mice in the 6 Hz seizure induction paradigm when compared to mice treated with empty nanoparticles. Intranasal NP-NPY treatment also reduced the average Racine score of Scn1a^+/- mice. Thus, NP-NPY confers protection from induced seizures in both wild-type CF1 mice and Scn1a^+/- mice. These formulations are undergoing further testing to determine if they also convey protection in other seizure induction paradigms.

Conclusions: We showed that intranasal administration of NP-NPY confers protection against induced seizures. Nanoparticle encapsulation of NPY may enhance the therapeutic and translational potential of NPY as a treatment for epilepsy.

Funding: This project was supported by NIH training grant 5T32NS096050-24, NIH grant R01 NS120676, and a predoctoral fellowship from the American Epilepsy Society.