Department of Ophthalmology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand.
New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand.
Neurotherapeutics. 2017 Oct;14(4):1148-1165. doi: 10.1007/s13311-017-0536-9.
The cis benzopyran compound tonabersat (SB-220453) has previously been reported to inhibit connexin26 expression in the brain by attenuating the p38-mitogen-activated protein kinase pathway. We show here that tonabersat directly inhibits connexin43 hemichannel opening. Connexin43 hemichannels have been called "pathological pores" based upon their role in secondary lesion spread, edema, inflammation, and neuronal loss following central nervous system injuries, as well as in chronic inflammatory disease. Both connexin43 hemichannels and pannexin channels released adenosine triphosphate (ATP) during ischemia in an in vitro ischemia model, but only connexin43 hemichannels contributed to ATP release during reperfusion. Tonabersat inhibited connexin43 hemichannel-mediated ATP release during both ischemia and reperfusion phases, with direct channel block confirmed using electrophysiology. Tonabersat also reduced connexin43 gap junction coupling in vitro, but only at higher concentrations, with junctional plaques internalized and degraded via the lysosomal pathway. Systemic delivery of tonabersat in a rat bright-light retinal damage model (a model for dry age-related macular degeneration) resulted in significantly improved functional outcomes assessed using electroretinography. Tonabersat also prevented thinning of the retina, especially the outer nuclear layer and choroid, assessed using optical coherence tomography. We conclude that tonabersat, already given orally to over 1000 humans in clinical trials (as a potential treatment for, and prophylactic treatment of, migraine because it was thought to inhibit cortical spreading depression), is a connexin hemichannel inhibitor and may have the potential to be a novel treatment of central nervous system injury and chronic neuroinflammatory disease.
顺式苯并吡喃化合物托纳布沙（SB-220453）先前已被报道通过减弱 p38-丝裂原活化蛋白激酶通路来抑制脑内连接蛋白 26 的表达。我们在此表明，托纳布沙可直接抑制连接蛋白 43 半通道的开放。连接蛋白 43 半通道因其在中枢神经系统损伤后继发性病变扩散、水肿、炎症和神经元丢失以及慢性炎症性疾病中的作用而被称为“病理性孔道”。在体外缺血模型中，连接蛋白 43 半通道和 Pannexin 通道在缺血期间释放三磷酸腺苷（ATP），但只有连接蛋白 43 半通道在再灌注期间有助于 ATP 释放。托纳布沙在缺血和再灌注阶段均抑制连接蛋白 43 半通道介导的 ATP 释放，通过电生理学证实了直接通道阻断。托纳布沙还在体外减少连接蛋白 43 缝隙连接偶联，但仅在较高浓度下，通过溶酶体途径内化和降解连接斑。在大鼠强光视网膜损伤模型（干性年龄相关性黄斑变性模型）中全身性给予托纳布沙可显著改善使用视网膜电图评估的功能结果。托纳布沙还可防止视网膜变薄，特别是使用光学相干断层扫描评估的外核层和脉络膜。我们得出结论，托纳布沙已经在临床试验中口服给予超过 1000 人（作为皮质扩散性抑制的潜在治疗和预防性治疗偏头痛的药物，因为它被认为可抑制皮质扩散性抑制），是一种连接蛋白半通道抑制剂，可能具有成为治疗中枢神经系统损伤和慢性神经炎症性疾病的新型药物的潜力。
