Abstract
Background: Chemokine receptor type 4 (CXCR4) plays a role in neuronal survival/cell repair and also contributes to the progression of cancer and neurodegenerative diseases. Chemokine ligand 12 (CXCL12) binds to CXCR4. In this study, we have investigated whether CXCR4 blockade by AMD3100 (a CXCR4 antagonist, member of bicyclam family) may affect neuronal survival in the absence of insult. Thus, we have measured the mitochondrial membrane potential (MMP), Bax and Bcl-2 protein translocation, and cytochrome c release in AMD3100-treated brain cortical neurons at 7 DIV (days in vitro). Methods: For this aim, AMD3100 (200 nM) was added to cortical neurons for 24 h, and several biomarkers like cell viability, reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) release, caspase-3/9 activity, proteins Bax and Bcl-2 translocation, and cytochrome c release were analyzed by immunoblot. Results: CXCR4 blockade by AMD3100 (200 nM, 24 h) induces mitochondrial hyperpolarization and increases caspase-3/9 hyperpolarization without affecting LDH release as compared to untreated controls. AMD3100 also increases cytochrome c release and promotes Bax translocation to the mitochondria, whereas it raises cytosolic Bcl-2 levels in brain cortical neurons. Conclusion: CXCR4 blockade induces cellular death via intrinsic apoptosis in rat brain cortical neurons in absence of insult.
Highlights
Chemokine receptor type 4 (CXCR4) is a seven-transmembrane G-α-chemokine-coupled receptor (GPCR) [1] specific for stromal-derived-factor-1 (SDF-1α), called CXCL12
Since SDF-1α regulates axonal length [32], we have studied, in rat brain cortical neurons in absence of insults, whether CXCR4 blockade by AMD3100 (CXCR4 antagonist) could affect some physiological parameters related to cell viability and mitochondrial function
The main aim of the present study was to study whether CXCR4 blockade by AMD3100 could induce cell death in rat brain cortical neurons in the absence of insults
Summary
Chemokine receptor type 4 (CXCR4) is a seven-transmembrane G-α-chemokine-coupled receptor (GPCR) [1] specific for stromal-derived-factor-1 (SDF-1α), called CXCL12 (chemokine ligand 12, its ligand). CXCR4-mutant mice have aberrant neuronal distribution in brain [10] These findings highlight the diverse role of chemokines and their receptors (including CXCR4) in normal brain physiology (in the absent of insults). Chemokine receptor type 4 (CXCR4) plays a role in neuronal survival/cell repair and contributes to the progression of cancer and neurodegenerative diseases. Methods: For this aim, AMD3100 (200 nM) was added to cortical neurons for 24 h, and several biomarkers like cell viability, reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) release, caspase-3/9 activity, proteins Bax and Bcl-2 translocation, and cytochrome c release were analyzed by immunoblot. AMD3100 increases cytochrome c release and promotes Bax translocation to the mitochondria, whereas it raises cytosolic Bcl-2 levels in brain cortical neurons. Conclusion: CXCR4 blockade induces cellular death via intrinsic apoptosis in rat brain cortical neurons in absence of insult
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