Zaitsev Aleksey V, Kim Kira Kh, Vasilev Dmitry S, Lukomskaya Nera Ya, Lavrentyeva Valeria V, Tumanova Natalia L, Zhuravin Igor A, Magazanik Lev G
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia.
J Neurosci Res. 2015 Mar;93(3):454-65. doi: 10.1002/jnr.23500. Epub 2014 Oct 31.
Alterations in inhibitory and excitatory neurotransmission play a central role in the etiology of epilepsy, with overstimulation of glutamate receptors influencing epileptic activity and corresponding neuronal damage. N-methyl-D-aspartate (NMDA) receptors, which belong to a class of ionotropic glutamate receptors, play a primary role in this process. This study compared the anticonvulsant properties of two NMDA receptor channel blockers, memantine and 1-phenylcyclohexylamine (IEM-1921), in a pentylenetetrazole (PTZ) model of seizures in rats and investigated their potencies in preventing PTZ-induced morphological changes in the brain. The anticonvulsant properties of IEM-1921 (5 mg/kg) were more pronounced than those of memantine at the same dose. IEM-1921 and memantine decreased the duration of convulsions by 82% and 37%, respectively. Both compounds were relatively effective at preventing the tonic component of seizures but not myoclonic seizures. Memantine significantly reduced the lethality caused by PTZ-induced seizures from 42% to 11%, and all animals pretreated with IEM-1921 survived. Morphological examination of the rat brain 24 hr after administration of PTZ revealed alterations in the morphology of 20-25% of neurons in the neocortex and the hippocampus, potentially induced by excessive glutamate. The expression of the excitatory amino acid transporter 1 protein was increased in the hippocampus of the PTZ-treated rats. However, dark neurons did not express caspase-3 and were immunopositive for the neuronal nuclear antigen protein, indicating that these neurons were alive. Both NMDA antagonists prevented neuronal abnormalities in the brain. These results suggest that NMDA receptor channel blockers might be considered possible neuroprotective agents for prolonged seizures or status epilepticus leading to neuronal damage.
抑制性和兴奋性神经传递的改变在癫痫病因中起核心作用，谷氨酸受体的过度刺激会影响癫痫活动及相应的神经元损伤。N-甲基-D-天冬氨酸（NMDA）受体属于离子型谷氨酸受体，在这一过程中起主要作用。本研究比较了两种NMDA受体通道阻滞剂美金刚和1-苯基环己胺（IEM-1921）在大鼠戊四氮（PTZ）癫痫模型中的抗惊厥特性，并研究了它们预防PTZ诱导的脑形态学变化的效力。在相同剂量下，IEM-1921（5mg/kg）的抗惊厥特性比美金刚更显著。IEM-1921和美金刚分别将惊厥持续时间缩短了82%和37%。两种化合物在预防癫痫强直成分方面相对有效，但对肌阵挛性癫痫无效。美金刚显著降低了PTZ诱导的癫痫致死率，从42%降至11%，所有用IEM-1921预处理的动物均存活。给予PTZ后24小时对大鼠脑进行形态学检查发现，新皮质和海马中20%-25%的神经元形态发生改变，可能是由过量谷氨酸诱导的。PTZ处理大鼠海马中兴奋性氨基酸转运体1蛋白的表达增加。然而，深色神经元不表达半胱天冬酶-3，对神经元核抗原蛋白呈免疫阳性，表明这些神经元存活。两种NMDA拮抗剂均能预防脑内神经元异常。这些结果表明，NMDA受体通道阻滞剂可能被认为是用于预防导致神经元损伤的长时间癫痫发作或癫痫持续状态的潜在神经保护剂。
