Diagnostic and Neuroprotective Tools for Excitotoxicity and Brain Ischemia
The “Diagnostic and Neuroprotective Tools for Excitotoxicity and Brain Ischemia” group is dedicated to the identification of molecules with diagnostic value and the development of neuroprotective drugs relevant to stroke and other pathologies similarly associated to excitotoxicity. This form of neural cell death induced by overactivation of the receptors for the excitatory neurotransmitter glutamate is a central mechanism of stroke, although it is also important in acute disorders (hypoglycemia, trauma) or chronic conditions (neurodegenerative diseases such as Alzheimer disease or multiple sclerosis) of the nervous system. These studies are very relevant since these disorders are globally highly prevalent and constitute a first-order social and health problem, worsened by aging of the world population. However, neuroprotective strategies to pharmacologically treat these conditions have remained elusive over the years. In the case of ischemic stroke, a prominent cause of death (≈6 million per year), disability and dementia worldwide, we are exploring a new therapeutic approach involving restriction of the excitotoxic neuronal death in the infarct penumbra, a damaged brain area potentially recoverable, through the promotion of survival pathways. To reach these goals, we have the following specific objectives:
- Characterization in depth of the mechanisms of excitotoxicity, primarily the contribution of survival signaling cascades initiated by neurotransmitters and neurotrophins, which are subverted in neurons and oligodendrocytes by the overactivation of the glutamate receptors. For example, we have demonstrated that neurotrophic signaling mediated by brain-derived neurotrophic factor (BDNF) is challenged after ischemia by downregulation of its high-affinity receptor TrkB-FL due to calpain-degradation, regulated intramembrane proteolysis (RIP) of the TrkB-T1 truncated isoform producing a receptor ectodomain acting as a BDNF-scavenger or inactivation of the pro-survival transcription factor CREB.
- Identification of novel therapeutic targets which can be exploited for the design of neuroprotective strategies able to prevent, decrease or slow down excitotoxicity. Our results point to processing of the TrkB isoforms or that of postsynaptic density-95 protein (PSD-95) as important targets for interference of excitotoxicity.
- Recognition of novel mechanism-based biomarkers of brain damage to improve early detection and diagnosis of ischemic stroke and other excitotoxicity-associated conditions which could have an important clinical impact on prognosis and treatment.
- Development of peptides permeable to the blood-brain and blood-labyrinthine barriers able to respectively prevent death of neurons and oligodendrocytes or decrease cochlear synaptopathy in the inner ear, due to overactivation of glutamate receptors or decreased neurotrophic support. For instance, we have designed peptides able to preserve BDNF/TrkB/CREB signaling or the integrity of scaffold protein PSD-95 in excitotoxic conditions, which decrease the volume of cortical infarcts and improve the neurological outcome after a stroke.
In summary, our work is planned as a comprehensive study using animal models (stroke, multiple sclerosis or noise-induced hearing loss), primary culture of cortical cells (neurons and/or astrocytes) and cochlear explants to characterize in detail the cellular and molecular mechanisms subverted by disease in order to rationally and integrally develop therapeutic strategies based on brain- and inner ear-accessible protective peptides.