Stroke represents one of the most prevalent pathologies in humans and is a leading cause of death and disability. There is a narrow time window for therapeutic interventions based on recanalization procedures and attenuators of secondary damage to prevent neuronal death and damage. Most stroke patients are outside of the therapeutic window or are non-responders to r-tPA or surgical thrombectomy. We aim to validate therapeutic molecules to attenuate secondary injury specifically focused to target excitotoxicity, oxidative stress and spreading depolarization and their associated inverse hemodynamic responses.
The definitive damage is relatively well established several days after stroke, when neuroprotective agents are no longer efficient. It is after this point (sub-acute/chronic) that tissue reorganization in damaged circuitry and peri-injury areas can take place via rehabilitation and neural repair strategies. Because the injured brain has a limited ability to repair itself, we aim to stimulate structural and functional rewiring in damaged and peri-lesional areas by a combination of mesenchymal stem cells- and rehabilitation-based therapies. We also study the structural and functional substrates between cerebral areas that underlie cortical reorganization and support functional recovery.
Secondary injury increases lesion extension after stroke. (A) After hypoxia, stroke triggers excitotoxicity, blood flow changes, inflammation, and oxidative stress, which produce secondary damage, (B) The image shows a mouse brain (MCAO model) 24 hours after permanent ischemia. Immediately after MCAO, a wave of terminal depolarization was electrophysiological recorded in peri-lesional areas (parietal cortex, PtA) and in non-damaged distant areas (occipital, OcA). (C) At the top, representative coronal brain sections from two mice stained with TTC. In the middle, as part of the inflammatory response, an intense astrogliosis (Glial Fibrillary Acidic Protein staining) can usually be detected in the infarcted hemisphere. In the bottom, representative brain sections stained with dihydroethidium (DHE) to detect reactive oxygen species and intracellular superoxide (O2-). The image shows DHE staining (in red) in a mouse brain 8 hours after MCAO, which was localized in the peri-lesional tissue in perinuclear locations (the nuclei are stained with DAPI). González-Nieto et al. 2020. Biomaterials to Neuroprotect the Stroke Brain: A Large Opportunity for Narrow Time Windows. doi: 10.3390/cells9051074.
Somatosensory evoked potentials (SSEPs) are impaired after distal Middle cerebral artery occlusion. (A) Example SSEPs recorded from the damaged (black lines) and intact (blue lines) cortices in response to contralateral forepaw stimulation. Normalized EP response amplitudes after contralateral stimulation of the infarcted (B) and sham mice (C) across time post-surgery. Barios et al. 2016. Long-term dynamics of somatosensory activity in a stroke model of distal middle cerebral artery oclussion. doi: 10.1177/0271678X15606139..
(A) Representative diffusion-weighted MRI images of coronal sections showing infarct areas as a distinct hyperintense (white) area in two mice 48 hours after dMCAO surgery. Scores for (B) laterality index and (C) left forepaw footslips at different time points.
Post-stroke impairments in the functions of somatosensory and motor cortex territories. (A) Schematic showing the dorsal view of a mouse brain and the motor (green, FLm1) and the somatosensory (blue, FLs1) forelimb map. The soft red area represents the infarcted territory produced using the. The blue and green circles represent the site of electrodes implantation with respect to bregma (black diamond) that were used to record the evoked activity. Right panels show the position of the electrodes in coronal brain sections. (B) Evoked activity in FLs1 and cFLm1 after forelimb stimulation. (C, D) Amplitude of responses in FLs1 and cFLm1 for the left and right hemisphere under non-stroke (C, panel i) and stroke (D, panel i) conditions. Fernández-García et al. 2018. Cortical Reshaping and Functional Recovery Induced by Silk Fibroin Hydrogels-Encapsulated Stem Cells Implanted in Stroke Animals. doi: 10.3389/fncel.2018.00296.