Estudio de las subunidades reguladas por SUR1 (Kir6.2 i TRPM4) en las contusiones cerebrales traumáticas y la isquemia cerebral focal. Desarrollo de un modelo animal de infarto maligno en cerdo.

Student thesis: Doctoral thesis


Traumatic brain injury (TBI) has a great socio-economic and sanitary impact in the whole world and is one of the leading causes of mortality and disability in adult population with less than 40 years. Malignant cerebral infarction is a type of ischemic cerebral infarct that has an elevated mortality of around 80%, and its incidence increases with the age of the patient. The evolution of both pathologies can lead to severe ionic disarrangements in neurons and glial cells, osmotic water displacement and cytotoxic edema formation. Edema can evolve causing a mass effect that leads to compression, deformation and herniation of the cerebral structures that can result in patient’s death, due to the increase of the intracranial pressure (ICP), among other causes. TBIs and malignant infarcts are treated following the same strategies, which are the monitoring of lesion evolution, multimodal monitoring of the patient and as a last resort, surgical intervention. Understanding the processes involved in the pathophysiology of the TBI and cerebral infarct, is essential for their correct treatment. Many of the current studies, focus their attention on the mechanisms involved in the formation of the initial cytotoxic edema and specially, in the study of a new ionic channel that is related to the progression of the edema. This channel is constituted by a regulator subunit named sulfonylurea receptor 1 (SUR1) and a pore forming subunit called transient receptor potential melastatin 4 (TRPM4). Both subunits together form the channel SUR1-TRPM4 that is overexpressed in patients and in animal models of TBI and cerebral infarct, among other pathologies. The blockage of this channel with drugs like glibenclamide (an inhibitor of sulfonylureas), has demonstrated to improve neurological outcome in rodent animal models and also in clinical assays with patients. Regulator subunit SUR1 is not only associated to TRPM4, but also regulates the opening of adenosine phosphate (ATP)-sensitive potassium channels (KATPs), which include the inwardly rectifier potassium ion channel 6.2 (Kir6.2). The channel SUR1-Kir6.2 has been well studied in pancreatic and cardiac cells, among others. However, the expression of this channel has not been deeply studied in the human brain. This channel couples cell metabolism to electric activity, regulating the K+ flux through the cell membrane. It is considered that it has a neuroprotective function, inducing the cell hyperpolarization during hypoxic and/or ischemic episodes. The aim of this doctoral thesis is, first of all, the development of a new animal model of regional ischemia in common pig, stable and reproducible. This model will allow a better understanding of the ischemic processes that occur in patients with a malignant cerebral infarction, to extrapolate it in second place to traumatic brain lesions. The use of animal models is essential to achieve a better understanding of the mechanisms involved in any pathology, and to develop new treatment strategies. The aim of the second part of this thesis was to study in detail the channels regulated by SUR1, and especially Kir6.2 channel, the less studied in human brain to the date. For this purpose, Kir6.2 expression was studied in human pericontusional brain tissue, with the aim to achieve a better understanding of its function in this kind of pathologies.
Date of Award20 Sept 2019
Original languageSpanish
SupervisorJoan Sahuquillo Barris (Director) & Joan Sahuquillo Barris (Tutor)

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