Krahl S E, Clark K B, Smith D C, Browning R A
Neurology Service, West Los Angeles VA Medical Center, California 90073, USA.
Epilepsia. 1998 Jul;39(7):709-14. doi: 10.1111/j.1528-1157.1998.tb01155.x.
Although vagus nerve stimulation (VNS) is now marketed throughout most of the world as a treatment for drug-resistant epilepsy, the therapeutic mechanism of action of VNS-induced seizure suppression has not yet been established. Elucidation of this mechanism is an important first step in the development of strategies to improve VNS efficacy. Because the locus coeruleus (LC) has been implicated in the antinociceptive effects of VNS, we chemically lesioned the LC in the present study to determine if it is a critical structure involved in the anticonvulsant mechanisms of VNS.
Rats were chronically depleted of norepinephrine (NE) by a bilateral infusion of 6-hydroxydopamine (6-OHDA) into the LC. Two weeks later, they were tested with maximal electroshock (MES) to assess VNS-induced seizure suppression. In another experiment, the LC was acutely inactivated with lidocaine, and seizure suppression was tested in a similar fashion.
VNS significantly reduced seizure severities of control rats. However, in animals with chronic or acute LC lesions, VNS-induced seizure suppression was attenuated.
Our data indicate that the LC is involved in the circuitry necessary for the anticonvulsant effects of VNS. Seizure suppression by VNS may therefore depend on the release of NE, a neuromodulator that has anticonvulsant effects. These data suggest that noradrenergic agonists might enhance VNS-induced seizure suppression.
尽管迷走神经刺激（VNS）目前作为耐药性癫痫的一种治疗方法在世界大部分地区上市，但VNS诱导癫痫发作抑制的治疗作用机制尚未明确。阐明这一机制是制定提高VNS疗效策略的重要第一步。由于蓝斑（LC）与VNS的抗伤害感受作用有关，我们在本研究中对LC进行化学损伤，以确定它是否是VNS抗惊厥机制中涉及的关键结构。
通过向LC双侧输注6-羟基多巴胺（6-OHDA）使大鼠长期去甲肾上腺素（NE）耗竭。两周后，对它们进行最大电休克（MES）测试，以评估VNS诱导的癫痫发作抑制情况。在另一项实验中，用利多卡因急性灭活LC，并以类似方式测试癫痫发作抑制情况。
VNS显著降低了对照大鼠的癫痫发作严重程度。然而，在慢性或急性LC损伤的动物中，VNS诱导的癫痫发作抑制作用减弱。
我们的数据表明，LC参与了VNS抗惊厥作用所需的神经回路。因此，VNS诱导的癫痫发作抑制可能依赖于具有抗惊厥作用的神经调质NE的释放。这些数据表明，去甲肾上腺素能激动剂可能增强VNS诱导的癫痫发作抑制作用。
