Preclinical activity profile of α-lactoalbumin, a whey protein rich in tryptophan, in rodent models of seizures and epilepsy
Preclinical activity profile of α-lactoalbumin, a whey protein rich in tryptophan, in rodent models of seizures and epilepsy
复制标题
DOI：
10.1016/j.eplepsyres.2011.02.013
复制
发表时间：
2011-06-01
影响因子：
2.2
通讯作者：
Russo, Emilio
中科院分区：
文献类型：
--
作者：
Citraro, Rita;Scicchitano, Francesca;Russo, Emilio
目的：评估 α-乳白蛋白 (ALAC)（一种相对于其他大中性氨基酸 (LNAA) 而言富含色氨酸 (TRP) 的乳清蛋白）在癫痫发作和癫痫啮齿动物模型中的潜在抗惊厥活性。方法：通过标准方案评估口服 ALAC 对遗传性癫痫倾向大鼠 (GEPR-9 大鼠)、最大电击 (MES) 诱导的听源性癫痫发作的作用大鼠癫痫发作、毛果芸香碱诱导的小鼠癫痫发作、暴露于毛果芸香碱诱导的癫痫持续状态 (SE) 的小鼠自发性慢性癫痫发作以及 WAG/Rij 大鼠的失神癫痫发作。在某些模型中，卡马西平 (CBZ) 被用作主动对照。通过 GC-MS 测量血浆 TRP/LNAAs 比率。结果：单剂量 ALAC 高达 500 或 6000 mg/kg 在所有测试模型中均缺乏抗惊厥活性。相反，对 GEPR 大鼠进行 5 天和 12 天的 ALAC（250-1000 mg/kg/天）治疗可降低剂量依赖性癫痫评分并延长阵挛发作的潜伏期，且效果完全持续长达 12 小时。 ALAC（125-500 mg/kg/天，持续 15 天）可防止 250 mg/kg 毛果芸香碱引起的癫痫发作，但对较高剂量的毛果芸香碱诱导的癫痫发作效果较差。与 CBZ 类似，ALAC（125-500 mg/kg/天，持续 15 天）对毛果芸香碱后 SE 模型中的自发性癫痫发作也有效。 ALAC（高达 6000 mg/kg/天，持续 12 天）并不能预防 MES 诱发的癫痫发作，尽管它在 250 至 1000 mg/kg/天的剂量下缩短了强直延长的持续时间。 ALAC 对 WAG/Rij 大鼠的失神发作没有显着影响。服用 ALAC（250 mg/kg/天）7 天和 14 天后，血浆 TRP/LNAAS 比率分别增加 2 至 3 倍。结论：ALAC 对动物模型中的癫痫发作具有显着的保护活性，对于 GEPR-9 大鼠的听源性癫痫发作、小鼠低剂量毛果芸香碱诱导的癫痫发作以及暴露于毛果芸香碱诱导的小鼠自发性癫痫发作的作用尤其显着。 SE。这种作用可能是通过大脑中 TRP 可用性的增加来介导的，从而导致 5-HT 介导的传输增加。 (c) 2011 Elsevier B.V. 保留所有权利。
Purpose: To evaluate the potential anticonvulsant activity of alpha-lactalbumin (ALAC), a whey protein rich in tryptophan (TRP) relative to other large neutral aminoacids (LNAAs), in rodent models of seizures and epilepsy.Methods: The effects of ALAC administered per os were evaluated by standard protocols against audiogenic seizures in Genetic Epilepsy Prone Rats (GEPR-9 rats), maximal electroshock (MES)-induced seizures in rats, pilocarpine-induced seizures in mice, spontaneous chronic seizures in mice exposed to pilocarpine-induced status epilepticus (SE), and absence seizures in WAG/Rij rats. In some models, carbamazepine (CBZ) was included as an active control. Plasma TRP/LNAAs ratios were measured by GC-MS.Results: Single doses of ALAC up to 500 or 6000 mg/kg were devoid of anticonvulsant activity in all models tested. Conversely, 5- and 12-day treatment with ALAC (250-1000 mg/kg/day) in GEPR rats reduced dose-dependently seizure scores and prolonged latency to clonus onset, with full persistence of the effect for up to 12h. ALAC (125-500 mg/kg/day for 15 days) protected against seizures induced by 250 mg/kg pilocarpine, but was less effective against higher pilocarpine doses. Similarly to CBZ, ALAC (125-500 mg/kg/day for 15 days) was also effective against spontaneous seizures in the post-pilocarpine SE model. ALAC (up to 6000 mg/kg/day for 12 days) did not prevent MES-induced seizures, although it reduced the duration of tonic extension at doses between 250 and 1000 mg/kg/day. Absence seizures in WAG/Rij rats were not significantly affected by ALAC. Plasma TRP/LNAAS ratios increased 2- to 3-fold after dosing with ALAC (250 mg/kg/day) for 7 and 14 days, respectively.Conclusions: ALAC exerts significant protective activity against seizures in animal models, the effect being especially prominent against audiogenic seizures in GEPR-9 rats, seizures induced by low-dose pilocarpine in mice, and spontaneous seizures in mice exposed to pilocarpine-induced SE. This action is likely to be mediated by increased availability of TRP in the brain, with a consequent increase in 5-HT mediated transmission. (c) 2011 Elsevier B.V. All rights reserved.