Bax-inhibiting peptide protects glutamate-induced cerebellar granule cell death by blocking Bax translocation

• Published in: Neuroscience letters 2009-02, Vol.451 (1), p.11-15
• Main Authors: Iriyama, Takayuki, Kamei, Yoshimasa, Kozuma, Shiro, Taketani, Yuji
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Bax; Bax-inhibiting peptide; bcl-2-Associated X Protein - antagonists & inhibitors; bcl-2-Associated X Protein - metabolism; Biological and medical sciences; Caspase; Caspases - drug effects; Caspases - metabolism; Cerebellum; Cytochromes c - metabolism; Cytoprotection - drug effects; Cytoprotection - physiology; Dose-Response Relationship, Drug; Excitotoxicity; Fundamental and applied biological sciences. Psychology; Glutamate; Glutamic Acid - metabolism; Glutamic Acid - toxicity; Hypoxia-Ischemia, Brain - drug therapy; Hypoxia-Ischemia, Brain - metabolism; Hypoxia-Ischemia, Brain - physiopathology; In Situ Nick-End Labeling; Indicators and Reagents; Male; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Peptides - pharmacology; Peptides - therapeutic use; Protein Transport - drug effects; Protein Transport - physiology; Rats; Rats, Sprague-Dawley; Tetrazolium Salts; Vertebrates: nervous system and sense organs
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2008.12.021

Glutamate-induced excitotoxicity has been implicated in the pathogenesis of various neurological damages and disorders. In the brain damage of immature animals such as neonatal hypoxic-ischemic brain injury, the excitotoxicity appears to be more intimately involved through apoptosis. Bax, a member of the Bcl-2 family proteins, plays a key role in the promotion of apoptosis by translocation from the cytosol to the mitochondria and the release of apoptogenic factors such as cytochrome c. Recently, Bax-inhibiting peptide (BIP), a novel membrane-permeable peptide which can bind Bax in the cytosol and inhibit its translocation to the mitochondria, was developed. To investigate the possibility of a new neuroprotection strategy targeting Bax translocation in glutamate-induced neuronal cell death, cerebellar granule neurons (CGNs) were exposed to glutamate with or without BIP. Pretreatment of CGNs with BIP elicited a dose-dependent reduction of glutamate-induced neuronal cell death as measured by MTT assay. BIP significantly suppressed both the number of TUNEL-positive cells and the increase in caspases 3 and 9 activities induced by glutamate. In addition, immunoblotting after subcellular fractionation revealed that BIP prevented the glutamate-induced Bax translocation to the mitochondria and the release of cytochrome c from the mitochondria. These results suggest that agents capable of inhibiting Bax activity such as BIP might lead to new drugs for glutamate-related diseases in the future.