Department of Pharmacology, School of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.
Institute of Physiology I, Westfälische Wilhelms-University, Münster, Germany.
Epilepsy Behav. 2020 Oct;111:107251. doi: 10.1016/j.yebeh.2020.107251. Epub 2020 Jun 25.
Ziconotide (ω-conotoxin MVIIA peptide) is a novel analgesic agent acting on voltage-gated calcium channels and is administered intrathecally for neuropathic pain. While antiepileptic activities of other types of calcium channel blockers (T- or L-type) are well established, there is no information regarding the effect of ziconotide as an N-type calcium channel antagonist in pentylenetetrazol-induced seizures or its anxiolytic and sedative activities. The present study is the first to report on these effects.
To evaluate the anticonvulsant activity of ziconotide in the pentylenetetrazol (60 mg/kg) seizure model, ziconotide was administered intracerebroventricular (i.c.v.) as a single dose (1 μg/rat) or repeatedly (chronic administration: 0.1, 0.3, or 1 μg/rat once a day for seven days). The anxiolytic and sedative actions of ziconotide were evaluated with the elevated plus maze, light/dark (LD) box, and pentobarbital-induced sleep tests. Immediately after behavioral testing, the amygdala was completely removed bilaterally to determine corticosterone levels by immunoassay.
In all dosing regimens, ziconotide significantly decreased the seizure frequency and also delayed the latency period compared with control. Chronic administration affected the percentage of mortality protection, while a single dose of ziconotide did not. In behavioral tests, ziconotide significantly increased both the number of entries and the percentage of time spent in the open arms of the elevated plus maze. Furthermore, ziconotide significantly increased the latency period and the number of entries into the light compartment during the LD box examination. Chronic administration of ziconotide significantly reduced the latency to sleep and increased sleeping time, whereas these parameters were not affected by a single dose. Additionally, amygdala corticosterone levels were significantly decreased in rats treated with ziconotide compared with control.
Ziconotide displays beneficial neurobehavioral effects in a model of epilepsy with anxiety as its comorbid event. It seems that at least one of the mechanisms involved in these effects is associated with a decrease in brain corticosterone levels. The main advantage of ziconotide over benzodiazepines (routine anxiolytic and sedative drugs) is that it does not cause tolerance, dependency, and addiction. Therefore, more than ever, it is necessary to improve the convenience of drug delivery protocols and attenuate the adverse effects associated with ziconotide-based therapies.
Ziconotide（ω-conotoxin MVIIA 肽）是一种新型的痛觉调制药物，通过鞘内给药治疗神经性疼痛。虽然其他类型的钙通道阻滞剂（T 或 L 型）的抗癫痫活性已得到充分证实，但关于 Ziconotide 作为 N 型钙通道拮抗剂在戊四氮诱导的癫痫发作中的作用，以及其抗焦虑和镇静作用的信息尚属空白。本研究首次报道了这些作用。
为了评估 Ziconotide 在戊四氮（60mg/kg）癫痫模型中的抗惊厥活性，将 Ziconotide 单次鞘内给药（1μg/大鼠）或重复给药（慢性给药：0.1、0.3 或 1μg/大鼠，每天一次，共 7 天）。通过高架十字迷宫、明暗（LD）箱和戊巴比妥诱导的睡眠试验评估 Ziconotide 的抗焦虑和镇静作用。行为测试结束后，立即双侧完全切除杏仁核，通过免疫测定法测定皮质酮水平。
在所有给药方案中，与对照组相比，Ziconotide 均显著降低了癫痫发作频率，并延迟了潜伏期。慢性给药影响死亡率保护的百分比，而单次剂量的 Ziconotide 则没有影响。在行为测试中，Ziconotide 显著增加了高架十字迷宫的进入次数和开放臂停留时间的百分比。此外，Ziconotide 显著延长了 LD 箱检查中进入亮室的潜伏期和进入次数。慢性给予 Ziconotide 可显著缩短睡眠潜伏期并增加睡眠时间，而单次剂量则不会影响这些参数。此外，与对照组相比，用 Ziconotide 治疗的大鼠的杏仁核皮质酮水平显著降低。
Ziconotide 在伴有焦虑的癫痫模型中表现出有益的神经行为作用。似乎这些作用的至少一种机制与大脑皮质酮水平的降低有关。与苯二氮䓬类药物（常规抗焦虑和镇静药物）相比，Ziconotide 的主要优势在于它不会产生耐受性、依赖性和成瘾性。因此，比以往任何时候都更需要改进药物输送方案的便利性，并减轻与 Ziconotide 为基础的治疗相关的不良反应。
