Interactions between neural membrane glycerophospholipid and sphingolipid mediators: A recipe for neural cell survival or suicide

Abstract

The neural membranes contain phospholipids, sphingolipids, cholesterol, and proteins. Glycerophospholipids and sphingolipids are precursors for lipid mediators involved in signal transduction processes. Degradation of glycerophospholipids by phospholipase A(2) (PLA(2)) generates arachidonic acid (AA) and docosahexaenoic acids (DHA). Arachidonic acid is metabolized to eicosanoids and DHA is metabolized to docosanoids. The catabolism of glycosphingolipids generates ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. These metabolites modulate PLA(2) activity. Arachidonic acid, a product derived from glycerophospholipid catabolism by PLA(2), modulates sphingomyelinase (SMase), the enzyme that generates ceramide and phosphocholine. Furthermore, sphingosine 1-phosphate modulates cyclooxygenase, an enzyme responsible for eicosanoid production in brain. This suggests that an interplay and cross talk occurs between lipid mediators of glycerophospholipid and glycosphingolipid metabolism in brain tissue. This interplay between metabolites of glycerophospholipid and sphingolipid metabolism may play an important role in initiation and maintenance of oxidative stress associated with neurologic disorders as well as in neural cell proliferation, differentiation, and apoptosis. Recent studies indicate that PLA(2) and SMase inhibitors can be used as neuroprotective and anti-apoptotic agents. Development of novel inhibitors of PLA(2) and SMase may be useful for the treatment of oxidative stress, and apoptosis associated with neurologic disorders such as stroke, Alzheimer disease, Parkinson disease, and head and spinal cord injuries.

Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

“…Glycerophospholipids (PCs and LysoPCs) are the major class of complex lipids playing essential roles in neural membrane formation and intraneuronal signal transduction (Farooqui et al, 2000;Farooqui et al, 2007). PCs are the most abundant glycerophospholipids that have a choline polar headgroup attached to the phosphate group.…”

Deregulation of sphingolipid metabolism in Alzheimer's disease

“…The five most common hypotheses include: excessive Aβ production, tau protein abnormalities, genetic predisposition (including mutations or polymorphisms in the presenilin 1 and 2, Aβ peptide precursor [APP], and/or apolipoprotein E genes), oxidative stress, and lipid alterations (phospholipids and neutral lipids) (Farooqui et al, 2007;Hartmann et al, 2007;Yankner et al, 2007).…”

Effects of Synthetic Sphingosine-1-Phosphate Analogs on Cytosolic Phospholipase A2α–Independent Release of Arachidonic Acid and Cell Toxicity in L929 Fibrosarcoma Cells: the Structure–Activity Relationship

“…The eicosanoids produced from AA metabolism in cells may play a role in cell death. In addition, many enzymes responsible for metabolizing AA produce hydroperoxides and other oxidative species, which are highly reactive and show cytotoxicity at low intracellular concentrations (4,37). The identification of the molecule(s) that is derived from AA and shows cytotoxicity is in progress in our laboratory.…”