Excitotoxicity-induced endocytosis as a potential target for stroke neuroprotection.
Ontology highlight
ABSTRACT:
SUBMITTER: Diaz-Guerra M
PROVIDER: S-EPMC7896228 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Publications
Excitotoxicity-induced endocytosis as a potential target for stroke neuroprotection.
Neural regeneration research 20210201 2
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Project description:Neuroprotective strategies aimed to pharmacologically treat stroke, a prominent cause of death, disability and dementia, have remained elusive. A promising approach is restriction of excitotoxic neuronal death in the infarct penumbra through enhancement of survival pathways initiated by brain-derived neurotrophic factor (BDNF). However, boosting of neurotrophic signaling after ischemia is challenged by downregulation of BDNF high-affinity receptor, full-length tropomyosin-related kinase B (TrkB-FL), due to calpain-degradation and, secondarily, regulated intramembrane proteolysis. Here, we have designed a blood-brain barrier (BBB) permeable peptide containing TrkB-FL sequences (TFL457) which prevents receptor disappearance from the neuronal surface, early induced after excitotoxicity. In this way, TFL457 interferes TrkB-FL cleavage by both proteolytic systems and increases neuronal viability via a PLC?-dependent mechanism. By preserving downstream CREB and MEF2 promoter activities, TFL457 initiates a feedback mechanism favoring increased levels in excitotoxic neurons of critical prosurvival mRNAs and proteins. This neuroprotective peptide could be highly relevant for stroke therapy since, in a mouse ischemia model, it counteracts TrkB-FL downregulation in the infarcted brain, efficiently decreases infarct size and improves neurological outcome.
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