Acetylcholine synthesis
1. Effects of ethanol and pantothenic acid on brain acetylcholine synthesis.
Rivera-Calimlim L, Hartley D, Osterhout D.
Department of Pharmacology, University of Rochester, School of Medicine
and
Dentistry, NY 14642.
Br J Pharmacol. 1988 Sep;95(1):77-82.
Measurements of brain acetylcholine (ACh) synthesis from precursor
[14C]-pyruvate, pantothenic acid (PA) concentration in the brain, and
blood
ethanol (EtOH) concentration were made in rats treated with either ethanol
(5-6
g kg-1 body wt daily) alone or ethanol with PA supplementation (100-200
mg kg-1
body wt daily). EtOH with or without PA was administered orally by either
Lieber-Decarli liquid diet for 4 weeks and 4 months or by oral intubation
for 1
and 4 days. Matched controls were given either ethanol-free liquid diet
or
saline. 2. ACh synthesis in the brain of rats treated with ethanol alone
for 4
months was significantly (P less than 0.01) inhibited. PA concentration
of the
brain was diminished to 7.0% of the control value. 3. PA concentration
in the
brain of rats treated with ethanol plus PA for 4 months was three times
that of
rats treated with ethanol alone. ACh synthesis in rats with ethanol and
PA
supplementation was also significantly (P less than 0.01) higher. 4. There
was
no difference in blood EtOH concentration between rats treated with ethanol
with
or without PA supplement. 5. The EtOH effect on ACh synthesis and PA
concentration in the brain was observed in the chronic treatments but
not in the
acute treatments. 6. Data suggest that chronic ethanol exposure may decrease
ACh
synthesis by depleting PA, a precursor for the synthesis of acetyl CoA.
Acetyl
CoA is an essential substrate for ACh synthesis.
Transport and metabolism
2. Pantothenic acid transport and metabolism in the central nervous system.
Spector R.
Am J Physiol. 1986 Feb;250(2 Pt 2):R292-7.
The mechanisms by which pantothenic acid (PA) enters and leaves brain,
choroid
plexus, and cerebrospinal fluid (CSF) were investigated by injecting [3H]PA
either intravenously or intraventricularly into adult rabbits. [3H]PA,
either
alone or together with unlabeled PA, was infused at a constant rate into
conscious rabbits. At 180 min, [3H]PA readily entered CSF, choroid plexus,
and
brain. In brain, CSF, and plasma, greater than 90% of the 3H was associated
with
[3H]PA. The addition of 200 mumol/kg PA to the infusion syringe decreased
the
penetration of [3H]PA into brain and CSF by approximately 70%. Two hours
after
the intraventricular injection of [3H]PA, [3H]PA was rapidly cleared from
the
CSF by a probenecid-sensitive mechanism. No metabolism of the [3H]PA occurred
in
brain. However, 18 h after the intraventricular injection of 37 microCi
(34
nmol) of [3H]PA, approximately 40% of the 3H remaining in forebrain was
converted to [3H]CoA. These results show that PA enters and leaves CSF
and brain
by saturable transport systems. However, [3H]PA is very slowly converted
to
[3H]CoA in brain in vivo.
Vitamins and lipid metabolism.
3. Fidanza A, Audisio M.
Acta Vitaminol Enzymol. 1982;4(1-2):105-14.
Vitamins play an essential role in lipid metabolism reactions and their
presence
is therefore absolutely necessary for these reaction to occur. The effect
of
pantothenic acid, niacin and riboflavin is here described. By transformation
into coenzymes these vitamins are involved in fatty acid synthesis and
oxidation
reactions. Other vitamins, like vitamin B12, folic acid, vitamin C, and
essential fatty acids influence lipid metabolism by different mechanisms.
