Novel therapeutic strategies for ischemic stroke: a sensorimotor/cognitive functional approach using a mouse preclinical stroke model

• Autor(a) principal: Melo, Lúcia Inês Cruz
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/37146
• topic: Ischemic stroke; Transthyretin; Neuroprotection; Therapeutic treatments; X-ray microtomography; Behavioural tests

Ischemic stroke is considered a leading cause of disability and death worldwide, including in Portugal. The approved therapies rely on reperfusion of the affected brain area, being intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) the only treatments available. In the last years, a reduction in mortality has been observed, but with a cost of an increase in the number of patients with long-term disabilities. As a result, new and better treatments are urgently needed to help patients overcome these disabilities. Through the improvement in the knowledge of stroke pathophysiology, new neuroprotective strategies are emerging, that aim to improve the quality of life of stroke patients. Several cytoprotective compounds have shown promising results in preclinical studies, but they failed in clinical trials, probably due to weak preclinical data and poor predictive data. In the last years, the naturally occurring protein transthyretin (TTR) has been suggested as a potential neuroprotectant. Some studies have shown several activities of TTR regarding the physiology of the nervous system. Neurogenesis, neuron regeneration, axonal growth, behaviour, and cognition are among the processes known to be impacted by TTR. In this study, we aimed to assess the therapeutic potential of upregulating TTR, in a mouse (C57/Bl6) preclinical model (tMCAO - transient middle cerebral artery occlusion). For that purpose, we have evaluated the sensorimotor and cognitive functions, which show deficits following the induction of ischemia, through a behavioural workflow. In addition to outcome assessment, we have also evaluated the location and volume of the ischemic lesion. Most of the histological and functional assessments showed that daily intravenous administration of TTR, upregulation, led to a significant improvement in the incapacities induced by ischemic stroke. TTR should be further explored as a new functional therapy, after an ischemic stroke.