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Studies on Bioactive Lipid Mediators Involved in Brain Function and Neurodegenerative Disorders. The effect of ¿-3PUFA supplementation and lithium treatment on rat brain sphingomyelin species and endocannabinoids formation; changes in oxysterol profiles in blood of ALS patients and animal models of ALS.Drbal, Abed Alnaser A.A. January 2013 (has links)
Lipids are important for structural and physiological functions of neuronal cell membranes. They exhibit a range of biological effects many are bioactive lipid mediators derived from polyunsaturated fatty acids such as sphingolipids, fatty acid ethanolamides (FA-EA) and endocannabinoids (EC). These lipid mediators and oxysterols elicit potent bioactive functions in many physiological and pathological processes of the brain and neuronal tissues. They have been investigated for biomarker discovery of ageing, neuroinflammation and neurodegenerative disorders. The n-3 fatty acids EPA and DPA are thought to exhibit a range of neuroprotective effects many of which are mediated through production of such lipid mediators.
The aims of this study were to evaluate the effects of n-3 EPA and n-3 DPA supplementation on RBC membranes and in this way assess dietary compliance and to investigate brain sphingomyelin species of adult and aged rats supplemented with n-3 EPA and n-3 DPA to evaluate the effects and benefits on age-related changes in the brain. Furthermore, to study the effects of lithium on the brain FA-EAs and ECs to further understand the neuroprotective effects of lithium neuroprotective action on neuroinflammation as induced by LPS. Finally to examine if circulating oxysterols are linked to the prevalence of ALS and whether RBC fatty acids are markers of this action in relation to age and disease stages. These analytes were extracted from tissue samples and analysed with GC, LC/ESI-MS/MS and GC-MS.
It was found that aged rats exhibited a significant increase in brain AA and decrease in ¿n-3 and ¿n-6 PUFAs when compared to adult animals. The observed increase of brain AA was reversed following n-3 EPA and n-3 DPA supplementation. Sphingomyelin was significantly increased when aged animals were supplemented with n-3 DPA. LPS treatment following lithium supplementation increased LA-EA and ALA-EA, while it decreased DHA-EA. Both oxysterols 24-OH and 27-OH increased in ALS patients and SOD1-mice. Eicosadienoic acid was different in ASL-patients compared to aged SOD1-mice.
These studies demonstrated that dietary intake of n-3 EPA and n-3DPA significantly altered RBC fatty acids and sphingolipids in rat brain. They suggest that n-3 DPA can be a potential storage form for EPA, as shown by retro-conversion of n-3 DPA into EPA in erythrocyte membranes, ensuring supply of n-3 EPA. Also, n-3 EPA and n-3 DPA supplementation can contribute to an increase in brain sphingomyelin species with implications for age effects and regulation of brain development. Effects of lithium highlight novel anti-neuroinflammatory treatment pathways. Both 24-hydroxycholesterol and eicosadienoic acid may be used as biomarkers in ALS thereby possibly helping to manage the progressive stages of disease. / Libyan Government
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Biophysical studies of cholesterol in unsaturated phospholipid model membranesWilliams, Justin A. January 2013 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Cellular membranes contain a staggering diversity of lipids. The lipids are heterogeneously
distr
ibuted to create regions, or domains, whose physical properties differ from the bulk
membrane and play an essential role in modulating the function of resident proteins. Many
basic questions pertaining to the formation of these lateral assemblies remain. T
his research
employs model membranes of well
-
defined composition to focus on the potential role of
polyunsaturated fatty acids (PUFAs) and their interaction with cholesterol (chol) in restructuring
the membrane environment. Omega
-
3 (n
-
3) PUFAs are the main
bioactive components of fish
oil, whose consumption alleviates a variety of health problems by a molecular mechanism that is
unclear. We hypothesize that the incorporation of PUFAs into membrane lipids and the effect
they have on molecular organization may be, in part, responsible. Chol is a major constituent in
the plasma membrane of mammals. It determines the arrangement and collective properties of
neighboring lipids, driving the formation of domains via differential affinity for different lipids
. T
he m
olecular organization of 1
-[
2
H
31
]palmitoyl
-2-
eicosapentaenoylphosphatidylcholine (PEPC
-
d
31
) and 1
-[
2
H
31
]palmitoyl
-2-
docosahexaenoylphosphatidylcholine (PDPC
-d
31
) in membran
es with
sphingomyelin (SM) and chol (1:1:1 mol) was compared
by solid
-
state
2
H NMR spectroscopy.
Eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids are the two major n
-
3 PUFAs found in
fish oil, while PEPC
-d
31
and PDPC
-d
31
are phospholipids containing the respective PUFAs
at the
sn
-
2 position and a perdeuterated palmitic acid a
t the sn
-
1 position
.
Analysis of s
pectra
recorded as a function of temperature indicate
s
that in both cases, formation of PUFA
-
rich (less
ordered) and SM
-
rich (more ordered) domains occurred. A surprisingly substantial proportion of
PUFA was found to infil
trate the more ordered domain. There was almost twice as much DHA
(65%) as EPA (30%)
. The implication is
that n
-
3 PUFA
s
can incorporate
into lipid rafts, which
are
domains
enriched in SM and chol in the plasma membrane,
and
potentially
disrupt the activity of signaling proteins that reside therein. DHA, furthermore, may be the more potent component
of fish oil.
PUFA
-
chol interactions were also examined through affinity measurements. A novel method
utilizing electron paramagnetic resonance (EPR) was develope
d, to monitor
the partitioning of a
spin
-
labeled
analog
of chol
, 3β
-
doxyl
-
5α
-
cholestane (chlstn), between large unilamellar vesicles
(LUVs) and met
hyl
-
β
-
cyclodextrin (mβCD). The EPR spectra for
chlstn in the two environments
are distinguishable due to the substantial differences in tumbling rates
, allowing
the
population
distribution
ratio to
be determined by spectral simulation. Advantages of this approach include
speed of implementation and a
vo
idance of potential
artifact
s associated with
physical
separation of LUV and mβCD
. Additionally, in a check of the method, t
he relative partition
coefficients between lipids measured for the spin label analog agree with values obtained for
chol by isothermal titration calorimetry (ITC). Results from LUV with different composition
confirmed
a hierarchy of
decreased
sterol affinity for phospholipids with increasing
acyl chain
unsaturation
, PDPC possessing half the affinity of the corresponding monounsaturated
phospholipid.
Taken together, the results of
these studies
on model membranes demonstrate the potential for
PUFA
-
driven alteration of the architecture of biomembranes, a mechanism through which
human health may be impacted.
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