Department of Neurology, Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, 050000, Hebei, People's Republic of China.
Neurochem Res. 2023 Sep;48(9):2701-2713. doi: 10.1007/s11064-023-03932-w. Epub 2023 Apr 19.
N-(2-hydroxyethyl) nicotinamide nitrate (nicorandil), a nitrate that activates adenosine triphosphate (ATP)-sensitive potassium (K) channels, is generally used in the treatment of angina and offers long-term cardioprotective effects. It has been reported that several K channel openers can effectively alleviate the symptoms of seizure. The purpose of this study was to investigate the improvement in seizures induced by nicorandil. In this study, seizure tests were used to evaluate the effect of different doses of nicorandil by analysing seizure incidence, including minimal clonic seizure and generalised tonic-clonic seizure. We used a maximal electroshock seizure (MES) model, a metrazol maximal seizure (MMS) model and a chronic pentylenetetrazol (PTZ)-induced seizure model to evaluate the effect of nicorandil in improving seizures. Each mouse in the MES model was given an electric shock, while those in the nicorandil group received 0.5, 1, 2, 3 and 6 mg/kg of nicorandil by intraperitoneal injection, respectively. In the MMS model, the mice in the PTZ group and the nicorandil group were injected subcutaneously with PTZ (90 mg/kg), and the mice in the nicorandil group were injected intraperitoneally with 1, 3 and 5 mg/kg nicorandil, respectively. In the chronic PTZ-induced seizure model, the mice in the PTZ group and the nicorandil group were injected intraperitoneally with PTZ (40 mg/kg), and the mice in the nicorandil group were each given 1 and 3 mg/kg of PTZ at a volume of 200 nL. Brain slices containing the hippocampus were prepared, and cell-attached recording was used to record the spontaneous firing of pyramidal neurons in the hippocampal CA1 region. Nicorandil (i.p.) significantly increased both the maximum electroconvulsive protection rate in the MES model and the seizure latency in the MMS model. Nicorandil infused directly onto the hippocampal CA1 region via an implanted cannula relieved symptoms in chronic PTZ-induced seizures. The excitability of pyramidal neurons in the hippocampal CA1 region of the mice was significantly increased after both the acute and chronic administration of PTZ. To a certain extent, nicorandil reversed the increase in both firing frequency and proportion of burst spikes caused by PTZ (P < 0.05). Our results suggest that nicorandil functions by downregulating the excitability of pyramidal neurons in the hippocampal CA1 region of mice and is a potential candidate for the treatment of seizures.
N-(2-羟乙基)烟酰胺硝酸盐（硝酸尼克酰胺）是一种激活三磷酸腺苷（ATP）敏感性钾（K）通道的硝酸盐，通常用于治疗心绞痛，并具有长期的心脏保护作用。据报道，几种 K 通道开放剂可有效缓解癫痫发作症状。本研究旨在探讨硝酸尼克酰胺对癫痫发作的改善作用。在这项研究中，通过分析癫痫发作的发生率，包括最小阵挛性癫痫发作和全身性强直阵挛性癫痫发作，使用癫痫发作测试来评估不同剂量的硝酸尼克酰胺的效果。我们使用最大电休克癫痫发作（MES）模型、美索比妥最大癫痫发作（MMS）模型和慢性戊四氮（PTZ）诱导的癫痫发作模型来评估硝酸尼克酰胺改善癫痫发作的效果。MES 模型中的每只小鼠均接受电击，而接受腹腔注射 0.5、1、2、3 和 6mg/kg 硝酸尼克酰胺的小鼠分别为硝酸尼克酰胺组。在 MMS 模型中，PTZ 组和硝酸尼克酰胺组的小鼠皮下注射 PTZ（90mg/kg），硝酸尼克酰胺组的小鼠分别腹腔注射 1、3 和 5mg/kg 硝酸尼克酰胺。在慢性 PTZ 诱导的癫痫发作模型中，PTZ 组和硝酸尼克酰胺组的小鼠腹腔注射 PTZ（40mg/kg），硝酸尼克酰胺组的小鼠分别腹腔注射 1 和 3mg/kg，体积为 200nL。制备含有海马的脑切片，并进行细胞贴附记录，以记录海马 CA1 区锥体神经元的自发性放电。腹腔注射硝酸尼克酰胺（i.p.）显著提高了 MES 模型中的最大电惊厥保护率和 MMS 模型中的癫痫发作潜伏期。通过植入的套管直接将硝酸尼克酰胺输注到海马 CA1 区可缓解慢性 PTZ 诱导的癫痫发作。无论是急性还是慢性给予 PTZ 后，小鼠海马 CA1 区锥体神经元的兴奋性均明显增加。在一定程度上，硝酸尼克酰胺逆转了 PTZ 引起的放电频率和爆发尖峰比例的增加（P<0.05）。我们的结果表明，硝酸尼克酰胺通过下调小鼠海马 CA1 区锥体神经元的兴奋性起作用，是治疗癫痫发作的潜在候选药物。
