Globoid cell leukodystrophy (
Krabbe disease) is an inherited
neurological disorder caused by the pathogenomic accumulation of
psychosine (
galactosylsphingosine), a substrate for the deficient
enzyme galactocerebroside beta-galactosidase. This study underscores the mechanism of action of
psychosine in the regulation of oligodendrocyte cell death via the generation of
lysophosphatidylcholine (LPC) and
arachidonic acid (AA) by the activation of
secretory phospholipase A2 (
sPLA2). There was a significant increase in the level of LPC, indicating a
phospholipase A2 (PLA2)-dependent pathobiology, in the brains of
Krabbe disease patients and those of twitcher mice, an animal model of
Krabbe disease. In vitro studies of the treatment of primary oligodendrocytes and the oligodendrocyte MO3.13 cell line with
psychosine also showed the generation of LPC and the release of AA in a dose- and time-dependent manner, indicating
psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic
phospholipase A2 and
sPLA2 and
psychosine-mediated induction of
sPLA2 enzymatic activity in media supernatant suggest that
psychosine-induced release of AA and generation of LPC is mainly contributed by
sPLA2. An inhibitor of
sPLA2, 7,7-dimethyl eicosadienoic
acid, completely attenuated the
psychosine-mediated accumulation of LPC levels, release of AA, and generation of
reactive oxygen species, and blocked oligodendroyte cell death, as evident from cell survival, DNA fragmentation, and
caspase 3 activity assays. This study documents for the first time that
psychosine-induced cell death is mediated via the
sPLA2 signaling pathway and that inhibitors of
sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting
demyelination in
Krabbe disease.