Coenzyme B12 and folate coenzyme provide to balance, by methionine synthesis,
the pool of methyl radicals necessary for phospholipid biosynthesis. By
its
involvement in the microsomal respiratory chain, vitamin C promotes cholesterol
transformation into bile acids. The essential fatty acids, mainly linoleic
acid,
are directly connected with cholesterol transport and plasma cholesterol
decrease. It is suggested that many lipid metabolism disorders may be
due to
primary and secondary hypovitaminosis. Nicotinic acid and its derivatives
have a
particular pharmacological effect since they cause a HDL increase with
LDL
decrease and improve cholesterol transfer from LDL to HDL. Results of
several
experiments on the influence of pantothenic acid on polyunsaturated fatty
acid
metabolism are eventually reported, and these data are related to the
effect of
the administration of vitamin C at high doses on total cholesterol,
triglyceride, lipoprotein, vitamin C and fatty acids of the different
plasma
lipid fractions.
Cell protection
4. Pantothenic acid protects jurkat cells against ultraviolet light-induced
apoptosis.
Slyshenkov VS, Piwocka K, Sikora E, Wojtczak L.
Nencki Institute of Experimental Biology, Polish Academy of Sciences,
Warsaw,
Poland.
Free Radic Biol Med. 2001 Jun 1;30(11):1303-10.
Human leukemic T lymphocytes (Jurkat cells) were induced to undergo apoptosis
by
brief irradiation with ultraviolet C light (254 nm). This was accompanied
by
accumulation of lipid peroxidation products in the form of conjugated
dienes, a
decrease of total glutathione content, and a shift of its redox state
towards
the oxidized form. Preincubation of the cells with 1 mM pantothenate resulted
in
a significant elevation of total glutathione content of the cells, reaching
its
maximum level, 160% of the control, after 3 h. Similar increase was observed
after preincubation with 5 mM N-acetylcysteine, a known precursor of
glutathione. Both pantothenic acid and N-acetylcysteine alleviated the
ultraviolet-induced decrease of glutathione content, diminished lipid
peroxidation, and partly protected the cells against apoptosis produced
by
ultraviolet irradiation.
CoA
5. Mitochondrial, but not peroxisomal, beta-oxidation of fatty acids
is conserved
in coenzyme A-deficient rat liver.
Youssef JA, Song WO, Badr MZ.
Division of Pharmacology, University of Missouri-Kansas City 64108, USA.
Mol Cell Biochem. 1997 Oct;175(1-2):37-42.
Hepatic coenzyme A (CoA) plays an important role in cellular lipid metabolism.
Because mitochondria and peroxisomes represent the two major subcellular
sites
of lipid metabolism, the present study was designed to investigate the
specific
impact of hepatic CoA deficiency on peroxisomal as well as mitochondrial
beta-oxidation of fatty acids. CoA deficiency (47% decrease in free CoA
and 23%
decrease in total CoA) was produced by maintaining weanling male Sprague-Dawley
rats on a semipurified diet deficient in pantothenic acid (the precursor
of CoA)
for 5 weeks. Hepatic mitochondrial fatty acid oxidation of short-chain
and
long-chain fatty acids were not significantly different between control
and
CoA-deficient rats. Conversely, peroxisomal beta-oxidation was significantly
diminished (38% inhibition) in livers of CoA-deficient rats compared to
control
animals. Peroxisomal beta-oxidation was restored to normal levels when
hepatic
CoA was replenished. It is postulated that since the role of hepatic
mitochondrial beta-oxidation is energy production while peroxisomal
beta-oxidation acts mainly as a detoxification system, the mitochondrial
pathway
of beta-oxidation is spared at the expense of the peroxisomal pathway
when liver
CoA plummets. The present study may offer an animal model to investigate
mechanisms involved in peroxisomal diseases.
6. Amelioration of adverse effects of valproic acid on ketogenesis and
liver
coenzyme A metabolism by cotreatment with pantothenate and carnitine in
developing mice: possible clinical significance.
Thurston JH, Hauhart RE.
Department of Pediatrics, Washington University School of Medicine, St.
Louis,
MO 63110.
Pediatr Res. 1992 Apr;31(4 Pt 1):419-23.
