Elsevier

Neuroscience

Volume 110, Issue 2, 12 March 2002, Pages 237-243
Neuroscience

Seizure susceptibility and epileptogenesis are decreased in transgenic rats overexpressing neuropeptide Y

https://doi.org/10.1016/S0306-4522(01)00581-4Get rights and content

Abstract

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 μg 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.

Section snippets

Experimental animals

NPY transgenic rats (Sprague–Dawley rats, Department of Physiology, West Virginia University, Morgantown, WV, USA) were developed by pronuclear injection of fertilized oocytes with a 14-kb clone of the rat structural NPY gene (Michalkiewicz and Michalkiewicz, 2000). Incorporation of additional (five) copies of the NPY gene resulted in an average increase by 1.3–2.7-fold in NPY concentration in various tissues, including brain as assessed by radioimmunoassay (Michalkiewicz and Michalkiewicz, 2000

Kainate-induced seizures

Preliminary experiments showed that 0.3 μg kainate injected into the lateral ventricle was the lowest convulsant dose causing reproducible EEG seizure activity in 100% of the rats without mortality. Status epilepticus, as defined by behavioral stage 5 seizures and EEG seizures occurring without interruption for at least 30 min, occurred in 75% of rats. This dose of kainate induced degeneration mainly restricted to the CA3 area of the hippocampus, subiculum and layer III of the entorhinal cortex

Discussion

We showed that transgenic rats overexpressing NPY in CA1 pyramidal neurons are less susceptible to limbic seizures induced by kainate and to kindling epileptogenesis than their wild-type littermates.

The observation that NPY transgenic rats had a delayed kindling epileptogenesis is in agreement with pharmacological evidence showing that subchronic NPY infusion in the hippocampus retards kindling acquisition (Reibel et al., 2000). It is interesting to note that kindling progression is

Acknowledgements

This work was supported by NATO CGR.972956, HFSP RG0045/2000-B, the Austrian Scientific Research Funds and NIH HL57921.

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