The Anti-CGRP Antibody Fremanezumab Lowers CGRP Release from Rat Dura Mater and Meningeal Blood Flow

Abstract

Monoclonal antibodies directed against the neuropeptide calcitonin gene-related peptide (CGRP) belong to a new generation of therapeutics that are effective in the prevention of migraine. CGRP, a potent vasodilator, is strongly implicated in the pathophysiology of migraine, but its role remains to be fully elucidated. The hemisected rat head preparation and laser Doppler flowmetry were used to examine the effects on CGRP release from the dura mater and meningeal blood flow of the subcutaneously injected anti-CGRP monoclonal antibody fremanezumab at 30 mg/kg, when compared to an isotype control antibody. Some rats were administered glycerol trinitrate (GTN) intraperitoneally to produce a migraine-like sensitized state. When compared to the control antibody, the fremanezumab injection was followed by reduced basal and capsaicin-evoked CGRP release from day 3 up to 30 days. The difference was enhanced after 4 h of GTN application. The samples from the female rats showed a higher CGRP release compared to that of the males. The increases in meningeal blood flow induced by acrolein (100 µM) and capsaicin (100 nM) were reduced 13–20 days after the fremanezumab injection, and the direct vasoconstrictor effect of high capsaicin (10 µM) was intensified. In conclusion, fremanezumab lowers the CGRP release and lasts up to four weeks, thereby lowering the CGRP-dependent meningeal blood flow. The antibody may not only prevent the released CGRP from binding but may also influence the CGRP release stimulated by noxious agents relevant for the generation of migraine pain.

Exploring Novel Therapeutic Targets in the Common Pathogenic Factors in Migraine and Neuropathic Pain

“…Regarding the clinical studies of CGRP, many data remain unavailable, including data on interictal M0, MA, CM, and central NP. Hopefully, more clinical studies will reveal the consequences of CGRP modulator administration to clarify its efficacy in those subtypes of pain disorders [ 222 , 223 , 224 , 225 , 226 ]. Different TRP ion channels play distinct roles in both migraine and NP [ 227 ].…”

Role of neuropeptides in orofacial pain: A literature review

“…18 CGRP, generally considered a neurotransmitter, does not evoke pain directly but acts on the trigeminal system to regulate activities of vascular endothelial cells, immune-inflammatory cells, neurons, and glial cells, thus initiating and maintaining both peripheral and central sensitization (Figure 1). [19][20][21] Abundant experiments have shown that CGRP is crucial in promoting orofacial pain. In an experimental model of orthodontic pain, periodontal injection of CGRP increased the expression of CGRP in periodontal tissues and aggravated orofacial pain, while administration of CGRP receptor antagonists had the opposite effect, 4 suggesting that periodontal CGRP might participate in positive feedback aiming to amplify orofacial pain signals.…”

“…CGRP mainly mediate prolonged vasodilation and increased blood flow through endotheliumdependent and NO-dependent pathway, which can not only increase NO and make peripheral trigeminal afferent fibres hyperalgesia but also promotes the aggregation of inflammatory mediators and inflammatory cell, thereby exacerbating local inflammation. 19 Besides vascular effect, CGRP promoted neurogenic inflammation and subsequent peripheral sensitization by acting directly on local immune inflammatory cells, prompting the release of various inflammatory mediators and cytokines. 23 Some of these substances can induce phosphorylation of transient receptor potential vanilloid subfamily member 1 (TRPV1), the transient receptor potential ankyrin 1 ion channel (TRPA1), or voltage-gated sodium channels (VGSCs), triggering action potentials and thereby activating nociceptors, while others could lead to peripheral sensitization and hyperalgesia by reducing the activation threshold of peripheral nociceptors and increasing neuronal responses to stimuli.…”

OnabotulinumtoxinA: Still the Present for Chronic Migraine

“…The exocytosis of the CGRP determines three main phenomena. The first one is vasodilation at the meningeal level, as unequivocally demonstrated by an experiment with CGRP-blocking antibodies in rats [ 26 ]. Furthermore, the action of CGRP on pericytes at the endothelial levels determines an increase in the permeability of meningeal arteries [ 27 ].…”