Very young children with organic brain damage, intractable seizures,
and
developmental retardation are at particular risk of developing fatal hepatic
dysfunction coincident with valproate therapy, especially if the children
are
also receiving other anticonvulsant drugs. The mechanism of valproate-associated
hepatic failure in these children is unclear. There are two major theories
of
etiology. The first concerns the manyfold consequences of depletion of
CoA due
to sequestration into poorly metabolized valproyl CoA and valproyl CoA
metabolites. The other theory proposes that the unsaturated valproate
derivative
2-n-propyl-4-pentenoic acid and/or metabolically activated intermediates
are
toxic and directly cause irreversible inhibition of enzymes of beta-oxidation.
The present study shows for the first time that in developing mice, when
panthothenic acid and carnitine are administered with valproate, at least
some
of the effects of valproate are mitigated. Perhaps most importantly, the
beta-hydroxybutyrate concentration in plasma and the free CoA and acetyl
CoA
levels in liver do not fall so low. Cotreatment with carnitine alone was
without
effect. Findings support the CoA depletion mechanism of valproate inhibition
of
beta-oxidation and other CoA- and acetyl CoA-requiring enzymic reactions
and
stress the role of carnitine in the regulation of CoA synthesis at the
site of
action of pantothenate kinase.
Synthesis of phospholipids
7. Pantothenic acid and its derivatives protect Ehrlich ascites tumor
cells against
lipid peroxidation.
Slyshenkov VS, Rakowska M, Moiseenok AG, Wojtczak L.
Nencki Institute of Experimental Biology, Warsaw, Poland.
Free Radic Biol Med. 1995 Dec;19(6):767-72. Erratum in:Free Radic Biol
Med 1996;20(3):493.
Preincubation of Ehrlich ascites tumor cells at 22 or 32 degrees C, but
not at 0
degree C, with pantothenic acid, 4'-phosphopantothenic acid, pantothenol,
or
pantethine reduced lipid peroxidation (measured by production of thiobarbituric
acid-reactive compounds) induced by the Fenton reaction (Fe2+ + H2O2)
and partly
protected the plasma membrane against the leakiness to cytoplasmic proteins
produced by the same reagent. Pantothenic acid and its derivatives did
not
inhibit (Fe2+ + H2O2)-induced peroxidation of phospholipid multilamellar
vesicles, thus indicating that their effect on the cells was not due to
the
scavenging mechanism. Homopantothenic acid and its 4'-phosphate ester
(which are
not precursors of CoA) neither protected Ehrlich ascites tumor cells against
lipid peroxidation nor prevented plasma membrane leakiness under the same
conditions. Incubation of the cells with pantothenic acid, 4'-phosphopantothenic
acid, pantothenol, or pantethine significantly increased the amount of
cellular
CoA and potentiated incorporation of added palmitate into phospholipids
and
cholesterol esters. It is concluded that pantothenic acid and its related
compounds protect the plasma membrane of Ehrlich ascites tumor cells against
the
damage by oxygen free radicals due to increasing cellular level of CoA.
The
latter compound may act by diminishing propagation of lipid peroxidation
and
promoting repair mechanisms, mainly the synthesis of phospholipids.
Wound Healing/Skin
8. Topical use of dexpanthenol in skin disorders.
Ebner F, Heller A, Rippke F, Tausch I.
Technical University of Munich, Allershausen, Germany. fritz.ebner@t-online.de
Am J Clin Dermatol. 2002;3(6):427-33.
Pantothenic acid is essential to normal epithelial function. It is a
component
of coenzyme A, which serves as a cofactor for a variety of enzyme-catalyzed
reactions that are important in the metabolism of carbohydrates, fatty
acids,
proteins, gluconeogenesis, sterols, steroid hormones, and porphyrins.
The
topical use of dexpanthenol, the stable alcoholic analog of pantothenic
acid, is
based on good skin penetration and high local concentrations of dexpanthenol
when administered in an adequate vehicle, such as water-in-oil emulsions.
