Adeno-associated virus-mediated expression and constitutive secretion of NPY or NPY13-36 suppresses seizure activity in vivo.
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.
Foti
S
S
Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Haberman
R P
RP
Samulski
R J
RJ
McCown
T J
TJ
D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D007608:Kainic Acid; D023421:Models, Animal; D009478:Neuropeptide Y / Q000235:genetics* / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D012640:Seizures / Q000378:metabolism / Q000628:therapy*; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods
D009478:Neuropeptide Y; D010446:Peptide Fragments; D017476:Receptors, Neuropeptide Y; C062924:neuropeptide Y (13-36); C095889:neuropeptide Y2 receptor; D007608:Kainic Acid
Mol Pharmacol. 1998 Jan;53(1):6-13
9443927
Br J Pharmacol. 1994 Nov;113(3):737-40
7858862
Mol Cell Neurosci. 2005 Feb;28(2):347-60
15691715
Eur J Neurosci. 2005 Sep;22(6):1417-30
16190896
Epilepsia. 2006 Apr;47(4):773-80
16650144
Mol Ther. 2006 Jul;14(1):63-8
16730475
Neurosci Lett. 1997 Jul 18;230(2):129-32
9259481
Br J Pharmacol. 2000 Mar;129(6):1075-88
10725255
Can J Physiol Pharmacol. 2000 Feb;78(2):116-25
10737674
J Nutr. 2000 Apr;130(4S Suppl):1046S-8S
10736379
Epilepsia. 2000;41 Suppl 6:S115-21
10999532
J Neurosci. 2001 Aug 1;21(15):5804-12
11466452
Neuroscience. 2002;110(2):237-43
11958866
Br J Pharmacol. 2002 Jun;136(4):502-9
12055128
Nat Med. 2003 Aug;9(8):1076-80
12858168
Eur J Neurosci. 2003 Oct;18(7):2087-92
14622242
J Neurosci. 2004 Mar 24;24(12):3051-9
15044544
Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):281-94
4110397
Exp Neurol. 1986 Apr;92(1):102-13
3956642
Br J Pharmacol. 1991 Jan;102(1):41-4
1646061
Epilepsia. 1997 Jul;38(7):759-66
9579902