Modulació de marcadors de neuroreparació en teràpies rehabilitadores després de l’ictus i en un model preclínic d’isquèmia cerebral

Abstract

The high incidence of stroke leaves many people affected by physical and motor impairments. Currently, the only treatments available in the acute phase of stroke, which aims to minimize brain damage, are the thrombolitic therapies using drugs such as t-PA (<4.5h) or mechanical strategies such as endovascular therapies (<6h and within the first 24h in selected patients) for those patients who have an arterial occlusion. Unfortunately, due to the strict inclusion criteria of these treatments, only a minority of patients can benefit from these. Hence, there is a need to study alternative treatments during the chronic phases of stroke in order to improve the neurological deficits derived from this disease. To date, rehabilitation is the only approved treatment that target to recover the motor functions and improve the quality of life of those disabled patients. However, the individual response to rehabilitation therapies is heterogeneous and it is unknown why some patients do not respond to therapy as expected. The objective of this thesis is to explore new biomarkers to deeply understand the neurological status of stroke ischemic patients during rehabilitation strategies and to study the underlying cerebral mechanisms active during rehabilitation therapies in an animal model of neurorehabilitation. Angiogenin (ANG) and endothelial progenitor cells (EPCs) have been associated with vascular remodeling processes in different pathologies, and more specifically, EPCs have been described in patients as potential markers of neurological status. For this, they are the candidate biomarkers of our study. The results show an increase of ANG in patients after one month of intensive rehabilitation therapy compared to pre-therapy and healthy controls levels. On the other hand, the levels of EPCs increased before the therapy as a result of stroke and their levels have also been maintained during 3-6 months of therapy in comparison to healthy controls. Moreover, ANG has been associated with a functional improvement in the patient's condition in the Barthel index, Medical Research Council and Rankin scales. In parallel to clinic investigations, we used two different animal models of rehabilitation (task-specific and physical exercise) after an experimental cerebral ischemia. Task-specific exercise increases the expression of ang in both hemispheres after 12 days of rehabilitation, whereas physical exercise increases its expression in the contralateral hemisphere. Interestingly, both strategies activate the formation of vessels in the contralateral cortex. Besides, physical exercise stimulates the expression of neuroblasts in the subventricular zone (neurotrophic niche) and ANG expression is identified for the first time in neuroblasts. Finally, by in vitro studies, different stem cells and progenitors were treated with exogenous ANG and we report a stimulation of neural stem cell precursors of neuroblasts after treatment, however not in their differentiation. Additionally, ANG stimulates the function of EPCs in vitro, which demonstrates its implication in angiogenesis by increasing the formation of tubular structures and the rate of cell migration. In summary, this thesis proposes ANG and EPCs as future biomarkers to evaluate the patients’ response to rehabilitation and concludes that rehabilitation is capable to modify the endogenous response by enhancing neurorepair mechanisms related to angiogenesis and neurogenesis, where ANG could play a relevant role.

Date of Award	12 Jun 2018
Original language	Catalan
Supervisor	Anna Rosell Novel (Director) & Antonio Armario Garcia (Tutor)