Topical dexpanthenol acts like a moisturizer, improving stratum corneum
hydration, reducing transepidermal water loss and maintaining skin softness
and
elasticity. Activation of fibroblast proliferation, which is of relevance
in
wound healing, has been observed both in vitro and in vivo with dexpanthenol.
Accelerated re-epithelization in wound healing, monitored by means of
the
transepidermal water loss as an indicator of the intact epidermal barrier
function, has also been seen. Dexpanthenol has been shown to have an
anti-inflammatory effect on experimental ultraviolet-induced erythema.
Beneficial effects of dexpanthenol have been observed in patients who
have
undergone skin transplantation or scar treatment, or therapy for burn
injuries
and different dermatoses. The stimulation of epithelization, granulation
and
mitigation of itching were the most prominent effects of formulations
containing
dexpanthenol. In double-blind placebo-controlled clinical trials, dexpanthenol
was evaluated for its efficacy in improving wound healing. Epidermal wounds
treated with dexpanthenol emulsion showed a reduction in erythema, and
more
elastic and solid tissue regeneration. Monitoring of transepidermal water
loss
showed a significant acceleration of epidermal regeneration as a result
of
dexpanthenol therapy, as compared with the vehicle. In an irritation model,
pretreatment with dexpanthenol cream resulted in significantly less damage
to
the stratum corneum barrier, compared with no pretreatment. Adjuvant skin
care
with dexpanthenol considerably improved the symptoms of skin irritation,
such as
dryness of the skin, roughness, scaling, pruritus, erythema, erosion/fissures,
over 3 to 4 weeks. Usually, the topical administration of dexpanthenol
preparations is well tolerated, with minimal risk of skin irritancy or
sensitization.
9. Topical corticosteroid therapy for acute radiation dermatitis: a prospective,
randomized, double-blind study.
Schmuth M, Wimmer MA, Hofer S, Sztankay A, Weinlich G, Linder DM, Elias
PM,
Fritsch PO, Fritsch E.
Department of Dermatology, University of Innsbruck, Austria.
matthias.schmuth@uibk.ac.at
Br J Dermatol. 2002 Jun;146(6):983-91.
BACKGROUND: Radiation dermatitis is a common side-effect of radiation
therapy,
but there is no current consensus about its appropriate therapy. OBJECTIVES:
To
compare treatment with topical 0.1% methylprednisolone vs. 0.5% dexpanthenol
in
a cohort of patients undergoing fractionated radiation therapy for breast
cancer. METHODS: In a randomized, double-blind design, treatment was initiated
at the beginning of radiation therapy and continued for 2 weeks after
termination of radiation. Outcomes were compared by three different measures:
clinical (symptom score), functional (transepidermal water loss, TEWL)
and
subjective (quality of life, QOL). RESULTS: In a preliminary cohort of
untreated
patients undergoing radiation therapy, clinical signs and TEWL levels
increased
progressively during radiation therapy, reaching highest values at 5 and
4
weeks, respectively. Although neither topical treatment reduced the incidence
of
radiation dermatitis, both delayed the emergence of greatest clinical
and TEWL
scores until approximately 6 and 5 weeks, respectively. With topical
corticosteroids, clinical symptoms and TEWL were less pronounced than
with
dexpanthenol. Whereas general QOL improved after completion of radiation
therapy, skin-related QOL declined. However, the skin-related QOL decline
could
be at least in part reversed by use of topical corticosteroid vs.
dexpanthenol-containing emollient. CONCLUSIONS: We provide evidence that
prophylactic and ongoing use of topical therapy with either topical
corticosteroid or a dexpanthenol-containing emollient ameliorates, but
does not
prevent radiation dermatitis. Our data suggest, but do not prove, a benefit
of a
topical corticosteroid vs. a dexpanthenol-containing emollient. Further
controlled studies with larger cohorts will be needed to determine optimal
forms
of topical therapy for radiation dermatitis.
10. Effect of pantothenic acid and ascorbic acid supplementation on human
skin wound healing process. A double-blind, prospective and randomized
trial.
