The involvement of Phospholipase, A2 in Wallerian degeneration /

Abstract

Phospholipase A2 (PLA2) enzymes target membrane phospholipids to liberate free fatty acids, such as arachidonic acid, a precursor of inflammatory mediators, as well as lysophospholipids which disrupt membrane structure. Unlike the PNS, Wallerian degeneration is very slow in the injured adult mammalian CNS. This slow removal of myelin, which contains axon growth inhibitors, contributes to the failure of CNS regeneration. Via its metabolic products, PLA2 may help mediate myelin breakdown and macrophage recruitment for debris clearance in Wallerian degeneration. In this study, immunohistochemical analysis was used to assess whether PLA2 expression correlates with differing rates of Wallerian degeneration. Indeed, cytosolic (cPLA2) and secreted PLA2 (sPLA2) are strongly upregulated early (five hours) in the crushed adult rat sciatic nerve (PNS) and continue to be expressed for up to ten days, i.e. during the period of myelin breakdown and phagocytosis. In the injured optic nerve (CNS) however, both forms of PLA2 are upregulated very late (eight weeks) after lesioning. Furthermore, in C57BL/Wlds mutant mice, a strain that undergoes delayed Wallerian degeneration in injured peripheral nerves and also has a null mutation for the story type II sPLA2, no cPLA 2 expression was observed up to ten days post-crush (duration of study) in contrast to the wild-type mouse. Blocking cPLA2 activity in transected sciatic nerves of C57BL/6J mice, also deficient in sPLA2 type II, markedly slowed myelin breakdown and phagocytosis. Together, these observations show strong evidence for the involvement of both forms of PLA 2 in mediating rapid Wallerian degeneration