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DHA in Neurite Outgrowth
DHA supplementation of hippocampal cultures increased the population of neurons
with longer neurite length per neuron and with higher number of branches. However, supplementation with arachidonic,
oleic, or docosapentaenoic acid did not have such effect, indicating a specific
DHA action on neurite growth. Furthermore, hippocampal cultures from n-3 fatty
acid deficient animals had a lower DHA content and shorter neurite length per
neuron compared to those from animals with adequate n-3 fatty acids. DHA
supplementation to the deficient animals recovered the neurite length to the
level comparable to n-3 fatty acid adequate cultures. Inadequate neurite development due to DHA
deficiency may contribute to the cognitive impairment associated with n-3 fatty
acid deficiency. F. Calderon and H.-Y. Kim, Docosahexaenoic Acid Promotes Neurite
Growth in Hippocampal Neurons, J. Neurochem. in press 2004.
Chronic
ethanol exposure depleted PS, especially 22:6-containing species, and PC from
hippocampal membranes with concomitant increase of PE. High performance liquid chromatography-electrospray
ionization-mass spectrometry (HPLC-ESI-MS) analysis revealed that ethanol
lowered the levels of total PS by 15~20% at all ages examined, primarily due to
the reduction of 1-stearoyl-2-docosahexaenoyl-PS (18:0, 22:6n-3-PS) species. A decrease in phosphatidylcholine (PC) by the
ethanol exposure accompanied increased phosphatidylethanolamine (PE), while the
total phospholipid contents were not significantly changed. At the fatty acid level, the ethanol exposure
significantly decreased the 22:6n-3 content at
postnatal day 0 (
Microsomes
from cerebral cortex synthesized PS from 18:0, 22:6n-3-PC most favorably among
the PC substrates tested, with the order of preference being 18:0,
22:6n-3>18:0, 22:5n-6>18:0, 20:4n-6 = 18:0,18:1n-9. Liver microsomes also preferred 18:0,22:6-PC
as substrate in PS synthesis, but the 18:0,22:5-PC species was converted to PS
at the similar extent as 18:0,20:4- or 18:0,18:1-PC species. Both brain and liver microsomes preferred
18:0 over 16:0 as the sn-1 fatty
acid. Preferential conversion of
18:0,22:6-PC to the corresponding PS species appears at least partly
responsible for concentrating PS in neuronal tissues where 22:6n-3 is particularly abundant. The use of 18:0, 22:5n-6-PC observed with
brain microsomes may help maintain PS at a high level in the brain when 22:6n-3
is replaced by 22:5n-6 during n-3 fatty acid deficiency. H.-Y. Kim, J. Bigelow and J. H. Kevala, Substrate
Preference In Phosphatidylserine Biosynthesis For Docosahexaenoic Acid Containing
Species 2004, Biochemistry, 43, 1030-1036.
Enrichment of neuronal cells with DPAn-6
increased the total PS content in comparison to non-enriched control
significantly less than enrichment with DHAn-3, primarily due to the fact that 18:0,22:5n-6
not as effectively accumulated as 18:0,22:6n-3 in PS. As with DHA, DPA enrichment protected Neuro
2A cells against apoptotic cell death induced by the staurosporine treatment,
but to a lesser extent. The in vitro
interaction between Raf-1 and membrane was affected not only by the PS content
but also by the fatty acyl composition in PS.
Reduction of PS concentration in liposomes, as well as substitution of
18:0,22:6 with 16:0,18:1, considerably reduced interaction with Raf-1. Thus, depletion of DHAn-3from neuronal
tissues may have a compounding effect on Raf-1 translocation in growth factor
signaling. The fact that DPAn-6 cannot
fully support the protective role played by DHA may explain the adverse effect
of n-3 fatty acid deficiency on neuronal development and function. Hee-Yong Kim, Mohammed Akbar and Audrey Lau, Effects of
Docosapentaenoic Acid on Neuronal Apoptosis
2004, Lipids, 38, 453-457.
This
review describes (from both the animal and human literature) the biological
consequences of losses in nervous system docosahexaenoate (DHA) and mechanisms
that may explain changes in brain and retinal function. The role of
DHA-phospholipids in regulating G-protein signaling is presented in the context
of studies with rhodopsin. Through effects on PS, DHA may play an important
role in the regulation of cell signaling and in cell proliferation. Progress in
recent nuclear magnetic resonance studies delineate differences in molecular
structure and order in biomembranes due to small differences in phospholipid
unsaturation. Salem N Jr, Litman B, Kim HY,
Gawrisch K. Mechanisms of action of docosahexaenoic acid in the nervous system.
Lipids 2001 Sep;36(9):945-59
Enrichment of neuronal cells with 22:6n-3 increases the PS content and Raf-1 translocation, down-regulates caspase-3 activity, and prevents apoptotic cell death. Hindering PS accumulation by a serine-free medium diminished the protective effect of 22:6n-3. Both the antiapoptotic effect of 22:6n-3 and Raf-1 translocation are sensitive to 22:6n-3 enrichment-induced PS accumulation in neuronal membranes. Kim HY, Akbar M, Lau A, Edsall L. Inhibition of neuronal apoptosis by docosahexaenoic acid (22:6n-3). Role of phosphatidylserine in antiapoptotic effect. J Biol Chem 2000 Nov 10;275(45):35215-23.
Neuronal membranes are highly enriched with docosahexaenoic acid (22:6n-3). Electrospray liquid chromatography-mass spectrometry analysis revealed that cells treated with 22:6n-3 had more PS compared to nonenriched or 20:4n-6-enriched cells. After cells were exposed to 20 or 50 mM ethanol for 4 wk, accumulation of 18:0,22:6-PS upon 22:6n-3 supplementation was significantly lower, resulting in a drastic reduction of total PS. Attenuated accumulation of 22:6n-3 in PS and the reduction of PS thus may have significant implications in pathophysiological effects of ethanol, especially in tissues with abundant 22:6n-3. Kim HY, Hamilton J. Accumulation of docosahexaenoic acid in phosphatidylserine is selectively inhibited by chronic ethanol exposure in C-6 glioma cells. Lipids 2000 Feb;35(2):187-95
Brain
microsomes from offspring of rats reared on an n-3-deficient diet have low
22:6n-3 content (1.7 +/- 0.1%) compared with control animals (15.0 +/- 0.2%).
The decrease was accompanied by an increase in docosapentaenoic acid (22:5n-6)
content, which replaced the 22:6n-3 phospholipids with 22:5n-6 molecular
species, as demonstrated using HPLC/electrospray mass spectrometry. The n-3
deficiency did not affect the total amount of polyunsaturated phospholipids in
brain microsomes; however, it was associated with a decrease in the total
polyunsaturated PS content and with increased levels of
1-stearoyl-2-docosapentanoyl (18:0/22:5n-6) species, particularly in
phosphatidylcholine. Incorporation of [3H]serine into PS in rat brain
microsomes from n-3-deficient animals was slightly but significantly less than
that of the control animals. Similarly, C6 glioma cells cultured for 24 h in
22:6n-3-supplemented media (10-40 microM) showed a significant increase in the
synthesis of [3H]PS when compared with unsupplemented cells. Our data show that
neuronal and glial PS synthesis is sensitive to changes in the docosahexaenoate
levels of phospholipids and suggest that 22:6n-3 may be a modulator of PS
synthesis. Garcia MC, Ward G, Ma YC,
Phosphatidyl
serine levels in brain membranes are low when diets are deficient in n-3 fatty
acids. Garcia MC; Ward G; Ma YC;