Denekas Thomas, Tröltzsch Markus, Vater Axel, Klussmann Sven, Messlinger Karl
Institute of Physiology & Pathophysiology, University of Erlangen-Nürnberg, Germany.
Br J Pharmacol. 2006 Jun;148(4):536-43. doi: 10.1038/sj.bjp.0706742. Epub 2006 Apr 24.
Calcitonin gene-related peptide (CGRP) released from trigeminal afferents is known to play an important role in the control of intracranial blood flow. In a rat preparation with exposed cranial dura mater, periods of electrical stimulation induce increases in meningeal blood flow. These responses are due to arterial vasodilatation mediated in part by the release of CGRP. In this preparation, the effect of a CGRP-binding mirror-image oligonucleotide (Spiegelmer NOX-C89) was examined. Spiegelmer NOX-C89 applied topically at concentrations between 10(-7) and 10(-5) M to the exposed dura mater led to a dose-dependent inhibition of the electrically evoked blood flow increases. The highest dose reduced the mean increases in flow to 56% of the respective control levels. A nonfunctional control Spiegelmer (not binding to CGRP) was ineffective in changing blood flow increases. Intravenous injection of NOX-C89 (5 mg kg(-1)) reduced the evoked blood flow increases to an average of 65.5% of the control. The basal blood flow was not changed by any of the applied substances. In addition, an ex vivo preparation of the hemisected rat skull was used to determine CGRP release from the cranial dura mater caused by antidromic activation of meningeal afferents. In this model, 10(-6) M of NOX-C89 reduced the evoked CGRP release by about 50%. We conclude that increases in meningeal blood flow due to afferent activation can be reduced by sequestering the released CGRP and thus preventing it from activating vascular CGRP receptors. Moreover, the Spiegelmer NOX-C89 may inhibit CGRP release from meningeal afferents. Therefore, the approach to interfere with the CGRP/CGRP receptor system by binding the CGRP may open a new opportunity for the therapy of diseases that are linked to excessive CGRP release such as some forms of primary headaches.
已知三叉神经传入纤维释放的降钙素基因相关肽（CGRP）在颅内血流控制中起重要作用。在大鼠硬脑膜暴露的实验准备中，电刺激期会引起脑膜血流增加。这些反应是由于动脉血管舒张，部分是由CGRP释放介导的。在此实验准备中，研究了一种CGRP结合镜像寡核苷酸（Spiegelmer NOX - C89）的作用。将浓度在10^(-7)至10^(-5) M之间的Spiegelmer NOX - C89局部应用于暴露的硬脑膜，导致电诱发的血流增加呈剂量依赖性抑制。最高剂量将平均血流增加降低至各自对照水平的56%。无功能的对照Spiegelmer（不与CGRP结合）在改变血流增加方面无效。静脉注射NOX - C89（5 mg kg^(-1)）将诱发的血流增加平均降低至对照的65.5%。任何应用的物质均未改变基础血流。此外，使用半切大鼠颅骨的离体实验准备来确定脑膜传入纤维的逆向激活引起的硬脑膜CGRP释放。在该模型中，10^(-6) M的NOX - C89使诱发的CGRP释放减少约50%。我们得出结论，通过隔离释放的CGRP并因此阻止其激活血管CGRP受体，可以减少由于传入激活引起的脑膜血流增加。此外，Spiegelmer NOX - C89可能抑制脑膜传入纤维释放CGRP。因此，通过结合CGRP来干扰CGRP/CGRP受体系统的方法可能为治疗与CGRP过度释放相关的疾病（如某些形式的原发性头痛）开辟新的机会。
