Seizure susceptibility and epileptogenesis are decreased in transgenic rats overexpressing neuropeptide Y.
Functional studies in epileptic tissue indicate that neuropeptide Y and some of its peptide analogs potently inhibit seizure activity. We investigated seizure susceptibility in transgenic rats overexpressing the rat neuropeptide Y gene under the control of its natural promoter. Seizures were induced in adult transgenic male rats and their wild-type littermates by i.c.v. injection of 0.3 microg kainic acid or by electrical kindling of the dorsal hippocampus. Transgenic rats showed a significant reduction in the number and duration of electroencephalographic seizures induced by kainate by 30% and 55% respectively (P<0.05 and 0.01). Transgenic rats were also less susceptible to epileptogenesis than wild-type littermates as demonstrated by a 65% increase in the number of electrical stimuli required to induce stage 5 seizures (P<0.01). This phenotype was associated with a strong and specific expression of neuropeptide Y mRNA in area CA1, a brain area involved in the seizure network. We conclude that endogenous neuropeptide Y overexpression in the rat hippocampus is associated with inhibition of seizures and epileptogenesis suggesting that this system may be a valuable target for developing novel antiepileptic treatments.
Vezzani
A
A
Department of Neurosciences, Istituo di Richerche Farmacologie Mario Negri, Milan, Italy. vezzani@marionegri.it
Michalkiewicz
M
M
Michalkiewicz
T
T
Moneta
D
D
Ravizza
T
T
Richichi
C
C
Aliprandi
M
M
Mulé
F
F
Pirona
L
L
Gobbi
M
M
Schwarzer
C
C
Sperk
G
G
D000818:Animals; D030801:Animals, Genetically Modified; D004558:Electric Stimulation; D004569:Electroencephalography / Q000187:drug effects; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism* / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000187:drug effects / Q000235:genetics; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000235:genetics*
D018690:Excitatory Amino Acid Agonists; D009478:Neuropeptide Y; D012333:RNA, Messenger