■含α6亚基的GABAA受体(α6GABAAR)在三叉神经节(TG)中高度表达,三叉神经血管系统(TGVS)的感觉中枢。据报道,TG中的低GABA能传递有助于偏头痛相关的行为和组织病理学表型。以前,我们发现化合物6,一种α6GABAAR选择性正变构调节剂(PAM),在辣椒素诱导的偏头痛模拟模型中,TGVS激活诱导的外周和中枢敏化显著减轻。
■这里,我们测试了化合物6的氘代类似物,即DK-1-56-1和RV-I-29是否具有比母体化合物更长的半衰期,可以在同一模型中发挥相似的治疗效果。TGVS的激活是由雄性Wistar大鼠的胸骨内(i.c.)滴注辣椒素触发的。中央,i.c.辣椒素增加了三叉神经宫颈复合体(TCC)中c-Fos免疫反应性(c-Fos-ir)神经元的数量。外围,它增加了TG中降钙素基因相关肽免疫反应性(CGRP-ir),并导致CGRP释放,导致硬脑膜CGRP耗竭。
■DK-I-56-1和RV-I-29,腹膜内(腹膜内)给药,显着改善了TCC神经元的激活,TGCGRP-ir标高,辣椒素诱导的硬脑膜CGRP耗竭,DK-I-56-1显示更好的疗效。3mg/kgDK-I-56-1的治疗效果与30mg/kg托吡酯的治疗效果相当。值得注意的是,静脉注射呋塞米,一种不可渗透血脑屏障的α6GABAAR选择性拮抗剂,防止DK-I-56-1和RV-I-29的影响。最后,口服DK-I-56-1具有类似的药理作用。
■这些结果表明,DK-I-56-1是新型偏头痛药物治疗的有希望的候选药物,通过正向调节TGα6GABAAR抑制TGVS激活,具有相对有利的药代动力学特性。
UNASSIGNED: The α6 subunit-containing GABAA receptors (α6GABAARs) are highly expressed in the trigeminal ganglia (TG), the sensory hub of the trigeminovascular system (TGVS). Hypo-GABAergic transmission in the TG was reported to contribute to migraine-related behavioral and histopathological phenotypes. Previously, we found that Compound 6, an α6GABAAR-selective positive allosteric modulator (PAM), significantly alleviated TGVS activation-induced peripheral and central sensitization in a capsaicin-induced migraine-mimicking model.
UNASSIGNED: Here, we tested whether the deuterated analogues of Compound 6, namely DK-1-56-1 and RV-I-29, known to have longer half-lives than the parent compound, can exert a similar therapeutic effect in the same model. The activation of TGVS was triggered by intra-cisternal (i.c.) instillation of capsaicin in male Wistar rats. Centrally, i.c. capsaicin increased the quantity of c-Fos-immunoreactive (c-Fos-ir) neurons in the trigeminal cervical complex (TCC). Peripherally, it increased the calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG, and caused CGRP release, leading to CGRP depletion in the dura mater.
UNASSIGNED: DK-I-56-1 and RV-I-29, administered intraperitoneally (i.p.), significantly ameliorated the TCC neuronal activation, TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin, with DK-I-56-1 demonstrating better efficacy. The therapeutic effects of 3 mg/kg DK-I-56-1 are comparable to that of 30 mg/kg topiramate. Notably, i.p. administered furosemide, a blood-brain-barrier impermeable α6GABAAR-selective antagonist, prevented the effects of DK-I-56-1 and RV-I-29. Lastly, orally administered DK-I-56-1 has a similar pharmacological effect.
UNASSIGNED: These results suggest that DK-I-56-1 is a promising candidate for novel migraine pharmacotherapy, through positively modulating TG α6GABAARs to inhibit TGVS activation, with relatively favourable pharmacokinetic properties.