Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 28, 2025

Cerebral ischemia triggers a cascade of detrimental events, leading to brain damage mainly due the over-excitation neurons. Currently, clinically applicable neuroprotective treatments stop progressive neuronal death remain elusive. The GABAB receptor, crucial for inhibition, is promising target neuroprotection because it inhibits which otherwise leads excitotoxic death. However, ischemic conditions impair receptor function by downregulating receptors via pathologically altered trafficking events. Previously, we developed interfering peptides inhibit interaction with key interacting proteins, pathological downregulation receptors. These restored expression and function, resulting in reduced excitability neurons in-vitro ex-vivo models cerebral ischemia. were not effective in-vivo their limited proteolytic stability after systemic application. Here, aimed render three resistant degradation replacing natural L-amino acids D-amino acids. Additionally, optimized blood barrier shuttle (BBBpS) sequence derived from Rabies virus glycoprotein (RVG) that mediates neuron-specific uptake blood-brain crossing these peptides. By optimizing peptides, stable, successfully prevented following stress cultured In vivo testing middle artery occlusion (MCAO) mouse model demonstrated activity significantly infarct size. findings confirm potential as agents emphasize importance peptide drugs successful

Language: Английский