The Potentials of Uncariae Ramulus Cum Uncis for the Treatment of Migraine: Targeting CGRP in the Trigeminovascular System

Abstract

Migraine is a common chronic neurovascular disease characterized by headaches. Calcitonin gene-related peptide (CGRP) signaling in the trigeminovascular system plays a critical role in the development of migraine. The monoclonal antibodies against CGRP and its receptor have been used clinically for the prevention of migraine; however, they may not be a cost-effective option for patients with low-frequency episodic migraine. Thus, it is quite valuable to search for an alternative strategy to downregulate CGRP signaling. Uncariae Ramulus Cum Uncis (UR) has a longterm history for the treatment of cardiovascular and central nervous systems disorders in China and Eastern Asia. Several clinical studies showed that famous herbal formulas comprising UR were able to improve headaches in migraineurs. In addition, increasing in vivo studies further indicated that migraine-related changes, such as CGRP increase, inflammation, nitric oxide increase, and spontaneous behavior problems could be reduced by UR extraction and its active constituents. In this review, we summarize the pathophysiological factors affecting abnormal CGRP release in the trigeminovascular system during a migraine, and for the first time, analyze the effects of UR on these factors and evaluate the potentials of UR for the treatment of migraine.

Keywords: CGRP; Migraine; inflammation; nitric oxide.; trigeminovascular system; uncariae ramulus cum uncis.

Fig. (1)

The roles of CGRP in trigeminovascular system. (A) Mature peptide of human α-CGRP and β-CGRP. (B) In the trigeminovascular system, the released CGRP from non-myelinated C-fiber can bind to the CGRP receptor in vascular endothelial cells and vascular smooth muscle cells, subsequently promote the production of NO to trigger vasodilation. In addition, CGRP bind to the CGRP receptor in the terminal of nociceptive transmission from trigeminal nerves to the sensory cortex. Activation of 5-HT_1B/1D/1F receptors signaling can block the release of CGRP from C-fiber. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

The pathophysiological factors involved in abnormal CGRP release in the trigeminovascular system during migraine. Pro-inflammatory cytokines and NO can enhance CGRP expression during migraine. Their secretion may result from (1) the local inflammation at the end of C-fiber and (2) satellite glial cells within TG. (3) 5-HT signaling and (4) melatonin signaling can down-regulate CGRP expression. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (3)

Representative chemical structures of alkaloids of UR.

Fig. (4)

The effects of UR on down-regulating CGRP expression in the trigeminal nerve via reducing inflammation-derived NO and pro-inflammatory cytokines, as well as enhancing melatonin signaling. (A higher resolution / colour version of this figure is available in the electronic copy of the article).