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Maternal infusion of antioxidants (Trolox and
ascorbic acid) protects the fetal heart in rabbit fetal
hypoxia
Tan S, Liu YY, Nielsen VG, Skinner K, Kirk KA, Baldwin ST,
Parks DA
Department of Pediatrics, School of Medicine, University of
Alabama at Birmingham, 35233-7335, USA.
Division of Neonatology, 525 NHB, Birming (USA), 1996, 39/3
(499-503)
The antioxidants, Trolox
(6-hydroxy-2,5,7,8-tetramethylchroman-2 carboxylic acid, a
water soluble analog of vitamin E) and ascorbic acid (AA),
protect the heart from ischemia-reperfusion injury. We
hypothesized that maternal infusion of Trolox and AA, would
reduce the fetal bradycardia and myocardial damage observed in
fetal hypoxia and increase the total antioxidant activity in
fetal plasma. Either i.v. saline (control group) or Trolox +
AA (drug group) was randomly administered to 29 d-old pregnant
rabbits. Fetal hypoxia was induced by uterine ischemia. Fetal
heart rate, plasma CK-MB activity, and plasma total radical
antioxidant potential (TRAP) were measured in different sets
of animals. Fetal heart rate in the drug group was higher than
in the control group for the first 35 min (p < 0.05 at
every 5-min interval). Fetal bradycardia (<60 beats/min)
occurred after 39 min (median) in the drug group, and 29 min
in the control group (p < 0.05). After 50 min of hypoxia,
plasma CK-MB was lower in the drug group, 1204 plus or minus
132 U/L (mean plus or minus SEM), than in the control group,
2633 plus or minus 233 U/L (p < 0.05), TRAP was higher in
the drug group, 3.01 plus or minus 0.15 mM (Trolox equivalent
concentration), than in the control group, 1.48 plus or minus
0.27 mM (p < 0.05). Higher TRAP levels (greater than or
equal to2.0 mM) were associated with lower CK-MB levels
(<2500 U/L) (p < 0.05). Administration of Trolox and AA
to the mother has a beneficial effect on fetal myocardial
damage after fetal hypoxia, and a small beneficial effect on
fetal bradycardia during hypoxia. The beneficial effect may be
due to the augmentation of fetal plasma antioxidants from
maternal antioxidant pretreatment.
Amphiphilic alpha-tocopherol analogues as
inhibitors of brain lipid peroxidation.
Bolkenius FN, Verne-Mismer J, Wagner J, Grisar JM
Marion Merrell Dow Research Institute, Strasbourg,
France
FrankBolkenius@mmd.com
Eur J Pharmacol (Netherlands) Feb 29 1996, 298 (1)
p37-43
Neurological disorders, such as stroke, trauma, tardive
dyskinesia, Alzheimer's and Parkinson's diseases, may be
partially attributed to excessive exposition of the nervous
tissue to oxygen-derived radicals. A novel water-soluble
alpha-tocopherol analogue, 2,3-dihydro-2 ,2,4,6,7-pentam
ethyl-3methylpiperazino) methyl-1-benzofuran-5-ol
dihydrochloride (MDL), is a potent radical scavenger.
Following subcutaneous administration to mice, MDL inhibited
the lipid peroxidation induced in the 100-fold diluted brain
homogenates, with an ID50 of 8 mg/kg. Rapid brain penetration,
within 30-60 min postadministration, and even distribution
into different brain areas were observed. MDL was also
detected after oral administration. In brain homogenate
undergoing lipid peroxidation, MDL prevented the consumption
of an equal amount of alpha-tocopherol, while inhibiting the
concomitant malondialdehyde formation. The radical scavenging
capacity of MDL was superior to that of alpha-tocopherol,
although the peak and half-peak potentials were not
significantly different. However, MDL was much less
lipophilic, the partition coefficient (log P) at the
octanol/water interface being 1.91. Although it is yet
unknown, whether the applied criteria sufficiently predict its
usefulness, beneficial effects of MDL may be expected in the
above mentioned disorders.
Vitamin E plus aspirin compared with aspirin alone
in patients with transient ischemic attacks
Steiner M, Glantz M, Lekos A
Division of Hematology/Oncology, Memorial Hospital of Rhode
Island, Pawtucket, USA.
Am J Clin Nutr 1995 Dec;62(6 Suppl):1381S-1384S
One hundred patients with transient ischemic attacks, minor
strokes, or residual ischemic neurologic deficits were
enrolled in a double-blind, randomized study comparing the
effects of aspirin plus vitamin E (0.4 g (400 IU)/d; n = 52)
with aspirin alone (325 mg; n = 48). The patients received
study medication for 2 y or until they reached a termination
point. Preliminary results show a significant reduction in the
incidence of ischemic events in patients in the vitamin E plus
aspirin group compared with patients taking only aspirin.
