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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.

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References

  1. McCown TJ . Adeno-associated virus-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity in vivo. Mol Ther 2006; 14: 63–68.

    Article  CAS  Google Scholar 

  2. Klugmann M, Symes CW, Leichtlein CB, Klaussner BK, Dunning J, Fong D et al. AAV-mediated hippocampal expression of short and long Homer 1 proteins differentially affect cognition and seizure activity in adult rats. Mol Cell Neurosci 2005; 28: 347–360.

    Article  CAS  Google Scholar 

  3. Haberman RP, Samulski RJ, McCown TJ . Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion. Nat Med 2003; 9: 1076–1080.

    Article  CAS  Google Scholar 

  4. Freese A, Kaplitt MG, O'Connor WM, Abbey M, Langer D, Leone P et al. Direct gene transfer into human epileptogenic hippocampal tissue with an adeno-associated virus vector: implications for a gene therapy approach to epilepsy. Epilepsia 1997; 38: 759–766.

    Article  CAS  Google Scholar 

  5. Vezzani A, Michalkiewicz M, Michalkiewicz T, Moneta D, Ravizza T, Richichi C et al. Seizure susceptibility and epileptogenesis are decreased in transgenic rats overexpressing neuropeptide Y. Neuroscience 2002; 110: 237–243.

    Article  CAS  Google Scholar 

  6. Richichi C, Lin EJ, Stefanin D, Colella D, Ravizza T, Grignaschi G et al. Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus. J Neurosci 2004; 24: 3051–3059.

    Article  CAS  Google Scholar 

  7. Lin EJ, Richichi C, Young D, Baer K, Vezzani A, During MJ . Recombinant AAV-mediated expression of galanin in rat hippocampus suppresses seizure development. Eur J Neurosci 2003; 18: 2087–2092.

    Article  Google Scholar 

  8. Colmers WF, Klapstein GJ, Fournier A, St-Pierre S, Treherne KA . Presynaptic inhibition by neuropeptide Y in rat hippocampal slice in vitro is mediated by a Y2 receptor. Br J Pharmacol 1991; 102: 41–44.

    Article  CAS  Google Scholar 

  9. Dumont Y, Cadieux A, Doods H, Fournier A, Quirion R . Potent and selective tools to investigate neuropeptide Y receptors in the central and peripheral nervous systems: BIB03304 (Y1) and CGP71683A (Y5). Can J Physiol Pharmacol 2000; 78: 116–125.

    Article  CAS  Google Scholar 

  10. Dumont Y, Cadieux A, Doods H, Pheng LH, Abounader R, Hamel E et al. BIIE0246, a potent and highly selective non-peptide neuropeptide Y Y(2) receptor antagonist. Br J Pharmacol 2000; 129: 1075–1088.

    Article  CAS  Google Scholar 

  11. Greber S, Schwarzer C, Sperk G . Neuropeptide Y inhibits potassium-stimulated glutamate release through Y2 receptors in rat hippocampal slices in vitro. Br J Pharmacol 1994; 113: 737–740.

    Article  CAS  Google Scholar 

  12. Lin EJ, Young D, Baer K, Herzog H, During MJ . Differential actions of NPY on seizure modulation via Y1 and Y2 receptors: evidence from receptor knockout mice. Epilepsia 2006; 47: 773–780.

    Article  Google Scholar 

  13. El Bahh B, Balosso S, Hamilton T, Herzog H, Beck-Sickinger AG, Sperk G et al. The anti-epileptic actions of neuropeptide Y in the hippocampus are mediated by Y and not Y receptors. Eur J Neurosci 2005; 22: 1417–1430.

    Article  Google Scholar 

  14. El Bahh B, Cao JQ, Beck-Sickinger AG, Colmers WF . Blockade of neuropeptide Y(2) receptors and suppression of NPY's anti-epileptic actions in the rat hippocampal slice by BIIE0246. Br J Pharmacol 2002; 136: 502–509.

    Article  CAS  Google Scholar 

  15. Furtinger S, Pirker S, Czech T, Baumgartner C, Ransmayr G, Sperk G . Plasticity of Y1 and Y2 receptors and neuropeptide Y fibers in patients with temporal lobe epilepsy. J Neurosci 2001; 21: 5804–5812.

    Article  CAS  Google Scholar 

  16. Kofler N, Kirchmair E, Schwarzer C, Sperk G . Altered expression of NPY-Y1 receptors in kainic acid induced epilepsy in rats. Neurosci Lett 1997; 230: 129–132.

    Article  CAS  Google Scholar 

  17. Schwarzer C, Kofler N, Sperk G . Up-regulation of neuropeptide Y-Y2 receptors in an animal model of temporal lobe epilepsy. Mol Pharmacol 1998; 53: 6–13.

    Article  CAS  Google Scholar 

  18. Vezzani A, Moneta D, Mule F, Ravizza T, Gobbi M, French-Mullen J et al. Plastic changes in neuropeptide Y receptor subtypes in experimental models of limbic seizures. Epilepsia 2000; 41 (Suppl 6): S115–S121.

    Article  Google Scholar 

  19. Vezzani A, Rizzi M, Conti M, Samanin R . Modulatory role of neuropeptides in seizures induced in rats by stimulation of glutamate receptors. J Nutr 2000; 130: 1046S–1048S.

    Article  CAS  Google Scholar 

  20. Frush DP, McNamara JO . Evidence implicating dentate granule cells in wet dog shakes produced by kindling stimulations of entorhinal cortex. Exp Neurol 1986; 92: 102–113.

    Article  CAS  Google Scholar 

  21. Racine RJ . Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972; 32: 281–294.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Julie Hamra for expert technical assistance. The study was supported by NIH grant NINDS NS 35633 to TJM.

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Correspondence to T J McCown.

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Foti, S., Haberman, R., Samulski, R. et al. Adeno-associated virus-mediated expression and constitutive secretion of NPY or NPY13-36 suppresses seizure activity in vivo. Gene Ther 14, 1534–1536 (2007). https://doi.org/10.1038/sj.gt.3303013

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