Singh Ekta, Pillai Krishna K, Mehndiratta ManMohan
Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, India.
Basic Clin Pharmacol Toxicol. 2014 Nov;115(5):373-8. doi: 10.1111/bcpt.12238. Epub 2014 Apr 26.
The aims of this study were to characterize a lamotrigine-resistant kindled model of epilepsy in mice, to study the anticonvulsant effect of carbamazepine (CBZ) and valproic acid (VPA), and to probe into the mechanism for resistance. Swiss albino mice were kindled by a subconvulsive dose of pentylenetetrazole (PTZ, 30 mg/kg, i.p., every other day for 6 weeks). The mice were pre-treated (30 min.) either with a low dose of LTG (5 mg/kg, i.p.) or with vehicle, and the seizures were scored. The acute treatment with LTG (15 mg/kg, i.p.) on the last day blocked seizure in the vehicle-treated group, but the LTG pre-treated group showed resistance. This resistance was extended to CBZ, but not to VPA. The resistant model was successfully replicated in mice with less kindling development time (6 weeks versus 9 weeks 5 days in rats). A highly significant decrease in the level of histamine (p < 0.001) was found, and there were also decreases in serotonin, GABA and AChE levels (p < 0.05). A significantly low level of histamine correlates with drug resistance and indicates involvement of the H1/H3 receptors. It is suggested that the selective action on voltage-gated Na(+) and Ca(2+) channels could explain the differences in the sensitivity of CBZ and VPA.
本研究的目的是表征小鼠中对拉莫三嗪耐药的点燃癫痫模型，研究卡马西平（CBZ）和丙戊酸（VPA）的抗惊厥作用，并探究耐药机制。将瑞士白化小鼠用亚惊厥剂量的戊四氮（PTZ，30mg/kg，腹腔注射，隔天一次，共6周）点燃。小鼠在给药前（30分钟）分别用低剂量的拉莫三嗪（LTG，5mg/kg，腹腔注射）或溶剂预处理，然后对癫痫发作进行评分。在最后一天用LTG（15mg/kg，腹腔注射）进行急性治疗可阻断溶剂处理组的癫痫发作，但LTG预处理组表现出耐药性。这种耐药性扩展至CBZ，但不涉及VPA。在点燃发育时间较短的小鼠（6周，而大鼠为9周5天）中成功复制了耐药模型。发现组胺水平显著降低（p<0.001），血清素、GABA和乙酰胆碱酯酶水平也降低（p<0.05）。组胺水平显著降低与耐药性相关，并表明H1/H3受体参与其中。提示对电压门控性Na(+)和Ca(2+)通道的选择性作用可以解释CBZ和VPA敏感性的差异。
