Vigabatrin for focal drug delivery in epilepsy: Bilateral microinfusion into the subthalamic nucleus is more effective than intranigral or systemic administration in a rat seizure model
Vigabatrin for focal drug delivery in epilepsy: Bilateral microinfusion into the subthalamic nucleus is more effective than intranigral or systemic administration in a rat seizure model
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DOI：
10.1016/j.nbd.2012.01.017
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发表时间：
2012-05-01
影响因子：
6.1
通讯作者：
Loescher, Wolfgang
中科院分区：
文献类型：
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作者：
Broeer, Sonja;Backofen-Wehrhahn, Bianca;Loescher, Wolfgang
Vigabatrin是一种合理开发的抗癫痫药物，其作用是通过不可逆地抑制GABA的降解来增加大脑中GABA的水平。然而，它在癫痫中的临床应用受到严重副作用的限制，包括视力下降，这被认为是药物接触视网膜和非癫痫脑区的后果。靶向给药到与癫痫发作产生和传播有关的大脑区域将克服这一问题。先前对大鼠癫痫模型的研究表明，双侧微注射维加巴林到网状黑质（SNr）可以达到抗惊厥作用，SNr是基底节区输出结构，在癫痫发作的调节中起重要作用。在本研究中，我们在大鼠模型中比较了维加巴林在全身和黑质内给药后的抗惊厥疗效，该模型可以通过在个体动物注射药物前后定时静脉输注戊四唑（PTZ）来确定癫痫易感性。此外，由于丘脑下核（STN）通过向基底节区的两个输出核SNr和束内核提供兴奋性谷氨酸能输入，在基底节区流出中起着至关重要的调节作用，我们评估了双侧局灶性向STN递送维加巴林对PTZ发作阈值的影响。在全身（i.p）给予高剂量（600或1200mg /kg）维加巴特林后，观察到癫痫发作阈值显著增加。双侧微注射vigabatrin （10 μ g）到前侧或后侧信信区也增加了癫痫发作阈值，但比全身治疗效果要差。相反，局部注射到信信区比静脉内注射或全身注射vigabatrin更明显地增加了癫痫发作阈值。此外，SIN的局灶抑制与全身治疗相关的严重不良反应无关。数据表明，维加巴特林是一种有趣的癫痫局灶给药物质，与更常用的评价化合物（如muscimol）相比，可能更具优势。(C) 2012爱思唯尔公司版权所有。
Vigabatrin is a rationally developed antiepileptic drug, which acts by increasing GABA levels in the brain by irreversibly inhibiting GABA degradation. However, its clinical use in epilepsy is restricted by severe side effects, including vision loss, which is thought to be a consequence of drug exposure of the retina and nonepileptic brain regions. Targeted delivery into brain regions involved in seizure generation and propagation would overcome this problem. Previous studies in rat models of seizures or epilepsy have shown that anticonvulsant effects can be achieved by bilateral microinjection of vigabatrin into the substantia nigra pars reticulata (SNr), a basal ganglia output structure that plays an important role in the modulation of seizures. In the present study, we compared the anticonvulsant efficacy of vigabatrin after systemic and intranigral administration in a rat model, in which seizure susceptibility can be determined by timed intravenous infusion of pentylenetetrazol (PTZ) before and after drug injection in individual animals. Furthermore, because the subthalamic nucleus (STN) plays a crucial role as a regulator of basal ganglia outflow by providing excitatory glutamatergic input into the two output nuclei of the basal ganglia, SNr and entopeduncular nucleus, we evaluated the effects of bilateral focal delivery of vigabatrin into the STN on PTZ seizure threshold. A significant increase in seizure threshold was observed following systemic (i.p.) administration of high (600 or 1200 mg/kg) doses of vigabatrin. Bilateral microinjection of vigabatrin (10 mu g) into either the anterior or posterior SNr also increased seizure threshold, but less markedly than systemic treatment In contrast, focal delivery into the SIN increased seizure threshold more markedly than either intranigral or systemic administration of vigabatrin. Furthermore, focal inhibition of SIN was not associated with the severe adverse effects associated with systemic treatment The data demonstrate that vigabatrin is an interesting substance for focal drug delivery in epilepsy and may be advantageous compared to more commonly evaluated compounds such as muscimol. (C) 2012 Elsevier Inc. All rights reserved.