Metcalf Cameron S, Klein Brian D, McDougle Daniel R, Zhang Liuyin, Kaufmann Dan, Bulaj Grzegorz, White H Steve
Department of Pharmacology & Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah, U.S.A.
NeuroAdjuvants, Inc., Salt Lake City, Utah, U.S.A.
Epilepsia. 2017 Feb;58(2):239-246. doi: 10.1111/epi.13647. Epub 2017 Jan 18.
Potential clinical utility of galanin or peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia due to galanin receptor subtype 1 (GalR1) activation. NAX 810-2, a galanin receptor subtype 2 (GalR2)-preferring galanin analog, possesses 15-fold greater affinity for GalR2 over GalR1 and protects against seizures in the mouse 6 Hz, corneal kindling, and Frings audiogenic seizure models. The purpose of these studies was to further evaluate the preclinical efficacy and pharmacokinetics of NAX 810-2 in mice.
NAX 810-2 was administered by intravenous (i.v.; tail vein, bolus) injection to fully kindled (corneal kindling assay) or naive CF-1 mice (6 Hz assay and pharmacokinetic studies). Plasma NAX 810-2 levels were determined from trunk blood samples. NAX 810-2 was also added to human plasma at various concentrations for determination of plasma protein binding.
In the mouse corneal kindling model, NAX 810-2 dose-dependently blocked seizures following intravenous administration (median effective dose [ED ], 0.5 mg/kg). In the mouse 6 Hz (32 mA) seizure model, it was demonstrated that NAX 810-2 dose-dependently blocked seizures following bolus administration (0.375-1.5 mg/kg, i.v.; ED , 0.7 mg/kg), with a time-to-peak effect of 0.5 h posttreatment. Motor impairment was observed at 1.5 mg/kg, i.v., whereas one-half of this dose, 0.75 mg/kg, i.v., was maximally effective in the 6 Hz test. Plasma levels of NAX 810-2 show linear pharmacokinetics following intravenous administration and a half-life of 1.2 h. Functional agonist activity studies demonstrate that NAX 810-2 effectively activates GalR2 at therapeutic concentrations.
These studies further suggest the potential utility of NAX 810-2 as a novel therapy for epilepsy.
甘丙肽或其肽类似物的潜在临床应用受到代谢稳定性差、缺乏脑渗透性以及因甘丙肽受体亚型1（GalR1）激活导致高血糖的阻碍。NAX 810-2是一种优先作用于甘丙肽受体亚型2（GalR2）的甘丙肽类似物，对GalR2的亲和力比对GalR1高15倍，并且在小鼠6赫兹、角膜点燃和弗林斯听源性癫痫模型中可预防癫痫发作。这些研究的目的是进一步评估NAX 810-2在小鼠中的临床前疗效和药代动力学。
通过静脉内（尾静脉，推注）注射将NAX 810-2给予完全点燃的（角膜点燃试验）或未处理的CF-1小鼠（6赫兹试验和药代动力学研究）。从躯干血样中测定血浆NAX 810-2水平。还将不同浓度的NAX 810-2添加到人体血浆中以测定血浆蛋白结合情况。
在小鼠角膜点燃模型中，静脉注射后NAX 810-2剂量依赖性地阻断癫痫发作（半数有效剂量[ED]，0.5毫克/千克）。在小鼠6赫兹（32毫安）癫痫模型中，证明推注给药（0.375 - 1.5毫克/千克，静脉内；ED，0.7毫克/千克）后NAX 810-2剂量依赖性地阻断癫痫发作，治疗后达到峰值效应的时间为0.5小时。静脉注射1.5毫克/千克时观察到运动障碍，而该剂量的一半，即静脉注射0.75毫克/千克，在6赫兹试验中效果最佳。静脉注射后NAX 810-2的血浆水平呈现线性药代动力学，半衰期为1.2小时。功能激动剂活性研究表明，NAX 810-2在治疗浓度下可有效激活GalR2。
这些研究进一步表明NAX 810-2作为一种新型癫痫治疗药物的潜在应用价值。
