Exploring the Tryptophan Metabolic Pathways in Migraine-Related Mechanisms

Abstract

Migraine is a complex neurovascular disorder, which causes intense socioeconomic problems worldwide. The pathophysiology of disease is enigmatic; accordingly, therapy is not sufficient. In recent years, migraine research focused on tryptophan, which is metabolized via two main pathways, the serotonin and kynurenine pathways, both of which produce neuroactive molecules that influence pain processing and stress response by disturbing neural and brain hypersensitivity and by interacting with molecules that control vascular and inflammatory actions. Serotonin has a role in trigeminal pain processing, and melatonin, which is another product of this pathway, also has a role in these processes. One of the end products of the kynurenine pathway is kynurenic acid (KYNA), which can decrease the overexpression of migraine-related neuropeptides in experimental conditions. However, the ability of KYNA to cross the blood-brain barrier is minimal, necessitating the development of synthetic analogs with potentially better pharmacokinetic properties to exploit its therapeutic potential. This review summarizes the main translational and clinical findings on tryptophan metabolism and certain neuropeptides, as well as therapeutic options that may be useful in the prevention and treatment of migraine.

Keywords: CGRP; PACAP; kynurenic acid; kynurenic pathway; melatonin; migraine; primary headaches; serotonin; serotonin pathway; tryptophan.

Figure 1

The two main pathways of tryptophan metabolism: serotonin and kynurenine pathways.

Figure 2

Serotonin pathway. (1) L-tryptophan is converted to 5-HT by TPH and AADC enzymes. (2) 5-HT is then taken up into vesicles in the axon terminal via VMAT2. (3) After an action potential, 5-HT is released into the synapse. 5-HT can also interact with presynaptic and postsynaptic receptors. (4) All 5-HT receptors are post-synaptically expressed on non-serotonergic neurons, and autoreceptors are located pre-synaptically on the serotonergic neurons. (5) Free 5-HT is removed from the synapse by 5-HTT, which controls the extent and duration of 5-HT receptor activation. Furthermore, 5-HT can be metabolized by MAO and aldehyde dehydrogenase into 5-HIAA, which is excreted in the urine. L-Trp: L-tryptophan, TPH: L-tryptophan hydroxylase, AADC: L-aromatic amino acid decarboxylase, 5-HTP: 5-hydroxytryptophan, 5-HT: serotonin, VMAT2: vesicular monoamine transporter isoform 2, 5-HTT: serotonin transporter, 5-HIAA: 5-hydroxyindoleacetic acid, MAO: monoamine oxidase.

Figure 3

5-HT receptors and their relevance in migraine therapy.

Figure 4

Melatonin synthesis and its anti-nociceptive and anti-allodynic effects. Melatonin can probably induce an anti-nociceptive effect through the regulation of MT1/MT2 receptors in the spinal cord and brain. It also interacts with other receptors such as NMDA, opioids, the dopaminergic system, the GABAergic system, and the NO pathway to exert anti-nociceptive and anti-allodynic effects. MT1/2: melatonin receptor 1/2, NMDA: N-methyl-D-aspartate, GABA: gamma-aminobutyric acid, NO: nitric oxide.

Figure 5

Kynurenine pathway.

Figure 6

Proposed regulation of CGRP and PACAP gene expression. AC: adenylate cylase, ATP: adenosine monophosphate, CaM: calmodulin, cAMP: cyclic adenosine monophosphate, CGRP: calcitonin gene-related peptide CN: calcineurin, CREB: cAMP response element-binding protein, CRTC1: CN/Cre-binding protein, GPCR: G-protein-coupled receptor, Gs: stimulatory G protein, KYNA: kynurenic acid, MAPK: mitogen-activated protein kinase, NMDAR: NMDA receptor, PACAP: pituitary adenylate cyclase activating polypeptide PKC: protein kinase C.