CGRP and Brain Functioning: Cautions for Migraine Treatment

Abstract

Background 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. Methods Qualitative review of the preclinical literature on CGRP in brain physiology and pathophysiology. Results 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. Conclusions 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.

To Eat or Not to eat: A Review of the Relationship between Chocolate and Migraines

“…The release of CGRP starts a cascade of events, including the increased synthesis of nitric oxide, vasodilation, and causing mast cells to release inflammatory mediators and the sensitization of the trigeminal nerves, thus playing an essential role in the pathophysiology of migraines. The concentration of CGRP is elevated in the plasma of people with episodic and chronic migraines between and during migraine attacks; moreover, the administration of CGRP elicits a headache and sometimes a delayed migraine in migraineurs [53,54]. It should be emphasized that CGRP receptor antagonists are effective in migraine treatment.…”

Calcitonin gene related peptide in migraine: current therapeutics, future implications and potential off-target effects

“…While CGRP receptors are found in the anterior pituitary, their role is not clear and thus care should be considered in their blockade in particular patients such as adolescents, and those with existing pituitary dysfunction [33]. The impact of CGRP intracerebrally and on the blood-brain barrier is discussed elsewhere, however it may have a role in strengthening the blood-brain barrier and protecting the immune privilege of the brain [34].…”

Periorbital Nociception in a Progressive Multiple Sclerosis Mouse Model Is Dependent on TRPA1 Channel Activation

“…In addition, sumatriptan (a triptan) [10,22,23] and olcegepant (a gepant) [8,24,25] are extensively used, as positive control drugs, during the optimisation of different migraine-like mouse models. On the other hand, gepants and triptans generate diverse adverse effects, such as cardiovascular and central nervous system alterations [19,[26][27][28][29]. Thus, the development of new drugs for headache and migraine treatment is demanded.…”