Department of Pediatrics, Bldg. D, Room 285, Georgetown University Medical Center, 3900 Reservoir Rd, NW, Washington, DC 20057, USA.
Brain Res Bull. 2013 Jan;90:52-7. doi: 10.1016/j.brainresbull.2012.09.007. Epub 2012 Sep 17.
The Na⁺/Ca²⁺ exchanger (NCX) is thought to play an important role in the pathogenesis of pentylenetetrazole (PTZ)-induced tonic flexion in mice. Here, I investigated the expression of PTZ-induced generalized clonic and tonic-clonic seizures in rats, using two potent NCX reverse mode inhibitors, KB-R7943 and SN-6 for NCX subtypes 3 (NCX3) and 1 (NCX1), respectively. Pretreatment with KB-R7943 (3, 10, and 30 mg/kg; p.o.) significantly reduced the expression of PTZ-induced generalized seizures with clonic and tonic-clonic components in 12-62% and 25-62% of the treated animals, respectively. In the remaining animals that exhibited seizures, KB-R7943 (3 mg/kg; p.o.) pretreatment significantly delayed the onset of the first seizure episode and reduced the seizure severity. Following pretreatment with SN-6 (0.3, 1, 3, 10, and 30 mg/kg; p.o.), clonic and tonic-clonic PTZ-induced generalized seizures were reduced in 25-50% and 38-63% of treated animals, respectively. SN-6 (0.3, 1, and 3 mg/kg; p.o.) also significantly reduced PTZ-induced seizure severity scores, but did not alter seizure latencies. KB-R7943 (3 and 30 mg/kg; p.o.) or SN-6 (3 and 30 mg/kg; p.o.) administration potentiated the sub-anticonvulsant dose of diazepam (2.5 mg/kg; i.p.) that suppresses clonic and tonic-clonic PTZ-induced seizures. These findings suggested that Ca²⁺ influx via the NCX in reverse mode contributes to a neuronal hyperexcitability that leads to clonic and tonic-clonic generalized seizures and that the NCX1 and NCX3 isoforms may serve as novel molecular targets for seizure suppression.
钠离子/钙离子交换器（NCX）被认为在戊四氮（PTZ）诱导的小鼠强直性屈肌痉挛发病机制中发挥重要作用。在这里，我使用两种有效的 NCX 反向模式抑制剂 KB-R7943 和 SN-6（分别用于 NCX 亚型 3（NCX3）和 1（NCX1）），研究了 PTZ 诱导的大鼠全面强直阵挛性发作和强直阵挛性发作的表达。KB-R7943（3、10 和 30 mg/kg；口服）预处理可显著降低具有阵挛和强直阵挛成分的 PTZ 诱导的全面发作在 12-62%和 25-62%的治疗动物中的表达，分别。在表现出发作的其余动物中，KB-R7943（3 mg/kg；口服）预处理可显著延迟首次发作的发作时间，并降低发作严重程度。SN-6（0.3、1、3、10 和 30 mg/kg；口服）预处理后，25-50%和 38-63%的治疗动物的强直阵挛性全面发作减少。SN-6（0.3、1 和 3 mg/kg；口服）也显著降低了 PTZ 诱导的发作严重程度评分，但不改变发作潜伏期。KB-R7943（3 和 30 mg/kg；口服）或 SN-6（3 和 30 mg/kg；口服）给药增强了抑制阵挛和强直阵挛性 PTZ 诱导发作的亚抗惊厥剂量地西泮（2.5 mg/kg；腹腔内）。这些发现表明，通过反向模式的 NCX 进入的 Ca²⁺内流有助于导致阵挛和强直阵挛性全面发作的神经元过度兴奋，并且 NCX1 和 NCX3 同工型可能作为抑制发作的新的分子靶标。
