Herramientas diagnósticas y de neuroprotección en excitotoxicidad e isquemia

Stroke is the second leading cause of world mortality, the major cause of adult disability and the second of dementia. However, therapies for ischemic stroke (85% of cases) are still limited to thrombolytic drugs, only administered very early after stroke onset (<4.5 h) and contraindicated for hemorrhagic ischemia and other medical conditions. Thus, we urgently need to develop new neuroprotective therapies and identify blood biomarkers for acute stroke. Among therapies directed to prevent disease progression, the inhibition of secondary neuronal death affecting regions surrounding the infarct is very important. The main mechanism of this death is excitotoxicity induced by overactivation of the NMDA type of glutamate receptors (NMDARs), a process also associated to other acute and chronic brain disorders such as neurodegenerative diseases.

During ischemia, excitotoxicity affects the function of proteins central to survival/death choices such as the NMDAR subunits, neurotrophin receptor TrkB, and their interacting proteins Kidins220 and PSD-95. By characterizing these aberrant survival pathways, we have identified specific therapeutic targets that we are exploring for the design of neuroprotective molecules containing cell-penetrating peptides as carriers to cross the blood-brain barrier. The developed peptides interfere excitotoxicity in vitro and in vivo by maintaining glutamate and/or BDNF-dependent survival pathways, which results in a decrease of the infarct volume and recovery of neurological function in mice subjected to ischemia.