There was no significant difference in the incidence of
hemorrhagic stroke although both patients who developed it
were taking vitamin E. Platelet adhesion was also measured in
a randomized subgroup of both study populations by using
collagen III as the adhesive surface. There was a highly
significant reduction in platelet adhesiveness in patients who
were taking vitamin E plus aspirin compared with those taking
aspirin only. Measurement of alpha-tocopherol concentrations
confirmed compliance of the patients with the medication
schedule, showing a near doubling of serum concentrations of
alpha-tocopherol. We concluded that the combination of vitamin
E and a platelet antiaggregating agent (eg, aspirin)
significantly enhances the efficacy of the preventive
treatment regimen in patients with transient ischemic attacks
and other ischemic cerebrovascular problems.
Poor plasma status of carotene and Vitamin-C is
associated with higher mortality from ischemic heart disease
and stroke: Basel Prospective Study
Gey KF, Stahelin HB, Eichholzer M
Vitamin-Forschungseinheit and Reference Centre for Vitamins,
WHO/MONICA Project, Universitat Bern.
Clin. Invest. (Germany), 1993, 71/1 (3-6)
Previous cross-cultural comparisons of the mortality from
ischemic heart disease in European communities with associated
plasma levels of essential antioxidants have revealed strong
inverse correlations for vitamin E and relatively weak
correlations for other antioxidants. Similarly, in a
case-control study in Edinburgh low plasma levels of vitamin E
were significantly associated with an increased risk of
previously undiagnosed angina pectoris whereas low levels of
other essential antioxidants lacked statistical significance.
The current Basel Prospective Study is particularly well
suited to elucidate the impact of antioxidants other than
vitamin E. In this population (which was recently evaluated
regarding cancer mortality) the plasma levels of vitamins E
and A are exceptionally high and above the presumed threshold
level of risk for ischemic heart disease. The present 12-year
follow-up of cardiovascular mortality in this study reveals a
significantly increased relative risk of ischemic heart
disease and stroke at initially low plasma levels of carotene
(< 0.23 micromol/l) and/or Vitamin-C (< 22.7
micromol/l), independently of vitamin E and of the classical
cardiovascular risk factors. Low levels of both carotene and
vitamin C increase the risk further, in the case of stroke
even with significance for overmultiplicative interaction. In
conclusion, in cardiovascular disease independent inverse
correlations may exist for every major essential antioxidant
although the latter can also interact synergistically.
Therefore future intervention trials of antioxidants in the
prevention of ischemic heart disease should primarily test the
simultaneous optimization of the status of all principal
essential antioxidants.
Neuroprotective properties of Ginkgo biloba -
Constituents
Krieglstein J.
Inst. fur Pharmakol./Toxikologie, Philipps-Universitat,
Ketzerbach 63,35037 Marburg, Germany
Z. Phytother. (Germany), 1994, 15/2 (92-96)
More than 10 years ago it has been demonstrated, that an
extract of the leaves of Ginkgo biloba (EGb 761) clearly
increased the local cerebral blood flow and the tolerance
against hypoxia in rats and mice. Using various models of
cerebral ischemia and cultured neurons in vitro ginkgolides A
and B as well as bilobalide were shown to be neuroprotective.
The ginkgolides are known to be antagonists of the platelet
activating factor (PAF) and this activity could be responsible
for their neuroprotective potency. Bilobalide reduced the
infarct size after focal cerebral ischemiia of mice and rats
more efficaciously than the ginkgolides A and B and was
capable of protecting neurons and astrocytes against damage,
however, its mechanism of action however is still unknown.
Efficiency of ginkgo biloba extract (EGb 761) in
antioxidant protection against myocardial ischemia and
reperfusion injury
Shen JG, Zhou DY
Department of Chinese Medicine, First Military Medical
University, Guangzhou, China.
