Safar Marwa M, Abdallah Dalaal M, Arafa Nadia M, Abdel-Aziz Mohamed T
Departments of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Brain Res. 2010 Jun 2;1334:58-64. doi: 10.1016/j.brainres.2010.03.076. Epub 2010 Mar 28.
N-methyl-d-aspartate (NMDA) receptor antagonists appear to enhance the anticonvulsant activity of antiepileptic drugs in several models of epilepsy. Therefore, the current study evaluates the modulatory effect of magnesium (Mg(2+)), a non-competitive NMDA receptor antagonist, on a subprotective dose of valproate (VPA) against pentylenetetrazol (PTZ)-induced convulsions. Male Wister rats received either saline or PTZ (60mg/kg, i.p.). The other three groups were pretreated with Mg(2+) (40mg/kg, p.o., 4weeks), single subprotective dose of VPA (100mg/kg, i.p.), or Mg(2+) with VPA, before PTZ injection. PTZ provoked clonic convulsions, reduced GABA content, deranged brain redox status, and elevated nitric oxide (NO). Neither the subprotective dose of VPA nor Mg(2+) alone guarded against clonic seizures invoked by PTZ, an effect that was achieved only by their combination and supported by a significant delay in seizure latency. Moreover, VPA leveled off glycine and aspartate, exerted no effect on glutamate, and unexpectedly reduced GABA and taurine levels. Mg(2+) alone or in combination showed the same pattern on the aforementioned amino acids, except for taurine. All regimens restored glutathione (GSH) and total antioxidant capacity (TAC); however, only VPA normalized NO level. This study demonstrates that Mg(2+) could enhance the antiepileptic efficacy of a subprotective dose of VPA, possibly by improving redox balance and modulation of some brain amino acids.
N-甲基-D-天冬氨酸（NMDA）受体拮抗剂似乎能在多种癫痫模型中增强抗癫痫药物的抗惊厥活性。因此，本研究评估了非竞争性NMDA受体拮抗剂镁（Mg(2+)）对亚保护剂量丙戊酸盐（VPA）抗戊四氮（PTZ）诱导惊厥的调节作用。雄性Wistar大鼠分别接受生理盐水或PTZ（60mg/kg，腹腔注射）。另外三组在注射PTZ前，分别用Mg(2+)（40mg/kg，口服，4周）、单次亚保护剂量的VPA（100mg/kg，腹腔注射）或Mg(2+)与VPA预处理。PTZ引发阵挛性惊厥，降低GABA含量，扰乱脑氧化还原状态，并升高一氧化氮（NO）水平。单独使用亚保护剂量的VPA或Mg(2+)均不能预防PTZ引发的阵挛性惊厥，只有它们联合使用才能达到这一效果，且惊厥潜伏期显著延长支持了这一结果。此外，VPA使甘氨酸和天冬氨酸水平趋于平稳，对谷氨酸无影响，且意外地降低了GABA和牛磺酸水平。单独使用Mg(2+)或联合使用时，除牛磺酸外，对上述氨基酸的影响模式相同。所有给药方案均恢复了谷胱甘肽（GSH）和总抗氧化能力（TAC）；然而，只有VPA使NO水平恢复正常。本研究表明，Mg(2+)可能通过改善氧化还原平衡和调节某些脑内氨基酸来增强亚保护剂量VPA的抗癫痫疗效。
