Substance P (NK1) receptor inhibition does not prevent cortical spreading depression in a rodent model of migraine aura

Migraine is a common brain disorder, affecting more than 10% of the population (1). Approximately 30% of patients experience an aura, commonly manifesting as visual flashes of light or blind spots. Cortical Spreading Depression (CSD) is accepted to underlie the aura and is known to activate trigeminovascular afferents. Triggering of CSD is reduced after treatment with Topiramate, a therapeutic for migraine and epilepsy, in rats (2). Early clinical trials with Substance P (NK1) receptor antagonists failed to treat acute migraines(3), however its role in migraine aura has not been explored.

We investigated the effect of the NK1 receptor antagonist Fosaprepitant on the incidence and number of CSD in rats. Male Wistar rats were prepared for monitoring of steady state cortical potentials (DC) and cerebral blood flow (CBF) changes across the cortex, representative of CSD, as shown previously (4). First, CSDs were triggered using mechanical (needle prick) stimulation of the cortex, 6-8mm rostral to the recording site. CSDs triggered by mechanical means were not significantly reduced by pre-treatment with 1mg/kg i.v. Fosaprepitant compared with saline (control, 6/6 CSD; drug, 5/6 CSD; n=6, Fisher’s exact testp=1.0).

In order to assess whether NK1 antagonism attenuates CSD via a K⁺-mediated mechanism, 1M KCl was applied to the cortex to produce multiple CSDs over 1 hour. However, pre-treatment with 1mg/kg i.v. Fosaprepitant did not significantly alter the number of CSDs per hour compared with control (control, 9.0±1.5; drug, 8.0±0.7; n=4-5, unpaired Student’s t-test p=0.39).

In conclusion, blocking Substance P (NK1) receptor actions has no impact on two different methods of inducing CSDs in a rat model of migraine aura. Our data are in agreement with the failure of NK1 antagonists in previous migraine therapies.

This work is supported by FP7 project EUROHEADPAIN (no. 602633).

(1) Stovner, L.J., Hagen, K., et al. Cephalalgia. 2007; 27: 193-210.

(2) Akerman, S., Goadsby, P.J., Neuroreport. 2005; 16: 1383-7

(3) May, A., Goadsby, P.J., Expert Opinion in Investigational Drugs. 2001; 10:1-6.

(4) Holland, P.R., Akerman, S., et al. Ann Neurol 2012; 72 (4) 559-63.