Clinical translation: targeting cortical spreading depression.

In this edition of Cephalalgia, Dr Holland and colleagues report the very interesting findings from a series of in vivo cat and rodent experiments aimed at identifying potential therapeutic targets for the modulation of cortical spreading depression (CSD). Over the past two decades, a series of functional neuroimaging studies performed in human migraineurs during acute aura (1–4) have linked CSD, or at least a human CSD-like phenomenon occurring in the occipital cortex, with visual aura symptoms. Questions were raised early on as to the importance of understanding aura, given its seemingly benign course and the fact that it occurred in only a subgroup of migraineurs. However, a quick rough calculation of how many people are likely to experience aura (approximately 30 million migraineurs in the United States x 0.30 [the approximate number of migraineurs reporting aura] 1⁄4 approximately 10 million people), reveals that aura is actually much more common than many prominent and exhaustively studied neurological disorders. In addition, this estimate does not take into account the rather large group of people who present to ophthalmologists each year with aura symptoms not followed by migraine headaches. The aura symptoms of migraine are indeed quite common. Furthermore, recent data from large epidemiological studies (5) suggests that, at least in women, migraine aura is associated with (although not necessarily causative of) increased stroke risk, indicating that aura may not be so benign as previously thought. An increased awareness of the potential importance of CSD in migraine with aura, probably the largest identifiable migraine subgroup, has led to a series of experiments seeking to show how (1) CSD might be a mechanism for the initiation of the migraine headache (6,7); (2) it may be important in the generation of phenotypic symptoms of known genetic migraine subtypes (8); and (3) it might be useful as a therapeutic target in migraine treatment (9–11). Dr Holland’s study continues the progress in the third of these endeavors. In their paper, Dr Holland and his coworkers detail their use of mechanically induced CSD in both gyrencephalic (cat) and lissencephalic (rat) animals to study the effect of pretreatment with a glutamate (AMPA) receptor antagonist (GYK152466), a GABAA agonist (muscimol) and a GABAB agonist (R-baclofen) on the initiation and propagation rate of the CSD-induced hyperemic response. In control animals, all stimulations resulted in CSD inductions. In rats the AMPA antagonist and the GABAA agonist completely blocked CSD induction, and the GABAB agonist blocked CSD in 5/6 cases. Interestingly, in cats, gyrencephalic animals further up the evolutionary tree, the AMPA antagonist blocked only 3/7 CSD inductions, the GABAA agonist blocked only 1/5 inductions and R-baclofen (GABAB agonist) blocked only 2/6 inductions. Dr Holland’s findings are very encouraging as they suggest mechanisms that may be useful in suppressing CSD, and in those cases in which the CSD causes activation of trigeminal nociceptors, possibly the subsequent headache as well. Many of the medications used empirically in migraine prophylaxis have activity at AMPA and GABA receptors. If modulation at one or more of these receptor types proves to be reliably effective through suppression of CSD or CSD-like events in human migraineurs, new drugs, optimized for the effect in migraine, can be developed. Unfortunately, the road to effective new migraine treatments is a long and tortuous one. In fact, no new prophylactic treatment has been specifically developed for migraine since methysergide in the 1960s. Possible bumps along the road include species differences. We are all familiar with various compounds that have performed well in animal models only to fail in clinical trials. In the experiments reported by Dr Holland, it is notable that the compounds were much less effective at suppressing CSD in cats than in rats. While the results certainly suggest that CSD suppression may be