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Brain Advance Access published online on August 21, 2008
Brain, doi:10.1093/brain/awn188
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Intracellular phospholipase A2 group IVA and group VIA play important roles in Wallerian degeneration and axon regeneration after peripheral nerve injury

Rubèn López-Vales1, Xavier Navarro2, Takao Shimizu3, Constantinos Baskakis4, George Kokotos4, Violetta Constantinou-Kokotou5, Daren Stephens6, Edward A. Dennis6 and Samuel David1

1Centre for Research in Neuroscience, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada, 2Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Catalonia, Spain, 3Department of Biochemistry and Molecular Biology, University of Tokyo, Tokyo, Japan, 4Department of Chemistry, University of Athens, Athens, 5Chemical Laboratories, Agricultural University of Athens, Athens, Greece and 6Department of Chemistry & Biochemistry, School of Medicine, University of California, San Diego, La Jolla, CA, USA

Correspondence to: Dr Samuel David, Center for Research in Neuroscience, Research Institute of the McGill University Health Center, Livingston Hall, Room L7-210, 1650 Cedar Ave., Montreal, Québec H3G 1A4, Canada E-mail: sam.david{at}mcgill.ca

We provide evidence that two members of the intracellular phospholipase A2 family, namely calcium-dependent group IVA (cPLA2 GIVA) and calcium-independent group VIA (iPLA2 GVIA) may play important roles in Wallerian degeneration in the mouse sciatic nerve. We assessed the roles of these PLA2s in cPLA2 GIVA–/– mice, and mice treated with a selective inhibitor of iPLA2 GVIA (FKGK11). Additionally, the effects of both these PLA2s were assessed by treating cPLA2 GIVA–/– mice with the iPLA2 inhibitor. Our data suggest that iPLA2 GVIA may play more of a role in the early stages of myelin breakdown, while cPLA2 GIVA may play a greater role in myelin clearance by macrophages. Our results also show that the delayed myelin clearance and Wallerian degeneration after sciatic nerve crush injury in mice lacking cPLA2 and iPLA2 activities is accompanied by a delay in axon regeneration, target re-innervation and functional recovery. These results indicate that the intracellular PLA2s (cPLA2 GIVA and iPLA2 GVIA) contribute significantly to various aspects of Wallerian degeneration in injured peripheral nerves, which is then essential for successful axon regeneration. This work has implications for injury responses and recovery after peripheral nerve injuries in humans, as well as for understanding the slow clearance of myelin after CNS injury and its potential consequences for axon regeneration.

Key Words: axon regeneration; myelin; macrophage; phagocytosis; phospholipase A2; sciatic nerve injury

Abbreviations: cPLA2, calcium-dependent PLA2; iPLA2, calcium-independent PLA2; LPC, lysophosphatidylcholine; PLA2, phospholipase A2; SFI, sciatic functional index (SFI)

Received March 12, 2008. Revised July 17, 2008. Accepted July 28, 2008.


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