Biochemistry and Molecular Biology International (Australia),
1995, 35/1 (125-134)
The cardio-protective mechanisms of EGb 761, an extract of
Ginkgo biloba leaves, on myocardial ischemia reperfusion
injury were investigated using rabbits subjected to 30 minutes
of regional cardiac ischemia and 120 min of reperfusion under
anesthesia. Compared to the saline perfused group, Egb 761
treatment (10 mg/kg, injected into the coronary artery)
significantly inhibited the increase in lipid peroxidation and
maintained total and CuZn-SOD levels in both plasma and tissue
during and at the end of reperfusion. Both the decrease in
tissue type plasminogen activator (t-PA) and the increase in
plasminogen activator inhibitor-1 (PAI-1) caused by
ischemia-reperfusion were also significantly suppressed by EGb
761 treatment. Furthermore, the ultrastructure of the myocytes
of the EGb 761 treated heart was slightly damaged after
ischemia-reperfusion, while the control ischemic-reperfused
hearts demonstrated severe histological damages such as
swelling and vacuolization of the mitochondria. These results
suggest that EGb 761 protects hearts by its antioxidant
properties and by its ability to adjust fibrinolytic
activity.
Magnesium content of erythrocytes in patients with
vasospastic angina
Tanabe K, Noda K, Mikawa T, Murayama M, Sugai J
Second Department of Internal Medicine, St. Marianna
University, School of Medicine, Kanagawa, Japan.
Cardiovasc. Drugs Ther. (USA), 1991, 5/4
(677-680)
The possibility that a magnesium deficiency might be the
underlying cause of vasospastic angina (VA) and the efficacy
of Mg administration in its treatment were studied. Subjects
included 15 patients with VA and 18 healthy subjects as the
control group. The erythrocyte Mg content was measured by
atomic absorption, and serum Mg was measured by conventional
chemical assay. The efficacy of Mg administration was studied
in seven patients with VA. The results were as follows: (a)
The mean erythrocyte Mg content was less in the group with
frequent episodes of angina (1.59 plus or minus 0.11 mg/dl)
than in the group without angina (2.11 plus or minus 0.38
mg/dl, p < 0.01) and in the control group (2.22 plus or
minus 0.29 mg/dl, p < 0.01). There was no significant
difference between the control group and patients of each
group with respect to serum Mg. (b) Coronary arterial spasm
was induced by ergonovine maleate in seven patients and was
completely inhibited by the administration of Mg sulfate
(40-80 mEq, hourly) in six of these patients; in the remaining
patient neither obvious ST change nor chest pain occurred.
Thus, it was concluded that the measurement of erythrocyte Mg
content is useful to determine how easily vasospasm might
occur in VA and that the administration of Mg might be
developed as a new therapy for spasm associated with a low
erythrocyte Mg content.
Neuroprotective properties of Ginkgo biloba -
Constituents
Z. Phytother. (Germany), 1994, 15/2 (92-96)
More than 10 years ago it has been demonstrated, that an
extract of the leaves of Ginkgo biloba (EGb 761) clearly
increased the local cerebral blood flow and the tolerance
against hypoxia in rats and mice. Using various models of
cerebral ischemia and cultured neurons in vitro ginkgolides A
and B as well as bilobalide were shown to be neuroprotective.
The ginkgolides are known to be antagonists of the platelet
activating factor (PAF) and this activity could be responsible
for their neuroprotective potency. Bilobalide reduced the
infarct size after focal cerebral ischemiia of mice and rats
more efficaciously than the ginkgolides A and B and was
capable of protecting neurons and astrocytes against damage,
however, its mechanism of action however is still unknown.
Variant angina due to deficiency of intracellular
magnesium
Tanabe K, Noda K, Kamegai M, Miyake F, Mikawa T, Murayama M,
Sugai J
Second Department of Internal Medicine, St. Marianna
University School of Medicine, Kanagawa, Japan.
Clin. Cardiol. (USA), 1990, 13/9 (663-665)
A 51-year-old man was diagnosed as having variant angina by
documentation of typical ST elevation during anginal attack
and also by showing coronary arterial spasm (#2 and #12)
during hyperventilation on coronary arteriography. Large
quantities of calcium blocking agents and nitrates could not
improve his symptoms. Lack of intracellular magnesium was
suspected from a daily excretion of urine magnesium (5.3 mEq)
and magnesium tolerance test (56.7%). After hourly infusion of
magnesium sulfate (80 mEq), coronary spasm could not be
induced by ergonovine.
Magnesium and sudden death
Leary WP, Reyes AJ
S. Afr. Med. J. (South Africa), 1983, 64/18
(697-698)
Magnesium deficiency may result from reduced dietary intake
of the ion increased losses in sweat, urine or faeces. Stress
potentiates magnesium deficiency, and an increased incidence
of sudden death associated with ischaemic heart disease is
found in some areas in which soil and drinking water lack
magnesium. Furthermore, it has been demonstrated
experimentally that reduction of the plasma magnesium level is
associated with arterial spasm. Careful studies are required
to assess the clinical importance of magnesium and the
benefits of magnesium supplementation in man.
