The Role of Secretory Phospholipase A2 in the Central Nervous System and Neurological Diseases

Secretory phospholipase A(2) (sPLA(2)s) are small secreted proteins (14-18 kDa) and require submillimolar levels of Ca2+ for liberating arachidonic acid from cell membrane lipids. In addition to the enzymatic function, sPLA(2) can exert various biological responses by binding to specific receptors. Physiologically, sPLA(2)s play important roles on the neurotransmission in the central nervous system and the neuritogenesis in the peripheral nervous system. Pathologically, sPLA(2)s are involved in the neurodegenerative diseases (e.g., Alzheimer's disease) and cerebrovascular diseases (e.g., stoke). The common pathology (e.g., neuronal apoptosis) of Alzheimer's disease and stroke coexists in the mixed dementia, suggesting common pathogenic mechanisms of the two neurological diseases. Among mammalian sPLA(2)s, sPLA(2)-IB and sPLA(2)-IIA induce neuronal apoptosis in rat cortical neurons. The excess influx of calcium into neurons via l-type voltage-dependent Ca2+ channels mediates the two sPLA(2)-induced apoptosis. The elevated concentration of intracellular calcium activates PKC, MAPK and cytosolic PLA(2). Moreover, it is linked with the production of reactive oxygen species and apoptosis through activation of the superoxide producing enzyme NADPH oxidase. NADPH oxidase is involved in the neurotoxicity of amyloid beta peptide, which impairs synaptic plasticity long before its deposition in the form of amyloid plaques of Alzheimer's disease. In turn, reactive oxygen species from NADPH oxidase can stimulate ERK1/2 phosphorylation and activation of cPLA(2) and result in a release of arachidonic acid. sPLA(2) is up-regulated in both Alzheimer's disease and cerebrovascular disease, suggesting the involvement of sPLA(2) in the common pathogenic mechanisms of the two diseases. Thus, our review presents evidences for pathophysiological roles of sPLA(2) in the central nervous system and neurological diseases.