Adeno-associated virus-mediated expression and constitutive secretion of NPY or NPY13-36 suppresses seizure activity in vivo.

Abstract

Neuropeptide Y (NPY) is a 36-amino-acid peptide that attenuates seizure activity following direct infusion or adeno-associated virus (AAV)-mediated expression in the central nervous system. However, NPY activates all NPY receptor subtypes, potentially causing unwanted side effects. NPY13-36 is a C-terminal peptide fragment of NPY that primarily activates the NPY Y2 receptor, thought to mediate the antiseizure activity. Therefore, we investigated if recombinant adeno-associated virus-mediated expression and constitutive secretion of NPY or NPY13-36 could alter limbic seizure sensitivity. Rats received bilateral piriform cortex infusions of AAV vectors that express and constitutively secrete full-length NPY (AAV-FIB-NPY) or NPY13-36 (AAV-FIB-NPY13-36). Control rats received no infusion, as we have previously shown that vectors expressing and secreting reporter genes like GFP (AAV-FIB-EGFP), as well as vectors expressing peptides that lack secretion sequences (AAV-GAL) have no effect on seizures. One week later, all animals received kainic acid (10 mg kg(-1), intraperitoneally), and the latencies to wet dog shakes and limbic seizure behaviors were determined. Although both control and vector-treated rats developed wet dog shake behaviors with similar latencies, the latencies to class III and class IV limbic seizures were significantly prolonged in both NPY- and NPY13-36-treated groups. Thus, AAV-mediated expression and constitutive secretion of NPY and NPY13-36 is effective in attenuating limbic seizures, and provides a platform for delivering therapeutic peptide fragments with increased receptor selectivity.

• Authors: S Foti, R P Haberman, R J Samulski, T J McCown
• Journal: Gene therapy (Gene Ther) Vol. 14 Issue 21 Pg. 1534-6 (Nov 2007) ISSN: 0969-7128 [Print] England
• PMID: 17713567 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Neuropeptide Y
• Peptide Fragments
• Receptors, Neuropeptide Y
• neuropeptide Y (13-36)
• neuropeptide Y2 receptor
• Kainic Acid

Topics

• Animals
• Dependovirus (genetics)
• Gene Expression
• Genetic Therapy (methods)
• Genetic Vectors (administration & dosage, genetics)
• Hippocampus (metabolism)
• Kainic Acid
• Models, Animal
• Neuropeptide Y (genetics, metabolism)
• Peptide Fragments (genetics, metabolism)
• Rats
• Receptors, Neuropeptide Y (metabolism)
• Seizures (metabolism, therapy)
• Time Factors
• Transduction, Genetic (methods)