FINAL REPORT: N-Methyl-D-Aspartate Receptor Glycine Coagonist Site Modulation as a Potential Treatment for Migraine in Adolescent and Adult Females (2012)

Published in Experimental Neurology, Volume 273, November 2015

Summary

In previous work (see below), we developed a novel pharmacological agent, GLYX-13, that modulates the activation of the key neuronal glutamate receptor known as the N-methyl-D-aspartate receptor (NMDAR). This agent normalizes activation of this critical receptor, increasing it when it is too low, and suppressing it when it is too high. Studies have shown that the activation of NMDARs also promotes, and can even be necessary for, the phenomenon of Spreading Depression (SD) that may underlie the migraine aura. Therefore, compounds that prevent over-activation of this receptor could be important new therapies for lessening, and even preventing, the onset of migraine attacks.

In our first project supported by an MRF grant, we showed that GLYX-13 is, indeed, able to suppress the induction of SD in the brain tissue of male rats. GLYX-13 also improved the return of dendritic spines to their original sizes following an SD, suggesting that the drug could protect synaptic connections in the brain from possible damage from repeated migraine attacks. This project extended these findings to adolescent and adult female rats.

These experiments confirm the potential for GLYX-13 as a therapeutic meriting further evaluation as a possible migraine treatment for sufferers not helped by existing drug treatments.

Hypothesis vs. Findings

Our original working hypotheses were:

1. GLYX-13 would raise the threshold and/or prevent SD in hippocampal brain slices.

We have confirmed this, in that GLYX-13 significantly slowed the propagation of SD, and sometimes prevented it entirely.

2. GLYX-13 could also prevent the retraction and/or improve the recovery of dendritic spines in response to SD.

In reference to this hypothesis, we discovered that, while GLYX-13 does not alter the effects of SD in causing dendritic spines to retract, it does improve their recovery to their original sizes.

These studies confirm and extend our previous findings from males that GLYX-13 could be an excellent migraine treatment in females that could both reduce frequency of attacks and their long-term effects.

Unanswered Questions

There are some key unanswered questions posed by our work with immense importance to our understanding of the mechanisms underlying migraine and the search for new treatments.

1) Does slowing SD propagation and preventing generation of secondary SDs translate to fewer or less severe migraine attacks?

2) Do repeated SDs, as a model for repeated migraine attacks, have lasting effects on synaptic plasticity and/or dendritic spine architecture? Do they cause neuronal damage, or do they trigger neuroprotective changes?

3) Can GLYX-13 protect neurons from long-term toxicity produced by repeated SDs, as a model for repeated migraine attacks?

What This Research Means To You

For migraine sufferers for whom none of the available treatments is effective, our discovery that the novel therapeutic GLYX-13 can also slow and even suppress the propagation of Spreading Depression in the brain of rats offers hope for a new treatment for migraine. GLYX-13 may be useful both prophylactically and acutely to ameliorate the severity, or even abort, migraine attacks in females as well as males.

FINAL REPORT: N-Methyl-D-Aspartate Receptor Glycine Coagonist Site Modulation as a Potential Treatment for Migraine (2010)

Summary

In previous work, we developed a novel pharmacological agent, GLYX-13, with unprecedented modulatory effects on the activation of the key neuronal glutamate receptor known as the N-methyl-D-aspartate receptor (NMDAR). This agent normalizes activation of this critical receptor, increasing it when it is too low, and suppressing it when it is too high. Studies have shown that the activation of NMDARs also promotes, and can even be necessary for, the phenomenon of Spreading Depression (SD) that is thought to underlie the migraine aura. Therefore, compounds that prevent over-activation of this receptor could be important new therapies for lessening, and even preventing, the onset of migraine attacks.

In our work supported by MRF’s grant, we have shown that GLYX-13 is, indeed, able to suppress the induction of SD in brain tissue. Furthermore, GLYX-13 also improved the return of
dendritic spines to their original sizes following an SD, suggesting that the drug could protect synaptic connections in the brain from possible damage from repeated migraine attacks.

These experiments confirm the potential for GLYX-13 as a therapeutic worth further evaluation as a possible treatment that could help millions of migraine sufferers not helped by any existing drug treatments.

Hypothesis vs. Findings

Our original working hypotheses were:

1. GLYX-13 would raise the threshold and/or prevent SD in hippocampal brain slices.

We have confirmed this, in that GLYX-13 significantly slowed the propagation of SD, and sometimes prevented it entirely.

2. GLYX-13 could also prevent the retraction and/or improve the recovery of dendritic spines in response to SD.

In reference to this hypothesis, we discovered that, while GLYX-13 does not alter the effects of SD in causing dendritic spines to retract, it does improve their recovery to their original sizes.

Unanswered Questions

There are a number of unanswered questions:

1. We conducted our study only on brain slices from male animals. It is crucial to know whether GLYX-13 has similar regulatory actions on SD in the female brain, and whether these actions vary in the presence and absence of estrogen. This is because women are three times as likely to experience migraines as men, and migraine attacks can be most severe in the days leading up to menstruation, suggesting that the drop in estrogen during normal female hormonal cycles may be an important contributor to migraine attacks.

2. Does slowing SD propagation translate to fewer or less severe migraine attacks?

3. Do repeated SDs, as a model for repeated migraine attacks, have lasting effects on synaptic plasticity and/or dendritic spine architecture? Do they cause neuronal damage/death, or do they trigger neuroprotective changes?

4. Can GLYX-13 protect neurons from long-term toxicity produced by repeated SDs, as a model for repeated migraine attacks?

What This Research Means To You

For migraine sufferers for whom none of the available treatments is effective, our discovery that the novel therapeutic GLYX-13 can also slow and even suppress the propagation of Spreading Depression in the brain offers hope for an entirely new mechanistic treatment for migraine. GLYX-13 may be useful both prophylactically and acutely to ameliorate the severity, or even abort, migraine attacks.