Vaxman F, Olender S, Lambert A, Nisand G, Aprahamian M, Bruch JF, Didier
E,
Volkmar P, Grenier JF.
INSERM U 61, Hospices Civils, Strasbourg, France.
Eur Surg Res. 1995;27(3):158-66.
This study aimed at testing human skin wound healing improvement by a
21-day
supplementation of 1.0 g ascorbic acid (AA) and 0.2 g pantothenic acid
(PA). 49
patients undergoing surgery for tattoos, by the successive resections
procedure,
entered a double-blind, prospective and randomized study. Tests performed
on
both skin and scars determined: hydroxyproline concentrations, number
of
fibroblasts, trace element contents and mechanical properties. In the
18
supplemented patients, it was shown that in skin (day 8) Fe increased
(p < 0.05)
and Mn decreased (p < 0.05); in scars (day 21), Cu (p = 0.07) and Mn
(p < 0.01)
decreased, and Mg (p < 0.05) increased; the mechanical properties of
scars in
group A were significantly correlated to their contents in Fe, Cu and
Zn,
whereas no correlation was shown in group B. In blood, AA increased after
surgery with supplementation, whereas it decreased in controls. Although
no
major improvement of the would healing process could be documented in
this
study, our results suggest that the benefit of AA and PA supplementation
could
be due to the variations of the trace elements, as they are correlated
to
mechanical properties of the scars.
11. Role of pantothenic and ascorbic acid in wound healing processes:
in vitro study on fibroblasts.
Lacroix B, Didier E, Grenier JF.
INSERM Unite 61-Service de Chirurgie B, Hopital Civil, Strasbourg.
Int J Vitam Nutr Res. 1988;58(4):407-13.
In order to analyze the possible role of pantothenic acid (PA) and ascorbic
acid
(AA) in wound healing processes, the effects of these vitamins upon the
growth
of fibroblasts, obtained from human fetal skin or foreskin, were studied.
Cell
proliferation, protein synthesis and protein release were evaluated. The
rate of
cell growth remained identical when PA or AA were added to the culture
medium.
PA increased the basal incorporation of 14C proline into precipitated
material
while AA did not modify this action. However, when cultures were incubated
with
PA and AA, the release of intracellular protein into the culture medium
increased. These results suggest that the combined use of these two vitamins
might be of interest in postsurgical therapy and in wound healing.
12. Effects of supplemental pantothenic acid on wound healing: experimental
study in rabbit.
Aprahamian M, Dentinger A, Stock-Damge C, Kouassi JC, Grenier JF.
Am J Clin Nutr. 1985 Mar;41(3):578-89.
The effect of pantothenic acid supplementation and deficiency on wound
healing
was investigated over a one month postoperative period in rabbits. The
supplemented group was injected with pentothenate (20 mg/kg of body weight/24
h)
for three weeks and compared to a placebo group (0.5 ml of distilled water).
Deficient animals were fed with a pantothenate free diet also for three
weeks.
These three experimental groups were matched against a control group.
The degree
of wound healing was determined by the mean of postoperative breaking
strength
and wound fibroblast population changes. Pantothenic acid urinary excretion
measured by gas chromatography served as control of pantothenate consumption.
With regard to these three parameters no significant difference has been
found
between placebo and controls. The average urinary elimination in the pantothenic
acid group was significantly higher as far as the pantothenate supplemented
group was concerned, while the deficient group showed no significant decrease
when compared to controls. Chronic pre- and postoperative pantothenic
acid
supplementation significantly increased aponeurosis strength after surgery;
it
improved slightly, but not significantly the strength of the skin. Furthermore,
the fibroblast content of the scar became significantly greater during
the
fibroblast proliferation phase after pantothenic supplementation. These
data
suggest that pantothenic acid induces an accelerating effect of the normal
healing process. The mechanism responsible for this improvement seems
to be an
increase in cellular multiplication during the first postoperative period.
But
the exact intimate mechanism of the beneficial effect of pantothenate
remains
unclear.
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