Background: Migraine is a highly prevalent primary headache with an unclear pathomechanism. During the last 40 years, numerous hypotheses have arisen; among them, the theory of the trigeminovascular system is the primary one. It serves as a skeleton in successful preclinical studies and in the development of effective therapeutic options for migraine headache. Objective: The brain prize (awarded annually by the Lundbeck Foundation) is the most prestigious tribute in neuroscience. The winners in 2021 were Lars Edvinsson, Peter Goadsby, Michael Moskowitz and Jes Olesen. They are the fathers of migraine pathomechanism, which led to revolutionary new treatments. This review summarizes their landmark findings. Methods: Data related to this topic were reviewed from PubMed records published between 1979 and May 2021. Searches were based on preclinical and clinical studies in the covered field. The findings were listed in chronological order. From a therapeutic perspective, only randomized controlled trials and meta-analysis were discussed. Results: The calcitonin gene-related peptide-related pathogenesis of migraine is based on the activation of the trigeminovascular system. The therapeutic triad for migraine is triptans, gepants, and calcitonin gene-related peptide-targeted monoclonal antibodies. Conclusion: In the past 40 years, the systematic work of leading headache scientists has resulted in robust theoretical and therapeutic knowledge in the preclinical and clinical study of migraine.
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