Browsing by Author "Gómez Lozano, Inés"

Stroke is the third most prevalent cause of death worldwide. The ischemic stroke accounting for 80% of all stroke cases occurs when the blood flow towards a certain part of the brain is interrupted, resulting in a compromised supply of nutrients and oxygen. This leads to a series of events including excitotoxicity, production of reactive oxygen species and inflammation, that ends in cell death and ultimately tissue damage. Current treatments include tissue plasminogen activator (t-PA) and/or mechanical thrombectomy, however they present several limitations, such as narrow therapeutic time windows, risk of hemorrhagic stroke and probability of forming a lacune. Alternative treatment strategies are currently being explored and neuroprotective strategies targeting inflammatory mediators have been extensively studied with limited success. Peroxisome proliferator-activated receptor β/δ (PPAR-β/δ) is a type of nuclear receptor that regulates gene expression related to energy metabolism, inflammation, and neuroprotection. Its implication on neuroinflammation poses it as a potential candidate for the development of stroke treatments. In fact, its agonist GW0742 has shown anti-inflammatory and anti-apoptotic properties in non-human tissues. Animal models are limited by species-specific differences. An alternative is pluripotent stem cell-derived 3D structures, also known as human organoids. They recapitulate the details of the physiological and structural characteristics of human tissue formations, which makes them perfect for drug discovery. Here I propose the first steps of an optimization process that includes the culture of whole brain organoids, following Lancaster et al. protocol, that are then exposed to 1% oxygen concentration for 48 hours trying to mimic the hypoxic condition during stroke. This optimization also encompasses the initial trials with the PPAR-β/δ agonist GW0742 as a possible treatment for neuroprotection during stroke. As seen by immunohistochemistry and gene expression results, hypoxia caused extremely severe damage to the structure of the organoids, however in few instances GW0742 has slightly helped to mitigate this damage, as seen in the increase of cell markers. The limited sample size and structural damage of the organoids prevents us from reaching robust conclusions. Nevertheless, further investigation and modification of methodologies are required to reach a meaningful conclusion.