Department of Neurology University of California, San Francisco San Francisco California.
Department of Neurology University of California, San Francisco San Francisco California; Present address: Department of Oral and Maxillofacial Pathology, Radiology and Medicine New York University College of Dentistry New York City New York.
Ann Clin Transl Neurol. 2016 Jul 1;3(8):560-71. doi: 10.1002/acn3.302. eCollection 2016 Aug.
Many patients suffering from migraine gain little relief from existing treatments partly because many existing acute and preventive therapies used in migraine have been adopted from other neurologic conditions such as depression or epilepsy. Here, we present data supporting a new migraine-specific target, the mGlu5 receptor.
We studied the effect of mGlu5 blockade using ADX10059, on neuronal firing in the trigeminocervical complex (TCC) and durovascular effects of nociceptive trigeminovascular activation in the anesthetized rat. The clinical potential of the mGlu5 mechanism was tested with ADX10059 orally in a double-blind placebo-controlled, parallel group, clinical trial.
The negative allosteric mGlu5 modulator ADX10059 attenuated dural vasodilator responses to meningeal stimulation in a dose-dependent manner, comparable to naratriptan, while the N-methyl-d-aspartate receptor blocker MK-801 had no effect. ADX10059 reduced responses of trigeminocervical neurons to dural stimulation, most strikingly affecting their spontaneous firing rate. Immunostaining identified mGlu5 and not mGlu1a receptors in the TCC. The primary efficacy endpoint for the clinical trial, 2 h pain free, demonstrated a significant effect of ADX10059 375 mg, 17%, versus placebo, 5%. No serious adverse events were reported at the primary dose, with transient dizziness being the most common treatment-emergent event at 48%.
Our findings provide preclinical and clinical proof of concept establishing mGlu5 as a novel therapeutic target in the treatment of migraine. Although ADX10059 is unsuitable as a therapeutic candidate, because of hepatoxicity detected in a subsequent study, the data open a new direction for migraine research and therapy.
许多偏头痛患者从现有治疗中获益甚微，部分原因是偏头痛中使用的许多现有急性和预防性治疗方法是从抑郁症或癫痫等其他神经疾病中采用的。在这里，我们提出了支持新的偏头痛特异性靶点 mGlu5 受体的数据。
我们使用 ADX10059 研究了 mGlu5 阻断对三叉神经颈复合体 (TCC) 神经元放电的影响，以及在麻醉大鼠中伤害性三叉血管激活的杜罗血管效应。我们用 ADX10059 进行了一项双盲安慰剂对照、平行组临床试验，测试了 mGlu5 机制的临床潜力。
负变构 mGlu5 调节剂 ADX10059 以剂量依赖性方式减弱脑膜刺激引起的硬脑膜血管扩张反应，与那拉曲坦相当，而 N-甲基-D-天冬氨酸受体阻滞剂 MK-801 则无作用。ADX10059 降低了三叉神经颈神经元对硬脑膜刺激的反应，最显著的是影响其自发放电率。免疫染色鉴定了 TCC 中的 mGlu5 而不是 mGlu1a 受体。临床试验的主要疗效终点，2 小时无疼痛，显示 ADX10059 375mg 组有显著效果，17%，与安慰剂组 5%相比。主要剂量未报告严重不良事件，最常见的治疗后事件是短暂头晕，发生率为 48%。
我们的研究结果提供了临床前和临床概念验证，确立了 mGlu5 作为偏头痛治疗的新治疗靶点。尽管 ADX10059 由于随后的研究中发现的肝毒性而不适合作为治疗候选物，但这些数据为偏头痛研究和治疗开辟了新的方向。
