McLean M J, Gupta R C, Dettbarn W D, Wamil A W
Department of Neurology, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232.
Toxicol Appl Pharmacol. 1992 Jan;112(1):95-103. doi: 10.1016/0041-008x(92)90284-y.
Male Sprague-Dawley rats injected sc with a single sublethal dose of the organophosphate nerve agent, soman (100 micrograms/kg), had motor limbic seizures within 5-15 min. Pretreatment with a single dose of memantine HCl (MEM, 18 mg/kg, sc), alone or in combination with atropine sulfate (ATS, 16 mg/kg, sc), before soman prevented seizures without sedation or ataxia. Rats appeared normal or demonstrated increased exploratory activity. Excessive salivation, a peripheral manifestation of soman intoxication, was decreased by ATS, but pretreatment with ATS alone did not prevent seizures. After seizure onset, MEM +/- ATS, but not ATS, abolished seizures. Acetylcholinesterase (AChE) activity in several brain regions (cortex, stem, striatum, and hippocampus) was markedly reduced by soman, but not by MEM, ATS, or MEM + ATS. Preadministration of MEM + ATS in vivo significantly protected AChE from inhibition by soman. Memantine reduced inhibition of AChE activity in crude brain homogenates by soman, but not by edrophonium (anionic site inhibitor) or decamethonium (peripheral site inhibitor). Thus, MEM may bind to a different modulatory site, not yet characterized, to protect AChE. When given after onset of soman-induced seizures, treatment with MEM +/- ATS did not reactivate AChE although seizures were controlled, suggesting additional anticonvulsant mechanisms of action. At concentrations (10(-4) to 5 x 10(-4) M) which did not significantly alter the spontaneous firing of action potentials (APs), MEM limited sustained high frequency repetitive firing (SRF) induced by depolarization of spinal cord (mouse and rat) and neocortical (mouse) neurons in monolayer-dissociated cell culture. In the same range of concentrations, ATS both limited SRF and suppressed spontaneous activity, suggesting toxicity. In addition, MEM and ATS reversibly produced use-dependent block of depolarizing responses to acetylcholine (ACh) applied by pressure ejection to spinal cord neurons. Thus, the anticonvulsant efficacy of MEM, with or without ATS, may have resulted from a combination of actions, including protection of AChE from inhibition by soman, limitation of high frequency firing of APs, and blockade of excitatory postsynaptic responses to ACh.
给雄性Sprague-Dawley大鼠皮下注射单剂量亚致死量的有机磷酸酯类神经毒剂梭曼（100微克/千克）后，5 - 15分钟内出现肢体运动性边缘叶癫痫发作。在注射梭曼前，单独给予单剂量盐酸美金刚（MEM，18毫克/千克，皮下注射）或与硫酸阿托品（ATS，16毫克/千克，皮下注射）联合使用，可预防癫痫发作，且无镇静或共济失调现象。大鼠表现正常或探索活动增加。ATS可减少梭曼中毒的外周表现——流涎过多，但单独使用ATS预处理不能预防癫痫发作。癫痫发作后，MEM +/- ATS可终止癫痫发作，但ATS单独使用无效。梭曼可显著降低多个脑区（皮质、脑干、纹状体和海马体）的乙酰胆碱酯酶（AChE）活性，但MEM、ATS或MEM + ATS则无此作用。在体内预先给予MEM + ATS可显著保护AChE免受梭曼抑制。美金刚可减少梭曼对粗脑匀浆中AChE活性的抑制，但对依酚氯铵（阴离子位点抑制剂）或十烃季铵（外周位点抑制剂）则无此作用。因此，MEM可能与一个尚未明确的不同调节位点结合，以保护AChE。在梭曼诱导的癫痫发作开始后给予MEM +/- ATS治疗，尽管癫痫发作得到控制，但AChE并未重新激活，提示存在其他抗惊厥作用机制。在浓度为10⁻⁴至5×10⁻⁴ M时，MEM对单层解离细胞培养的脊髓（小鼠和大鼠）和新皮质（小鼠）神经元去极化诱导的持续高频重复放电（SRF）有抑制作用，但对动作电位（AP）的自发放电无显著影响。在相同浓度范围内，ATS既能抑制SRF，又能抑制自发放电，提示有毒性。此外，MEM和ATS可对脊髓神经元通过压力喷射施加的乙酰胆碱（ACh）去极化反应产生可逆的使用依赖性阻断。因此，MEM无论有无ATS的抗惊厥效果，可能是多种作用的组合，包括保护AChE免受梭曼抑制、限制AP的高频放电以及阻断对ACh的兴奋性突触后反应。
