Department of Neurology, The University of Chicago, Chicago, IL, 60637, USA.
Department of Neurology, The University of Chicago, Chicago, IL, 60637, USA.
Neurosci Lett. 2021 Apr 23;751:135809. doi: 10.1016/j.neulet.2021.135809. Epub 2021 Mar 10.
Migraineurs experience increased oxidative stress which drives the initiation and maintenance of migraine-related pain in animal models and, by extension, migraine in humans. Oxidative stress augments calcitonin gene-related peptide (CGRP) levels, a mediator of migraine pain. Insulin-like growth factor-1 (IGF-1), a neuroprotective growth factor, reduces susceptibility to spreading depression, a preclinical model of migraine, in cultured brain slices by blocking oxidative stress and neuroinflammation from microglia. Similarly, nasal delivery of IGF-1 inhibits spreading depression in vivo. After recurrent cortical spreading depression, nasal administration of IGF-1 also significantly reduces trigeminal ganglion oxidative stress and CGRP levels as well as trigeminocervical c-Fos activation. Here, we probed for the impact of nasal IGF-1 pretreatment on trigeminal system activation using a second well-established preclinical model of migraine, systemic nitroglycerin injection. Adult male rats were treated with one of three doses of IGF-1 (37.5, 75 or 150 μg) and the optimal dose found in males was subsequently used for treatment of female rats. One day later, animals received an intraperitoneal injection of nitroglycerin. Measurements taken two hours later after nitroglycerin alone showed increased surrogate markers of trigeminal activation - oxidative stress and CGRP in the trigeminal ganglion and c-Fos in the trigeminocervical complex compared to vehicle control. These effects were significantly reduced at all doses of IGF-1 for trigeminal ganglion metrics of oxidative stress and CGRP and only at the lowest dose in both males and females for c-Fos. The latter inverted U-shaped or hormetic response is seen in enzyme-targeting drugs. While the specific mechanisms remain to be explored, our data here supports the ability of IGF-1 to preserve mitochondrial and antioxidant pathway homeostasis as means to prevent nociceptive activation in the trigeminal system produced by an experimental migraine model.
偏头痛患者经历氧化应激增加，这在动物模型中驱动偏头痛相关疼痛的发生和维持，并在人类中扩展为偏头痛。氧化应激增加降钙素基因相关肽 (CGRP) 水平，这是偏头痛疼痛的一种介质。胰岛素样生长因子-1 (IGF-1) 是一种神经保护生长因子，通过阻断小胶质细胞的氧化应激和神经炎症，减少培养脑片中偏头痛的临床前模型扩散性抑制的易感性。同样，IGF-1 的鼻内给药也抑制体内扩散性抑制。在反复皮质扩散抑制后，IGF-1 的鼻内给药也显著降低三叉神经节的氧化应激和 CGRP 水平以及三叉神经根颈复合体的 c-Fos 激活。在这里，我们使用另一种成熟的偏头痛临床前模型，全身给予硝化甘油，来探测鼻内 IGF-1 预处理对三叉神经系统激活的影响。成年雄性大鼠接受三种剂量 IGF-1（37.5、75 或 150 μg）中的一种治疗，然后在雄性中找到最佳剂量，随后用于治疗雌性大鼠。一天后，动物接受腹膜内注射硝化甘油。单独给予硝化甘油两小时后测量的替代三叉神经激活标志物显示，与载体对照相比，三叉神经节中的氧化应激和 CGRP 以及三叉神经根颈复合体中的 c-Fos 增加。与载体对照相比，所有剂量的 IGF-1 都显著降低了三叉神经节氧化应激和 CGRP 的指标，而在雄性和雌性中仅在最低剂量时降低了 c-Fos 的指标。这种倒置的 U 形或应激反应见于针对酶的药物。虽然具体机制仍有待探索，但我们的数据支持 IGF-1 保护线粒体和抗氧化途径稳态的能力，作为预防实验性偏头痛模型引起的三叉神经系统伤害性激活的手段。
