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Journal of Neuroinflammation

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Open Access 01-12-2016 | Research

CXCL12-induced neurotoxicity critically depends on NMDA receptor-gated and l-type Ca²⁺ channels upstream of p38 MAPK

Authors: Ana B. Sanchez, Kathryn E. Medders, Ricky Maung, Paloma Sánchez-Pavón, Daniel Ojeda-Juárez, Marcus Kaul

Published in: Journal of Neuroinflammation | Issue 1/2016

Abstract

Background

The chemokine receptor CXCR4 (CD184) and its natural ligand CXCL12 contribute to many physiological processes, including decisions about cell death and survival in the central nervous system. In addition, CXCR4 is a co-receptor for human immunodeficiency virus (HIV)-1 and mediates the neurotoxicity of the viral envelope protein gp120. However, we previously observed that CXCL12 also causes toxicity in cerebrocortical neurons but the cellular mechanism remained incompletely defined.

Methods

Primary neuronal-glial cerebrocortical cell cultures from rat were exposed to a neurotoxicity-inducing CXCL12 concentration for different times and the activity of the stress-associated mitogen-activated protein kinase p38 (p38 MAPK) was assessed using an in vitro kinase assay. Neurotoxicity of CXCL12 and cellular localization of p38 MAPK was analyzed by immunofluorescence microscopy. Pharmacological inhibition of NMDA-type glutamate receptor-gated ion channels (NMDAR) of l-type Ca²⁺ channels was employed during 12- and 24-h exposure to neurotoxic amounts of CXCL12 to study the effects on active p38 MAPK and neuronal survival by Western blotting and microscopy, respectively. Neurotoxicity of CXCL12 was also assessed during pharmacological inhibition of p38 MAPK.

Results

Here, we show that a neurotoxic amount of CXCL12 triggers a significant increase of endogenous p38 MAPK activity in cerebrocortical cells. Immunofluorescence and Western blotting experiments with mixed neuronal-glial and neuron-depleted glial cerebrocortical cells revealed that the majority of active/phosphorylated p38 MAPK was located in neurons. Blockade of NMDAR-gated ion channels or l-type Ca²⁺ channels both abrogated an increase of active p38 MAPK and toxicity of CXCL12 in cerebrocortical neurons. Inhibition of l-type Ca²⁺ channels with nimodipine kept the active kinase at levels not significantly different from baseline while blocking NMDAR with MK-801 strongly reduced phosphorylated p38 MAPK below baseline. Finally, we confirmed that directly blocking p38 MAPK also abrogated neurotoxicity of CXCL12.

Conclusions

Our findings link CXCL12-induced neuronal death to the regulation of NMDAR-gated ion channels and l-type Ca²⁺ channels upstream of p38 MAPK activation.

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Title: CXCL12-induced neurotoxicity critically depends on NMDA receptor-gated and l-type Ca2+ channels upstream of p38 MAPK
Authors: Ana B. Sanchez
Kathryn E. Medders
Ricky Maung
Paloma Sánchez-Pavón
Daniel Ojeda-Juárez
Marcus Kaul
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-016-0724-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

CXCL12-induced neurotoxicity critically depends on NMDA receptor-gated and l-type Ca²⁺ channels upstream of p38 MAPK

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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