- News - animals are a poor migraine model
Animals are a poor migraine model
“...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 a part of the mechanism of, say, topiramate or Depakote (valproic acid) in migraine prophylaxis, the leap to humans can be a problematic one.”
Amazingly, despite this statement the authors want to carry on with animal experiments. - VIN
Clinical translation: Targeting cortical spreading depression
Mayo Clinic, Department of Neurology, 200 First Street SW, Rochester, Minnesota 55902, USA.
Correspondence: F Michael Cutrer, Mayo Clinic, Department of Neurology, 200 First Street SW, Rochester, Minnesota 55902, USA. Email: firstname.lastname@example.org
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] = 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 a part of the mechanism of, say, topiramate or Depakote (valproic acid) in migraine prophylaxis, the leap to humans can be a problematic one.
Another complication is that modulation at glutamate and GABA receptors is also associated with direct effects on pain, further clouding the issue.
It is also important to remember that details of the experimental conditions can influence the result. For example, in other reports of induced CSD, the ability of calcium-channel blockers to suppress CSD differed with the method of CSD induction (chemical vs. mechanical) (10,12).
Nevertheless, despite these limitations, the use of animal modeling for rationale development is absolutely crucial. And the importance of clarifying the mechanism(s) of our current empirically used treatments can hardly be overstated. Identification of the mechanisms of action relevant to blocking the attacks rather than suppressing the pain of migraine attacks may bring us closer to developing medications with less of the sedation, cognitive slowing and appetite modulation that our patients are currently called upon to endure. This report represents another very useful step in our journey to new, more effective treatment for a large, suffering and underserved population.
1 Woods, RP, Iacoboni, M, & Mazziotta, JC. Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 1994; 331: 1689–1692.[Free Full Text]
2 Cutrer, FM, Sorensen, AG, Weisskoff, RM, et al. Perfusion-weighted imaging defects during spontaneous migrainous aura. Ann Neurol 1998; 43(1): 25–31.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3 Cao, Y, Welch, KM, Aurora, S, & Vikingstad, EM. Functional MRI-BOLD of visually triggered headache in patients with migraine. Arch Neurol 1999; 56(5): 548–554.[Abstract/Free Full Text]
4 Hadjikhani, N, Sanchez Del Rio, M, Wu, O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 2001; 98(8): 4687–4692.[Abstract/Free Full Text]
5 Kurth, T, Schürks, M, Logroscino, G, & Buring, JE. Migraine frequency and risk of cardiovascular disease in women. Neurology 2009; 73(8): 581–588.[Abstract/Free Full Text]
6 Moskowitz, MA, Nozaki, K, & Kraig, RP. Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms. J Neurosci 1993; 13(3): 1167–1177.[Abstract]
7 Bolay, H, Reuter, U, Dunn, AK, Huang, Z, Boas, DA, & Moskowitz, MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002; 8(2): 136–142.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8 Eikermann-Haerter, K, Dileköz, E, Kudo, C, et al. Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J Clin Invest 2009; 119(1): 99–109.[Web of Science][Medline] [Order article via Infotrieve]
9 Ayata, C, Jin, H, Kudo, C, Dalkara, T, & Moskowitz, MA. Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol 2006; 59(4): 652–661.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10 Akerman, S, Holland, PR, & Goadsby, PJ. Mechanically-induced cortical spreading depression associated regional cerebral blood flow changes are blocked by Na+ ion channel blockade. Brain Res 2008; 1229: 27–36.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11 Akerman, S, & Goadsby, PJ. Topiramate inhibits cortical spreading depression in rat and cat: impact in migraine aura. Neuroreport 2005; 16(12): 1383–1387.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12 Van den Maagdenberg, AMJM, Pietrobon, D, Pizzorusso, T, et al. A Cacna1a knock-in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 2004; 41: 701–710.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
This version was published on May 1, 2010
Cephalalgia, Vol. 30, No. 5, 515-516 (2010)