Role of Ca²⁺‐independent phospholipase A₂ and n−3 polyunsaturated fatty acid docosahexaenoic acid in prostanoid production in brain: perspectives for protection in neuroinflammation

Abstract

Various diseases of the central nervous system are characterized by induction of inflammatory events, which involve formation of prostaglandins. Production of prostaglandins is regulated by activity of phospholipases A(2) and cyclooxygenases. These enzymes release the prostaglandin precursor, the n-6 polyunsaturated fatty acid, arachidonic acid and oxidize it into prostaglandin H(2). Docosahexaenoic acid, which belongs to the n-3 class of polyunsaturated fatty acids, was shown to reduce production of prostaglandins after in vivo and in vitro administration. Nevertheless, the fact that in brain tissue cellular phospholipids naturally have a uniquely high content of docosahexaenoic acid was ignored so far in studies of prostaglandin formation in brain tissue. We consider the following possibilities: docosahexaenoic acid might attenuate production of prostaglandins by direct inhibition of cyclooxygenases. Such inhibition was found with the isolated enzyme. Another possibility, which has been already shown is reduction of expression of inducible cyclooxygenase-2. Additionally, we propose that docosahexaenoic acid could influence intracellular Ca(2+) signaling, which results in changes of activity of Ca(2+)-dependent phospholipase A(2), hence reducing the amount of arachidonic acid available for prostaglandin production. Astrocytes, the main type of glial cells in the brain control the release of arachidonic acid, docosahexaenoic acid and the formation of prostaglandins. Our recently obtained data revealed that the release of arachidonic and docosahexaenoic acids in astrocytes is controlled by different isoforms of phospholipase A(2), i.e. Ca(2+)-dependent phospholipase A(2) and Ca(2+)-independent phospholipase A(2), respectively. Moreover, the release of arachidonic and docosahexaenoic acids is differently regulated through Ca(2+)- and cAMP-dependent signal transduction pathways. Based on analysis of the current literature and our own data we put forward the hypothesis that Ca(2+)-independent phospholipase A(2) and docosahexaenoic acid are promising targets for treatment of inflammatory related disorders in brain. We suggest that Ca(2+)-independent phospholipase A(2) and docosahexaenoic acid might be crucially involved in brain-specific regulation of prostaglandins.

Chronic Lithium Chloride Administration Attenuates Brain NMDA Receptor-Initiated Signaling via Arachidonic Acid in Unanesthetized Rats

“…sPLA 2 activation requires a much higher Ca 2 + concentration, 16-18 mM, and is involved mainly in the presynaptic release of synaptic vesicles (Dennis, 1994;Matsuzawa et al, 1996;Wei et al, 2003). iPLA 2 is Ca 2 + -independent and selective for DHA acid rather than AA (Dennis, 1994;Strokin et al, 2004). The chronic LiCl diet of this study is reported to reduce global brain mRNA, protein and activity levels of cPLA 2 in rats, but not to affect expression of sPLA 2 or iPLA 2 (Bosetti et al, 2002a, b;Chang and Jones, 1998;Rapoport and Bosetti, 2002;Rintala et al, 1999;Weerasinghe et al, 2004).…”

“…All have been identified in neurons (Kishimoto et al, 1999;Strokin et al, 2004;Yang et al, 1999;Yegin et al, 2002). cPLA 2 has been localized at postsynaptic neuronal membranes in the brain (Basavarajappa et al, 1998;Ong et al, 1999;Pardue et al, 2003) and is activated by 300 nM to 1 mM Ca 2 + (Clark et al, 1995), in the physiological range of intracellular Ca 2 + during neuronal activation (Ismailov et al, 2004).…”

Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

“…[57][58][59] Like AA, docosahexaenoic acid (DHA; 22:6nÀ3; Figure 2) is esterified in the sn-2 position of brain phospholipids. It is released by a PLA 2 (most likely iPLA 2 ), [60][61][62][63] and the majority is then reesterified into brain phospholipids, while a portion of the non-esterified DHA can be converted to docosanoids which along with DHA, play important roles in brain signaling, 64 anti-inflammation 65 and neuroprotection. 36 The actions of DHA and the docosanoids are generally antagonistic to AA and its eicosanoid derivatives, respectively.…”

Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex

“…DHA is mainly released by calcium-independent phospholipase A 2 (iPLA 2 ) with a more limited regulation by calcium-dependent phospholipases A 2 in rat astrocytes. 11,12 AA is mainly released by calcium-dependent cytosolic phospholipase A 2 (cPLA 2 ) and secretory phospholipase A 2 (sPLA 2 ), 13,14 explaining how metabolic AA and DHA regulation can be independent in the brain. 15 Studies indicate that there is cross-talk between cPLA 2 and sPLA 2 and that their expression and activity are interdependent.…”