Vezzani A, Moneta D, Mulé F, Ravizza T, Gobbi M, French-Mullen J
Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano, Italy.
Epilepsia. 2000;41 Suppl 6:S115-21. doi: 10.1111/j.1528-1157.2000.tb01569.x.
Neuropetide Y (NPY)-mediated neurotransmission in the hippocampus is altered by limbic seizures. The functional consequences of this change are still unresolved and clearly depend on the type of NPY receptors involved. NPY Y2 and Y1 receptors are increased on mossy fiber terminals and decreased on granule cell dendrites after seizures, respectively. We investigated (a) whether seizures modify the NPY Y5 receptors in the hippocampus, and (b) the effect of an agonist at Y2/Y5 receptors and antagonists at Y1 receptors on acute and chronic seizure susceptibility.
Limbic seizures were induced in rats by electrical stimulation of the dorsal hippocampus, leading to stage 5 kindled seizures, or by intrahippocampal or systemic injections of kainic acid. Pentylentetrazol was administered to epileptic rats to assess their enhanced susceptibility to seizures. NPY Y5 receptor protein was measured in hippocampal homogenates using a specific polyclonal antibody and quantitative Western blotting.
Y5 receptors (57-kD band) were transiently decreased (23 to 35%) in all hippocampal subregions 2 and 7 days, but not 2.5 hours, after seizures induced by systemic kainic acid. A minor band of 51 kD was reduced significantly in CA3 and dentate gyrus, although it was increased in CA1, 30 days after seizures, suggesting long-term posttranslational changes in this protein. NPY Y5 receptors were increased by 200% in total homogenate from the stimulated hippocampus 2 days but not 30 days after fully kindled seizures. Intracerebral injections of NPY 13-36 (Y2/Y5 receptor agonist) or BIBP 3225 and BIBO 3304 (selective Y1 receptor antagonists) decreased seizure susceptibility in rats.
These results indicate that NPY Y5 receptors change after limbic seizures and suggest that NPY receptors may provide novel target(s) for the treatment of epilepsy.
边缘性癫痫发作可改变海马中神经肽Y（NPY）介导的神经传递。这种变化的功能后果仍未解决，显然取决于所涉及的NPY受体类型。癫痫发作后，苔藓纤维终末上的NPY Y2受体增加，颗粒细胞树突上的NPY Y1受体减少。我们研究了（a）癫痫发作是否会改变海马中的NPY Y5受体，以及（b）Y2/Y5受体激动剂和Y1受体拮抗剂对急性和慢性癫痫易感性的影响。
通过电刺激大鼠背侧海马诱发边缘性癫痫发作，导致5期点燃癫痫发作，或通过海马内或全身注射 kainic 酸。向癫痫大鼠注射戊四氮以评估其对癫痫发作易感性的增强。使用特异性多克隆抗体和定量蛋白质免疫印迹法测量海马匀浆中的NPY Y5受体蛋白。
全身注射 kainic 酸诱发癫痫发作后2天和7天，所有海马亚区的Y5受体（57-kD条带）短暂减少（23%至35%），但在2.5小时后未减少。癫痫发作30天后，CA3和齿状回中51 kD的一条小条带显著减少，尽管CA1中增加，表明该蛋白存在长期翻译后变化。在完全点燃癫痫发作后2天而非30天，受刺激海马的总匀浆中NPY Y5受体增加了200%。脑内注射NPY 13-36（Y2/Y5受体激动剂）或BIBP 3225和BIBO 3304（选择性Y1受体拮抗剂）可降低大鼠的癫痫易感性。
这些结果表明边缘性癫痫发作后NPY Y5受体发生变化，并提示NPY受体可能为癫痫治疗提供新的靶点。
