Future targets for migraine treatment beyond CGRP

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Migraine is a chronic neurovascular disorder where trigeminal vascular activation and CGRP release are key.
• Existing CGRP(-receptor) therapies are ineffective for a significant patient subset, necessitating alternative treatment targets.
• This review comprehensively examines potential non-CGRP targets in migraine pathophysiology.

Purpose of the Study:

• To review the pathophysiological roles of non-CGRP targets in migraine.
• To identify alternative therapeutic strategies for migraine patients unresponsive to CGRP-targeted treatments.

Main Methods:

• Narrative review of scientific literature.
• Analysis of targets including metabotropic receptors (PACAP, VIP, amylin, adrenomedullin), intracellular targets (NO, PDE3, PDE5), and ion channels (potassium, calcium, TRP, ASIC).

Main Results:

• Metabotropic receptors, NO, and certain ion channels (potassium, TRP, ASIC) were implicated in migraine-like attacks, with varying degrees of investigation.
• Existing drugs target PACAP, NO, and some channels; others have indirect effects or lack selective agents.
• Clinical trials for PACAP, NO, potassium channels, TRP channels, and PAC1 antibodies yielded ambiguous outcomes.

Conclusions:

• Non-CGRP targets offer valuable insights into migraine mechanisms, despite not yet yielding effective therapies.
• Further research into these alternative targets is crucial for non-responders to CGRP therapies.
• The ultimate goal is to develop novel treatments for a migraine-free future.