Rapamycin has age-, treatment paradigm-, and model-specific anticonvulsant effects and modulates neuropeptide Y expression in rats.
Rapamycin has age-, treatment paradigm-, and model-specific anticonvulsant effects and modulates neuropeptide Y expression in rats.
复制标题
DOI：
10.1111/j.1528-1167.2012.03674.x
复制
发表时间：
2012-11
期刊：
影响因子：
5.6
通讯作者：
Velíšek L
中科院分区：
文献类型：
--
作者：
Chachua T;Poon KL;Yum MS;Nesheiwat L;DeSantis K;Velíšková J;Velíšek L
雷帕霉素（RAP）具有一定的抗癫痫特性。然而，尚不清楚这些作用是否可以通过 RAP 的抗惊厥作用来解释，尚未进行研究。为了解决这个问题，我们使用不同的癫痫发作模型和治疗范例测试了 RAP 对未成熟和成年大鼠的潜在抗惊厥作用。此外，我们研究了RAP诱导的神经肽Y（NPY）表达的变化，这可能作为RAP作用的间接靶标。采用复杂的方法来评估 RAP 的抗惊厥潜力：我们使用氟噻草、戊四唑 (PTZ)、NMDA 和红藻氨酸 (KA) 诱导的癫痫发作来测试 RAP 在未成熟和成年大鼠中使用不同预处理方案的效果。我们还评估了未成熟大鼠经 RAP 不同预处理后初级运动皮层、海马 CA1 和齿状回 (DG) 内 NPY 的表达。我们发现（1）短期预处理模式下的 RAP 在抑制受损的癫痫模型中具有较弱的抗惊厥潜力。 (2) RAP 功效的缺乏与皮质、CA1 和 DG 中 NPY 表达的降低相关。特别是在未成熟大鼠中，在癫痫发作测试前 4 或 24 小时单剂量 RAP（3 mg/kg）对 PTZ 诱发的癫痫发作具有抗惊厥作用。在氟洛西癫痫发作模型中，仅用 RAP 进行四小时预处理对两个年龄组都具有抗惊厥作用。在未成熟大鼠中测试，用 RAP 进行短期预处理对 NMDA 和 KA 诱导的癫痫发作没有影响。在所有测试的发育大鼠癫痫模型中，八天以上的 RAP 长期预处理并未显示出有益效果。此外，长期用 RAP 预处理对 KA 诱发的癫痫发作有轻微的促惊厥作用。在未成熟大鼠中，任何抗惊厥作用（包括多剂量 RAP 的促惊厥作用）的缺乏都与皮质和 DG 中 NPY 表达的下调有关。在未成熟动物中，延迟 24 小时单剂量 RAP 后，我们发现 CA1 和 DG 中 NPY 表达下降。我们的数据显示，RAP 的年龄、治疗范式和模型特异性抗惊厥作用较弱，并且长期 RAP 预处理后这些作用的丧失与 NPY 表达下调相关。这些发现表明 RAP 是一种较差的抗惊厥药，可能仅对癫痫发生有有益作用。此外，我们的数据对 RAP 对癫痫发作的作用机制提出了新的见解，表明 mTOR 信号传导和 NPY 系统之间可能存在联系。
Rapamycin (RAP) has certain antiepileptogenic features. However, it is unclear whether these effects can be explained by the anticonvulsant action of RAP, which has not been studied yet. To address this question, we tested potential anticonvulsant effects of RAP in immature and adult rats using different seizure models and treatment paradigms. In addition, we studied changes in the expression of neuropeptide Y (NPY) induced by RAP, which may serve as an indirect target of the RAP action. A complex approach was adopted to evaluate the anticonvulsant potential of RAP: We used flurothyl-, pentylenetetrazole (PTZ)-, NMDA-, and kainic acid (KA)-induced seizures to test the effects of RAP using different pretreatment protocols in immature and adult rats. We also evaluated expression of NPY within the primary motor cortex, hippocampal CA1, and dentate gyrus (DG) after different pretreatments with RAP in immature rats. We found that (1) RAP administered with short-term pretreatment paradigms has a weak anticonvulsant potential in the seizure models with compromised inhibition. (2) Lack of RAP efficacy correlates with decreased NPY expression in the cortex, CA1 and DG. Specifically in immature rats, a single dose of RAP (3 mg/kg) four or 24 hrs prior to seizure testing had anticonvulsant effects against PTZ-induced seizures. In the flurothyl seizure model only the four-hour pretreatment with RAP was anticonvulsant in the both age groups. Short-term pretreatments with RAP had no effects against NMDA- and KA-induced seizures tested in immature rats. Long-term pretreatments with RAP over eight days did not show beneficial effect in all tested seizure models in developing rats. Moreover, the long-term pretreatment with RAP had a slight proconvulsant effect on KA-induced seizures. In immature rats, any lack of anticonvulsant effect (including proconvulsant effect of multiple doses of RAP) was associated with downregulation of NPY expression in the cortex and DG. In immature animals, after a single dose of RAP with 24 hrs delay, we found a decrease of NPY expression in CA1 and DG. Our data show a weak age-, treatment paradigm-, and model-specific anticonvulsant effects of RAP as well as loss of those effects after long-term RAP pretreatment associated with downregulation of NPY expression. These findings suggest that RAP is a poor anticonvulsant and may have beneficial effects only against epileptogenesis. In addition, our data present new insights into mechanisms of RAP action on seizures indicating a possible connection between mTOR signaling and NPY system.
登录
查看更多内容
影响因子：
158.5
作者：
Krueger, Darcy A.;Care, Marguerite M.;Franz, David Neal
通讯作者：
Franz, David Neal
影响因子：
56.9
作者：
Cota, D;Proulx, K;Seeley, RJ
通讯作者：
Seeley, RJ
影响因子：
3.5
作者：
Lansky, P;Veliskova, J;Velisek, L
通讯作者：
Velisek, L
影响因子：
2.5
作者：
McDaniel SS;Wong M
通讯作者：
Wong M
影响因子：
2.5
作者：
Huber, KM;Roder, JC;Bear, MF
通讯作者：
Bear, MF