Non-Metal PN Scavenger/Decomposition Catalysts for Treatment of Migraine

Project SummaryAbstract The World Health Organization ranks migraine as therd most prevalent disease worldwide andth most disablingth most in womenmaking it the most common neurological disorderOne of the primary reasons for the disabling nature of migraine is the poor efficacy of currently available therapeuticsLess thanof patients achieve complete relief with acute agents such as triptans and only half of patients achieverelief with preventative agentsOur long term goal is to identify new targets and develop novel therapeutics against these targets to treat this common and debilitating disorderOne of the most consistent triggers for migraine is administration of a nitric oxideNOdonorApproximatelyof human migraine patients will develop an attack withinhours of NO donor administrationDespite this observationmigraine therapeutics based on NO or its downstream mechanisms have not yet been developedThe objective of this proposal is to test whether several compounds under development by CerSci Therapeutics that scavenge or catalyze the decomposition of peroxynitritePNthe reaction product of NO and superoxidehave efficacy in preclinical models of migraineStudies over the last decade have shown that PN is an important activator sensitizer of sensory neurons in preclinical pain models of neuropathicinflammatoryand cancer pain and agents that eliminate PN have demonstrated efficacy in preclinical pain modelsHoweverstudies have not examined whether targeting PN is efficacious for migraine despite the observation that the only pain state triggered by administration of a PN producing stimulus is migraineNO donors do not directly cause other types of painThuswe propose to test the hypothesis that CST compounds will decrease NO donorinduced migraine related behavior in preclinical models via decreased PNThe rationale for the proposed study is that itwill demonstrate that scavenging or catalyzing the decomposition of PN is a novel therapeutic avenue to treat migraineandwill provide the preclinical rationale for the development of CerSci compounds that are PN scavengers decomposition catalysts to treat migraineWe will test the hypothesis withAims using preclinical rodent modelsAimwill test the efficacy of CerSci compoundsCSTCSTand CSTagainst NO donor induced migraine behavior in rats primed by dura mater administration of the cytokine interleukinILAimwill test the efficacy of CerSci compoundsCSTCSTand CSTagainst NO donor induced migraine behavior in mice primed by repetitive stressThis innovative study will for the first time investigate the efficacy of nonmetal basedorally available PN scavengers decomposition catalysts in preclinical model that mimic conditions relevant to migraineThe significance of the proposal is that it both advances our understanding of migraine mechanisms and has the potential to lead to novel therapeutics Project Narrative One of the most consistent triggers for migraine is administration of a nitric oxideNOdonor and it is well established that approximatelyof human migraineurs will develop an attack withinhours of NO donor administrationNO readily reacts with the superoxide radical to form peroxynitritePNwhich is known to contribute to a variety of non headache pain statesWe propose to test the efficacy of orally bioavailablenonmetal based PN scavengers and PN decomposition catalystsunder development by CerSci Therapeuticsfor efficacy in preclinical models of migraine which may lead to the identification of a novel class of migraine therapeutics