Department of Psychology, University of Maine, Orono, ME, USA.
Health Psych Maine, Waterville, ME, USA.
Headache. 2019 Sep;59(8):1339-1357. doi: 10.1111/head.13591. Epub 2019 Jul 21.
Calcitonin gene-related peptide has emerged as a therapeutic target in migraine. Monoclonal antibodies and small molecule receptor antagonists (gepants) directed against CGRP have been approved or are in Phase II or III clinical trials. For monitoring the long-term safety of these drugs, it is helpful to consider the role of CGRP in brain functioning.
Qualitative review of the preclinical literature on CGRP in brain physiology and pathophysiology.
Within the brain, CGRP is upregulated by stresses such as ischemia, injury, hyperthermia, and seizure, and activates neuroprotective processes. Thus, CGRP buffers intracellular calcium, triggers antiapoptotic signaling, upregulates a number of neurotrophins (including insulin-like growth factor-1/IGF-1, basic fibroblast growth factor/bFGF, and nerve growth factor/NGF), reduces brain edema, and likely increases antioxidant defenses. When released outside the blood-brain barrier, CGRP likely protects the endothelium, upregulates growth factor signaling from the endothelium to the brain parenchyma, strengthens the blood-brain barrier, protects the immune privilege of the brain by inhibiting the movement of neutrophils and monocytes, and facilitates neurogenesis and angiogenesis at stem cell niches.
CGRP participates in a wide range of neuroprotective processes. In theory, migraineurs with comorbid brain pathology might be at increased risk from CGRP inhibition. However, the extent of compensating processes is unknown and will determine whether these risks materialize in practice.
降钙素基因相关肽已成为偏头痛治疗的靶点。针对 CGRP 的单克隆抗体和小分子受体拮抗剂（ gepants ）已被批准或处于 II 期或 III 期临床试验阶段。为了监测这些药物的长期安全性，考虑 CGRP 在大脑功能中的作用将有所帮助。
对 CGRP 在大脑生理学和病理生理学中的临床前文献进行定性综述。
在大脑中，CGRP 可被缺血、损伤、高热和癫痫等应激上调，并激活神经保护过程。因此，CGRP 缓冲细胞内钙，触发抗细胞凋亡信号，上调多种神经营养因子（包括胰岛素样生长因子-1/IGF-1、碱性成纤维细胞生长因子/bFGF 和神经生长因子/NGF），减少脑水肿，并可能增加抗氧化防御。当从血脑屏障释放到血液中时，CGRP 可能保护内皮细胞，上调内皮细胞向脑实质的生长因子信号，增强血脑屏障，通过抑制中性粒细胞和单核细胞的运动来保护大脑的免疫特权，并促进干细胞龛中的神经发生和血管生成。
CGRP 参与了广泛的神经保护过程。理论上，伴有脑病理的偏头痛患者可能因 CGRP 抑制而面临更高的风险。然而，补偿过程的程度尚不清楚，这将决定这些风险是否会在实践中出现。
