Elucidation of botulinum neurotoxin A mediated cerebral revascularization graft spasmolysis mechanisms

项目总结

Project Summary The primary goal of this study is to investigate the effects of botulinum toxin A (BTX A) adrenergic and Rho kinase pathways elucidating, for the first time, its spasmolytic mechanism of action in human cerebral revascularization grafts. Revascularization graft stenosis and occlusion remains a formidable complication which can lead to significant morbidity and mortality. Graft stenosis and occlusion from vasospasm is thought to be at least partially mediated through increased activity in adrenergic vasospastic pathways. Additionally, evidence supporting the role of the RhoA/Rho kinase (ROCK) pathway in vasospasm has been described. Despite various proposed spasmolytics, there is no single effective agent. Factors including anatomic and physiologic variability in revascularization conduits, patient demographics and comorbidities have been associated with graft vasospasm pathogenesis and response to spasmolytics. Given this knowledge, the ideal spasmolytic agent likely needs to modulate multiple pathways to exert therapeutic effect. BTX A is a powerful neurotoxin widely used in clinical practice for the treatment of a variety of spastic conditions. Although its classic paradigm of cholinergic neural transmission blockade has been widely accepted, evidence for other possible mechanisms has been described. Other mechanisms involving modulation of adrenergic, ROCK and endothelial vasomotor pathways has been reported in animal studies. Recently, our group published the first pilot study describing use of BTX A for cerebral revascularization graft spasm prevention. The proposed study will utilize leftover arterial tissue samples collected pre- and post-BTX A treatment during cerebrovascular bypass surgery. We have recently established an Institutional Review Board approved fresh- frozen vascular tissue bank where the vascular tissue samples are stored and can be retrieved for research purposes. Targeted tissue, protein and molecular level analyses of BTX A effects on two major vasospastic pathways will be performed utilizing core facilities and research laboratories affiliated with our institution. Elucidating the mechanism of action for BTX A spasmolysis will help to fill a current gap in knowledge between human and animal studies and could provide the basis for a phase 2 clinical efficacy study. These findings also have the potential to expand the use of BTX A for vasospastic complications in cardiac revascularization and reconstructive surgery. Our basic science collaborations, vascular tissue bank and high clinical volume make our Cerebral Revascularization center a unique environment to perform this research.