Abstracts

RATIONALE: Previous studies have shown that Neuropeptide Y (NPY) has anticonvulsant effects through presynaptic effects in hippocampus that depress excitatory synaptic events, without affecting inhibition. Seizures enhance NPY expression, particularly in the frontal pyriform and entorhinal cortices and in the amygdala and hippocampus. We tested the seizure susceptibility of NPY knock-out (KO) mice in different seizure models. We compared 129S6/SvEv NPY(+ / +) and NPY (- / -) mice in the kindling model and as well as the kainate and pilocarpine seizure models. In addition, we determined the anticonvolsant effects of carbamazepine and levetiracetam in kindled NPY (+ / +) and (- / -) mice.
METHODS: A bipolar electrode was stereotaxically implanted into the right amygdala of 129S6/SvEv NPY (+ / +) and 129S6/SvEv NPY (- / -) mice. Mice were given daily stimulations (400 uA, 60 Hz, 1 sec) until at least 10 stage-5 (Racine scale) seizures occurred; behavioral seizure scores and EEG after-discharge (AD) durations were recorded throughout. Post-kindling seizure thresholds and AD durations were determined weekly for 4 weeks. After thresholds stabilized, the anticovulsant effects of carbamazepine (30 mg/kg, IP) and levetiracetam (50 mg/kg, IP) were determined. In chemically-induced seizure models, kainic acid (20 mg/kg, IP) or pilocarpine (100 mg/kg, IP) were injected every 20 minutes until the first limbic seizure. The number of doses and minutes to onsete of limbic seizures were recorded.
RESULTS: During kindling development, the NPY (- / -) mice had more severe behavioral seizure scores and longer AD durations than the NPY (+ / +) mice. However, the differences between the two groups was not large in magnitude. Post-kindling, the NPY (- / -) mice had markedly lower thresholds and longer AD durations than NPY (+ / +) mice (p[lt] 0.0001). Carbamazepine and levetiracetam increased the seizure thresholds of both NPY (- / -) and (+ / +) mice. In addition, NPY KO mice required significantly fewer doses and less time to onset of limbic seizures after both kainic acid and pilocarpine.
CONCLUSIONS: NPY (- / -) mice were more seizure-prone than NPY (+ / +) mice in all seizure models, in agreement with previous investigators. The present results in the kindling model suggest that NPY may play a role in the inhibition of epileptogenesis. In addition, the present results indicate that NPY likely plays a substantial role in the severity of seizures in that both electrically- and chemically-induced seizures were more severe in NPY(-/-) than in NPY(+/+) mice. On the other hand, a lack of NPY does not appear to make seizures drug-resistant in that carbamazepine and levetiracetam were anticonvulsant in both wild type and NPY null mutant mice.
[Supported by: Eli Lilly and Company]; (Disclosure: Salary - Eli Lilly and Company, Equity - Eli Lilly and Company, Stock - Eli Lilly and Company)