Turski L, Ikonomidou C, Turski W A, Bortolotto Z A, Cavalheiro E A
Department of Pharmacology, Medical School, Lublin, Poland.
Synapse. 1989;3(2):154-71. doi: 10.1002/syn.890030207.
High-dose treatment with pilocarpine hydrochloride, a cholinergic muscarinic agonist, induces seizures in rodents following systemic or intracerebral administration. Pilocarpine seizures are characterized by a sequential development of behavioral patterns and electrographic activity. Hypoactivity, tremor, scratching, head bobbing, and myoclonic movements of the limbs progress to recurrent myoclonic convulsions with rearing, salivation, and falling, and status epilepticus. The sustained convulsions induced by pilocarpine are followed by widespread damage to the forebrain. The amygdala, thalamus, olfactory cortex, hippocampus, neocortex, and substantia nigra are the most sensitive regions to epilepsy-related damage following convulsions produced by pilocarpine. Spontaneous seizures are observed in the long-term period following the administration of convulsant doses of pilocarpine. Developmental studies show age-dependent differences in the response of rats to pilocarpine. Seizures are first noted in 7-12 day-old rats, and the adult pattern of behavioral and electroencephalographic sequelae of pilocarpine is seen in 15-21-day-old rats. During the third week of life the rats show an increased susceptibility to the convulsant action of pilocarpine relative to older and younger animals. The developmental progress of the convulsive response to pilocarpine does not correlate with evolution of the brain damage. The adult pattern of the damage is seen after a delay of 1-2 weeks in comparison with the evolution of seizures and status epilepticus. The susceptibility to seizures induced by pilocarpine increases in rats aged over 4 months. The basal ganglia curtail the generation and spread of seizures induced by pilocarpine. The caudate putamen, the substantia nigra, and the entopeduncular nucleus govern the propagation of pilocarpine-induced seizures. The antiepileptic drugs diazepam, clonazepam, phenobarbital, valproate, and trimethadione protect against pilocarpine-induced convulsions, while diphenylhydantoin and carbamazepine are ineffective. Ethosuximide and acetazolamide increase the susceptibility to convulsant action of pilocarpine. Lithium, morphine, and aminophylline also increase the susceptibility of rats to pilocarpine seizures. The pilocarpine seizure model may be of value in designing new therapeutic approaches to epilepsy.
用毒蕈碱型胆碱能激动剂盐酸毛果芸香碱进行高剂量治疗，在全身或脑内给药后可诱导啮齿动物癫痫发作。毛果芸香碱癫痫发作的特征是行为模式和脑电图活动的顺序发展。活动减少、震颤、抓挠、点头和四肢肌阵挛性运动发展为反复的肌阵挛性惊厥，伴有站立、流涎和跌倒，以及癫痫持续状态。毛果芸香碱诱导的持续性惊厥之后是前脑的广泛损伤。杏仁核、丘脑、嗅觉皮层、海马体、新皮层和黑质是毛果芸香碱惊厥后对癫痫相关损伤最敏感的区域。在给予惊厥剂量的毛果芸香碱后的长期观察中可观察到自发性癫痫发作。发育研究表明，大鼠对毛果芸香碱的反应存在年龄依赖性差异。癫痫发作首先在7 - 12日龄的大鼠中出现，而毛果芸香碱的行为和脑电图后遗症的成年模式在15 - 21日龄的大鼠中可见。在出生后的第三周，大鼠相对于年龄较大和较小的动物对毛果芸香碱的惊厥作用表现出更高的易感性。对毛果芸香碱惊厥反应的发育进程与脑损伤的演变不相关。与癫痫发作和癫痫持续状态的演变相比，成年期的损伤模式在延迟1 - 2周后出现。4个月以上的大鼠对毛果芸香碱诱导的癫痫发作的易感性增加。基底神经节可减少毛果芸香碱诱导的癫痫发作的产生和扩散。尾状壳核、黑质和内苍白球控制毛果芸香碱诱导的癫痫发作的传播。抗癫痫药物地西泮、氯硝西泮、苯巴比妥、丙戊酸和三甲双酮可预防毛果芸香碱诱导的惊厥，而苯妥英和卡马西平则无效。乙琥胺和乙酰唑胺增加了对毛果芸香碱惊厥作用的易感性。锂、吗啡和氨茶碱也增加了大鼠对毛果芸香碱癫痫发作的易感性。毛果芸香碱癫痫发作模型可能对设计新的癫痫治疗方法有价值。
