University years

Which are the new therapeutic targets for migraine?

Since last week I started talking about the most common drugs used to treat the migraine symptoms, this week I would like to talk about the new targets that are started to be addressed for the treatment of migraine.

As a matter of fact, thanks to the most recent intuitions on the aetiology of migraine, new therapeutic targets are continuously developed and tested. Among the many different categories of targets, the most promising one seems to be the inhibitors of the nitric oxide synthase (NOS). Indeed, the nitric oxide (NO) might have a central role in the perception and control of pain (have a look at my previous post to get an idea about what pain is) and, in particular, in the pathogenesis of migraine. It has been suggested that the release of nitric oxide from the blood vessels, nerve endings or brain tissue might be implied in the induction of spontaneous migraine attacks. Moreover, the NO release is involved in the development and maintenance of hyperalgesia (a form of sensitization characterised by the increased response to nociceptive stimuli, where the pain threshold lowers and the intensity of the perceived pain increases). Therefore, according to the central role that the NO seems to have in pain perception, pain maintenance and migraine pathogenesis, inhibiting the enzymes that produce this molecule in our bodies, appeared a good therapeutic target. Several different drugs targeting the NOS were developed, such as L- NAME (a NOS non-selective inhibitor), GW274150 (a NOS selective inhibitor, able to target only the iNOS, the one involved in immune response) o NXN-188 (a selective inhibitor for the neuronal isoform of NOS, nNOS). The first clinical trials showed an efficacy only for the NOS non-specific inhibitor, but the clinical trial stopped due to its collateral effects on the cardiovascular system.

A new class of drugs that might be a good therapeutic option is composed by the antagonists of the CGRP receptor. The CGRP is a neuroactive peptide released during the sensitization of the nociceptors, that plays a role in the formation of the hyperalgesia phenomenon. Few clinical trials showed the efficacy of this class of drugs, as well as liver impairment, and they are currently under evaluation.

As I am keeping on emphasising, the pathogenic mechanism of migraine is still not fully understood, but one of the molecules involved is the glutamate (have a look at this previous post for a very quick mention of what glutamate does), that has receptors on all the neurons and brain areas involved in the migraine development and maintenance (see picture below for a schematic of the possible glutamate sites of action). Indeed, the glutamatergic transmission has a pivotal role in the pain processes and it has been demonstrated that its altered homeostasis is most likely implied in the pathogenesis of migraine.

Schematic of the possible glutamate sites of action in the pathogenesis of migraine. From “Kynurenines in the CNS: recent advances and new questions” by Vécsei et al., 2013 DOI: 10.1038/nrd3793

During the metabolism of tryptophan, an amino acid used in the biosynthesis of proteins, there is the generation of neuroactive compounds that are able to interact with the glutamate receptors in the central nervous system (CNS). One of these neuroactive compounds was the main character of my thesis and, after this kind of long introduction to my master thesis in Neurobiology that lasted for almost two posts, I will introduce to you the protagonist of my thesis, the kynurenic acid, in next week’s post.

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