NEUROPROTECTIVE PEPTIDES IN EXOCITOTOXICITY AND STROKE (PI: Dra M. Diaz-Guerra)

Research topics

Keywords: neuroprotection, neurodegeneration, stroke, excitotoxicity, cell-penetrating peptides, glutamate/NMDAR, BDNF/TrkB, calpain, CREB/MEF2, PSD-95


Stroke is the second cause of death worldwide and leading cause of adult disability and dementia. Pharmacological therapies for ischemic stroke (85% of cases) are still limited to thrombolytic drugs, which can be only administered to very few patients.

Cerebrovascular accidents are unpredictable and, therefore, primary death of neurons in the ischemic core cannot be avoided. However, secondary neuronal death progressively affecting the ischemic penumbra might be potentially prevented to reduce brain damage. In order to develop neuroprotective drugs for stroke therapy, we propose:

  •  A comprehensive characterization of the pathological processes induced by excitotoxicity, main mechanism of the secondary neuronal death, which subvert pro-survival pathways such as those regulated by neurotrophins and neurotrasmitters.
  • Selection of rational targets for stroke neuroprotection such as increased endocytosis/processing of BDNF receptor TrkB or dephosphorylation/calpain processing of CREB transcription factor, both induced in excitotoxicity.
  • Development and refinement of cell-penetrating peptides (CPPs) able to cross the blood-brain barrier and preserve functioning of those critical survival pathways in pathological conditions.

Tile image of mice cortical and sub-cortical areas showing entry of an intravenously injected biotinylated-CPP into brain

 

  •  In depth characterization of these CPPs’ mechanisms of action in neurons and/or astrocytes.
  • Test of these neuroprotective peptides in pre-clinical models of stroke and neurodegenerative diseases associated to excitotoxicity. The complexity of these pathologies instructs us to combine peptides having different targets or those CPPs with BDNF, TrkB agonists or certain NMDAR antagonists

 

Model explaining the mechanism of action of neuroprotective peptide TFL457 which prevents excitotoxicity-induced processing of BDNF receptor TrkB-FL

 

To accomplish these objectives, we are using primary cultures of cortical neurons and/or astrocytes, animal models of brain ischemia and human samples from stroke patients (plasma and brain necropsias).

 

 

 




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