Project 1: Migraine Drug Prophylaxis (Michael Moskowitz, PI) Migraine afflicts 20% of the population and is 3x more common in females. Understanding the mechanisms of migraine pain has led to the recent development of more effective acute medications. In contrast, prophylactic drugs belonging to distinct therapeutic classes (valproate, topiramate, amitriptyline, propranolol and methysergide) have been discovered empirically, and each of them only suppresses attacks by approximately 50%. Because prophylactic therapy is indicated in patients with 3+ days/month of headache- related disability, it is essential to improve migraine-preventing agents by first identifying relevant tissue or drug targets. In preliminary experiments, we discovered that chronic daily administration of each drug suppressed the susceptibility to cortical spreading depression (CSD), a poorly understood, slowly propagating electrophysiological event. Acute treatments were ineffective in this model and longer-term treatments (2-3 months) appeared more effective in preliminary experiments. Based on these observations, we propose 4 specific aims to test the hypothesis that prophylactic drugs suppress CSD as a fundamental mechanism contributing to migraine prophylaxis. To our knowledge, this is the first coherent target identified for migraine prophylaxis.
The first aim proposes to establish the dose and time characteristics for drugs successfully tested so far in this model, and to expand the list of tested drugs in an attempt to establish a correspondence between animal and human drug treatments and to validate the rodent model.
Aim 2 will build upon this information to determine whether overlapping patterns of gene expression within cerebral cortex explain common mechanisms important for CSDsuppression after chronic treatments using optimized doses and times determined in Aim 1. In order to improve treatment for a migraine subtype (Familial Hemiplegic Migrainel), Aim 3 proposes to determine whether the effective drugs tested to date suppress CSD threshold not only in wild type animals, but also in genetically-engineered mice expressing a knock-in human mutation in the a-1 subunit of Cav2.1 (P/Q) channel. This mutation causes a severe migraine subtype (FHM1) and renders mutant mice more susceptible to CSD than wild type. There is emerging evidence implicating sex hormones as an important determinant of cortical excitability.
Aim 4 proposes to build on preliminary data showing that estrogen withdrawal (butnot estrogen administration itself) increases the susceptibility of rat cortex to CSD. We propose to explore the extent to which estrogen contributes to CSD threshold in rats, and therefore, possibly in adult human females as well. Taken together, these aims are seeking novel information impacting our understanding of migraine and its prophylaxis, and data to evaluate the validity and merits of a potentially useful animal model for screening drugs as candidates for migraine prophylaxis.
|Burstein, Rami; Blake, Pamela; Schain, Aaron et al. (2017) Extracranial origin of headache. Curr Opin Neurol 30:263-271|
|Eikermann-Haerter, Katharina; Lee, Jeong Hyun; Yalcin, Nilufer et al. (2015) Migraine prophylaxis, ischemic depolarizations, and stroke outcomes in mice. Stroke 46:229-36|
|Ayata, Cenk; Lauritzen, Martin (2015) Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature. Physiol Rev 95:953-93|
|Hadjikhani, Nouchine; Ward, Noreen; Boshyan, Jasmine et al. (2013) The missing link: enhanced functional connectivity between amygdala and visceroceptive cortex in migraine. Cephalalgia 33:1264-8|
|Eikermann-Haerter, Katharina; Lee, Jeong Hyun; Yuzawa, Izumi et al. (2012) Migraine mutations increase stroke vulnerability by facilitating ischemic depolarizations. Circulation 125:335-45|
|Borsook, D; Burstein, R (2012) The enigma of the dorsolateral pons as a migraine generator. Cephalalgia 32:803-12|
|Burstein, Rami; Strassman, Andrew; Moskowitz, Michael (2012) Can cortical spreading depression activate central trigeminovascular neurons without peripheral input? Pitfalls of a new concept. Cephalalgia 32:509-11|
|Arboleda-Velasquez, Joseph F; Manent, Jan; Lee, Jeong Hyun et al. (2011) Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease. Proc Natl Acad Sci U S A 108:E128-35|
|Zhang, Xichun; Levy, Dan; Kainz, Vanessa et al. (2011) Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol 69:855-65|
|Eikermann-Haerter, Katharina; Yuzawa, Izumi; Dilekoz, Ergin et al. (2011) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression. Ann Neurol 69:413-8|
Showing the most recent 10 out of 95 publications