Background: Migraine is a primary headache disorder. Despite numerous studies
conducted with the aim to understand the pathophysiology of migraine, several aspects are
still unclear. The trigeminovascular system plays a key role. Neurogenic inflammation is presumed
to be an important factor in migraine pathophysiology, mediated by the activation of
primary neurons, leading to the release of various pro-inflammatory neuropeptides and neurotransmitters
such as Calcitonin Gene-Related Peptide (CGRP), substance P (SP), and vasoactive
intestinal peptide (VIP). Nitric oxide (NO), Pituitary adenylate cyclase-activating polypeptide
(PACAP) and Glutamate (Glu) also play an important role in the modulation of inflammatory
Objective: To review the literature focusing on novel therapeutic targets in migraine, related
to neurogenic inflammation.
Method: A systematic literature search in the database of PUBMED was conducted regarding
therapeutic strategies in migraine, focusing on substances and cytokines released during neurogenic
inflammation, published until January 2017.
Results: Ongoing phase III clinical studies with monoclonal antibodies against CGRP and
CGRP receptors offer promising novel aspects for migraine treatment. Preclinical and clinical
studies targeting SP and nitric oxide synthase (NOS) were all terminated with no significant
results compared to placebo. New promising therapeutic goal could be PACAP and its receptor
(PAC1), and kynurenic acid (KYNA) analogues.
Conclusion: Current migraine treatment offers pain relief only for a small proportion of migraine
patients and might not be adequate for patients with cardiovascular comorbidity due to
side effects. Better understanding of migraine pathophysiology might, therefore, lead to novel
therapeutic lines both in migraine attack treatment and prophylaxis.