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Neurotrasmitters and neurotrophic factors play fundamental roles in developing and adult mammalian nervous system, and a tightly regulated interplay between glutamate and BDNF signaling has been previously described. Glutamate, mainly throughout activation of the NMDA type of receptors (NMDARs), is central to synaptic plasticity, learning and memory as well as survival/death pathways. The activation by BDNF of its high-affinity TrkB receptor is likewise important.
The NMDARs are dichotomous molecules also involved in diverse pathologies including brain ischemia and neurodegenerative disorders, in which delayed neuronal death is mainly due to excitotoxicity induced by overstimulation of these receptors. Similarly, dysfunction of BDNF/TrkB pathways has been reported in some neurodegenerative diseases but to date evidence of similar modifications in stroke is lacking. Interestingly, decreased BDNF/TrkB signaling has been also proposed as a pathological mechanism of depression, a highly prevalent psychiatric condition among stroke survivors.
In our laboratory we are trying to characterize if NMDAR and BDNF/TrkB pathways are also interrelated under pathological conditions such as those found in cerebrovascular diseases. By analyzing the coordinated regulation of these proteins, we will: 1) get a better knowledge of the pathological mechanisms underlying stroke, post-stroke depression and, perhaps, neurodegenerative diseases; 2) develop mechanism-based surrogate markers of brain damage to improve the diagnosis of ischemic stroke; 3) identify new molecular targets for neuroprotection, and 4) develop novel therapeutic strategies in stroke and neurodegenerative diseases.
Our work is planned as a comprehensive study where we are using several experimental paradigms: animal models of cerebral ischemia where excitotoxicity takes place in vivo, and cellular models based on NMDAR-agonist treatment of primary cultures of cortical neurons. More important findings are also being challenged in human samples from patients suffering cerebrovascular disease (blood and necropsies).