title: Anti-edema action of thyroid hormone in MCAO model of ischemic brain stroke: Possible association with AQP4 modulation.
abstract: The use of neuroprotective strategies to mitigate the fatal consequences of ischemic brain stroke is a focus of robust research activity. We have previously demonstrated that thyroid hormone (T3; 3,3',5-triiodo-l-thyronine) possesses neuroprotective and anti-edema activity in pre-stroke treatment regimens when administered as a solution or as a nanoparticle formulation. In this study we have extended our evaluation of thyroid hormone use in animal models of brain stroke. We have used both transient middle cerebral artery occlusion (t-MCAO) and permanent (p-MCAO) models of ischemic brain stroke. A significant reduction of tissue infarction and a concurrent decrease in edema were observed in the t-MCAO model of brain stroke. However, no benefit of T3 was observed in p-MCAO stroke setting. Significant improvement of neurological outcomes was observed upon T3 treatment in t-MCAO mice. Further, we tested T2 (3,5-diiodo-l-thyronine) a natural deiodination metabolite of T3 in MCAO model of brain stroke. T2 potently decreased infarct size as well as edema formation. Additionally, we report here that T3 suppresses the expression of aquaporin-4 (AQP4) water channels which could be a likely mechanism of its anti-edema activity. Our studies provide evidence to stimulate clinical development of thyroid hormones for use in ischemic brain stroke.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA. Electronic address: psadana@neomed.edu.
authors.forename: Prabodh
authors.initials: P
authors.lastname: Sadana
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Coughlin
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Burke
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Woods
authors.affiliation: Department of Rehabilitation Sciences, College of Allied Health, The University of Oklahoma, Health Sciences Center, Oklahoma City, OK 73117-1215, USA. Electronic address: Alexander-Mdzinarishvili@ouhsc.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mdzinarishvili
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000502:physiology*; D001929:Brain Edema / Q000188:drug therapy* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004104:Diiodothyronines / Q000008:administration & dosage*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D014284:Triiodothyronine / Q000008:administration & dosage*
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D004104:Diiodothyronines; D014284:Triiodothyronine; C030103:3,5-diiodothyronine
keywords: Aquaporin-4; Cerebral edema; Erythropoietin; Ischemic brain stroke; Middle cerebral artery occlusion (MCAO); Thyroid hormone