Inhibition of Neuronal Apoptosis by Polyunsaturated Fatty Acids

Abstract

The effect of polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (22:6n-3; DHA) and arachidonic acid (20:4n-6; AA), on apoptotic cell death was evaluated based on DNA fragmentation and caspase-3 activity induced by serum starvation using Neuro-2A and PC-12 cells. The presence of 20:4n-6 in the medium during serum starvation decreased DNA fragmentation and this initial protective effect was diminished with prolonged serum starvation. The observed protective effect of 20:4n-6 was not affected by the inhibitors of cyclooxygenase (COX) and lipoxygenase. Conversely, 22:6n-3 became protective only after the enrichment of cells with this fatty acid at least for 24 h prior to the serum deprivation. DNA fragmentation as well as caspase-3 activity was reduced in 22:6n-3 enriched cells with a concomitant decrease in protein and mRNA levels. During the enrichment period, 22:6n-3 steadily increased its incorporation into PS leading to a significant increase in the total PS content; the protective effect of 22:6n-3 paralleled the PS accumulation. Neither direct exposure of cells to nor enrichment with 18:1n-9 had any protective effect. In conclusion, it is proposed that 20:4n-6 prevents neuronal apoptosis primarily due to the action of nonesterified 20:4n-6 but 22:6n-3, at least in part, through PS accumulation.

Mechanisms of action of docosahexaenoic acid in the nervous system

“…The insensitivity of the protective effect of AA to indomethacin or nordihydroguaiaretic acid indicated that the observed protective effect of AA was not mediated by either cyclooxygenase or LO derivatives, but rather through the direct action of AA (132). In contrast to the effect of AA, DHA became protective only after a prolonged period of incubation.…”

“…Enrichment of cells with DHA also altered expression of various proteins at the gene level because the levels of mRNA for caspase-3 decreased, whereas mRNA of Raf-1 increased (131,132). DHA has been shown to affect transcriptional activities through nuclear hormone receptors such as the peroxisome proliferator-activated receptor (133) or the retinoid X receptor (134).…”

Pigment Epithelium-derived Factor (PEDF) Prevents Retinal Cell Death via PEDF Receptor (PEDF-R)

“…Phospholipase PLA 2 can also release bioactive lysophospholipids, which are known to interact with their G proteincoupled receptors to influence cell signaling (57). The retina and CNS contain high levels of -3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid, that are required for proper function and survival of retinal and neuronal cells (58,59). Given that DHA constitutes more than 50% of the fatty acids in photoreceptor membrane phospholipids (60), it is likely that DHA-containing phospholipids are available substrates for PEDF-R in the retina.…”

Phospholipase A2 and Signaling Pathways in Pheochromocytoma PC12 Cells

“…This acid decreases time-course activity of cytosolic PLA2 (Martin, 1998) and attenuates (Kim et al, 2001) or accelerates (Schonfeld et al, 2007) apoptotic death in PC12 cells. On the other hand arachidonic acid suppresses neurite outgrowth induced by nerve growth factor (Ikemoto et al, 1997) and also may be both anti-apoptotic (Kim et al, 2001) and pro-apoptotic at deprivation of NGF and serum (Atsumi et al, 1997) in PC12 (see also section 4). The above mentioned phospholipase D2 hydrolyzes the lysophospholipids with the formation of lysophosphatidic acid, which enhances cell proliferation.…”