http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383770/
Abstract
Enrichment of polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA, 22:6n–3),
in the brain is known to be critical for optimal brain development and
function. Mechanisms for DHA’s beneficial effects in the nervous system
are not clearly understood at present. DHA is incorporated into the
phospholipids in neuronal membranes, which in turn can influence not
only the membrane chemical and physical properties but also the cell
signaling involved in neuronal survival, proliferation and
differentiation. Our studies have indicated that DHA supplementation
promotes phosphatidylserine (PS) accumulation and inhibits neuronal cell
death under challenged conditions, supporting a notion that DHA is an
important neuroprotective agent. This article summarizes our findings on
the DHA-mediated membrane-related signaling mechanisms that might
explain some of the beneficial effects of DHA, particularly on neuronal
survival.
Other sections at the link.
3. DHA-mediated protection of neuronal cell death
We
have previously demonstrated that DHA supplementation results in
inhibition of neuronal apoptosis induced by serum starvation [15,17] or staurosporine (ST, a general PKC inhibitor) treatment [16]
in a PS-dependent manner. Activation of caspase-3, a member of cysteine
protease family that produces apoptotic cell death in mammalian cells,
was significantly inhibited in cells enriched with DHA in both apoptotic
models (Fig. 2A).
We found that the PS accumulation by DHA is at least in part
responsible for the protective effect of DHA. Enrichment of neuro 2A
cells with DPAn–6, which accumulates less PS than with DHA
enrichment, produced less protection, while OA enrichment, which does
not alter PS levels did not have any effects on neuronal cell death (Figs. 1B, ,2B).2B). When the DHA- or DPAn–6-induced PS accumulation was reduced by supplementing cells in the absence of serine (Fig. 1B),
the protective effect of these fatty acids was significantly diminished
in comparison to the cells supplemented with these fatty acids in the
presence of serine (Fig. 2B).
It is well-established that CGC neurons undergo apoptosis when they are
cultured in media containing physiological KCl concentrations (5 mM,
low KCl) while depolarizing KCl concentrations (25 mM, high KCl)
protects CGC neurons from apoptotic cell death [35].
In this primary neuronal culture model, the protective effect of DHA
was also apparent. The DHA-supplemented culture showed significantly
less TUNEL (TdT-mediated dUTP-biotin nick end-labeling) positive
apoptotic cells and contained reduced level of active caspase-3 (Fig. 2C).
The protective effects also appear to correlate with the PS
accumulation in this model, as the CGC neurons supplemented with DHA
contained higher PS levels in comparison to the non-supplemented neurons
(Fig. 1D). Similarly, when DHA and PS levels were lowered in vivo by dietary n–3
fatty acid depletion, the hippocampal neuronal cell death observed in
culture was significantly increased, particularly when the trophic
factor was removed [17].
These data consistently support the notion that DHA’s anti-apoptotic
protective effect is at least in part mediated through PS accumulation.
No comments:
Post a Comment