| Abstract No.: | A-C1088 |
| Country: | Canada |
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| Title: | INTRACELLULAR PHOSPHOLIPASE A2 GROUP IVA AND GROUP VIA PLAY AN IMPORTANT ROLE IN WALLERIAN DEGENERATION AND AXON REGENERATION IN PERIPHERAL NERVE |
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| Authors/Affiliations: | 1 Rubčn López-Vales*; 2 Xavier Navarro; 5 Takao Shimuzu; 3 Constantino Baskakis; 3 George Kokotos; 3 Violetta Constantinou-Kokotou; 4 Daren Stephens; 4 Edward A. Dennis;
1 McGill University, Montreal, QC, Canada; 2 Universitat Autňnoma de Barcelona, Spain; 3 University of Athens, Greece; 4 University of California, San Diego, CA, USA; 5 University of Tokyo, Japan
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| Content: | Phospholipase A2s plays a normal physiological role in phospholipid metabolism, membrane turnover, host defence, signal transduction and inflammation. In previous studies we showed that the intracellular PLA2 family plays a crucial role in Wallerian degeneration. However, the specific contributions of the two members of the intracellular PLA2 family, namely calcium-dependent group IVA (cPLA2 GIVA) and calcium-independent group VIA (iPLA2 GVIA), in Wallerian degeneration are still unknown. Therefore, the aim of the present study is to dissect out the role of cPLA2 GIVA and iPLA2 GVIA in Wallerian degeneration after sciatic nerve crush injury. To carry out these experiments we did sciatic nerve crush in cPLA2 GIVA-/- mice or in wild-type littermates mice treated with a novel selective inhibitor of iPLA2 GVIA (FKGK11). Additionally, the effects of both these PLA2s were assessed by treating cPLA2 GIVA null mice with the iPLA2 inhibitor. Wallerian degeneration was assessed by studying the levels mRNA expression levels of MCP-1 and IL1 at day 1 post-injury (dpi), and by counting the number of phagocytic macrophages and fibers in degeneration in toluidine blue stained sections of the nerve at 7 and 21dpi. Axonal regeneration was assessed by counting the GAP-43 positive fibers at 4 dpi, by studying the reinnervation of PGP 9.5 fibers in the plantar pad at 21dpi, and by using several functional tests. Our data suggest that iPLA2 GVIA may play a role in the early stages of myelin breakdown, while cPLA2 GIVA may play a 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 provide direct evidence that intracellular PLA2s (cPLA2 GIVA and iPLA2 GVIA), contribute importantly to various aspects of Wallerian degeneration in injured peripheral nerves which is then essential for successful axon regeneration. |
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