Magnesium deficiency produces spasms of coronary
arteries: Relationship to etiology of sudden death ischemic
heart disease
Turlapaty PD, Altura BM
Science (USA), 1980, 208/4440 (198-200)
Isolated coronary arteries from dogs were incubated in
Krebs-Ringer bicarbonate solution and exposed to normal, high,
and low concentrations of magnesium in the medium. Sudden
withdrawal of magnesium from the medium increased whereas high
concentrations of magnesium decreased the basal tension of the
arteries. The absence of magnesium in the medium significantly
potentiated the contractile responses of both small and large
coronary arteries to norepinephrine, acetylcholine, serotonin,
angiotensin, and potassium. These data support the hypothesis
that magnesium deficiency, associated with sudden death
ischemic heart disease, produces coronary arterial spasm.
Effect of vitamin E on hydrogen peroxide production
by human vascular endothelial cells after
hypoxia/reoxygenation
Martin A, Zulueta J, Hassoun P, Blumberg JB, Meydani M
Antioxidant Research Laboratory, Jean Mayer USDA Human
Nutrition Research Center on Aging at Tufts University,
Boston, MA, USA.
Free Radical Biology and Medicine (USA), 1996, 20/1
(99-105)
Changes in oxidative stress status play an important role
in tissue injury associated with ischemia-reperfusion events
such as those that occur during stroke and myocardial
infarction. Endothelial cells (EC) from human saphenous vein
and aorta were incubated for 22 h and found to take up vitamin
E from media containing 0-60 mM vitamin E in a dose-dependent
manner. EC supplemented with 23 or 28 mM vitamin E in the
media for 22 h were maintained at normoxia (20% O2, 5% CO2,
and balance N2) or exposed to hypoxic conditions (3% O, 5%
CO2, and balance N2) for 12 h, followed by reoxygenation (20%
O2) for 30 min. Saphenous EC supplemented with 23 mM vitamin E
produced less (p < 0.05) H2O2 than unsupplemented controls,
both at normoxic condition (supplemented: 4.9 plus or minus
0.05 vs. control: 10.9 plus or minus 1.3 pmol/min/106 cells)
and following hypoxia/reoxygenation (supplemented: 6.4 plus or
minus 0.78 vs. control:17.0 plus or minus 2.7 nmol/min/106
cells). In contrast, aortic EC, which were found to have
higher superoxide dismutase and catalase activity than EC from
saphenous vein, did not produce any detectable levels of H2O2.
Following hypoxia/reoxygenation, the concentration of vitamin
E in supplemented saphenous EC was 62% lower than cells
maintained at normoxia (0.19 plus or minus 0.03 vs. 0.5 plus
or minus 0.12 nmoles/106 cells. p <0.001); in aortic EC
vitamin E content was reduced by 18% following reoxygenation
(0.86 plus or minus 0.16 vs, 070 plus or minus 0.09 nmoles/106
cells, p < 0.05). Therefore, enrichment of vitamin E in EC
decreases H2O2 production and thus may reduce the injury
associated with ischemia-reperfusion events.
On the mechanism of the anticlotting action of
vitamin E quinone
Dowd P, Zheng ZB
Department of Chemistry, University of Pittsburgh, PA 15260,
USA.
Proceedings of the National Academy of Sciences of the United
States of America (USA), 1995, 92/18 (8171-8175)
Vitamin E in the reduced, alpha-tocopherol form shows very
modest anticlotting activity. By contrast, vitamin E quinone
is a potent anticoagulant. This observation may have
significance for field trials in which vitamin E is observed
to exhibit beneficial effects on ischemic heart disease and
stroke. Vitamin E quinone is a potent inhibitor of the vitamin
K- dependent carboxylase that controls blood clotting. A newly
discovered mechanism for the inhibition requires attachment of
the active site thiolgroups of the carboxylase to one or more
methyl groups on vitamin E quinone. The results from a series
of model reactions support this interpretation of the
anticlotting activity associated with vitamin E.
Vitamin E may enhance the benefits of aspirin in
preventing stroke
Steiner M.
Memorial Hospital,Pawtucket, RI, United States
American Family Physician (USA), 1995, 51/8
(1977)
No abstract.
Antioxidant vitamins and disease - Risks of a
suboptimal supply
Ballmer PE, Reinhart WH, Gey KF
Departement Medizin, Inselspital, Universitat Bern.
Ther. Umsch. (Switzerland), 1994, 51/7 (467-474)
Reactive oxygen species (ROS) such as the superoxide (O2.-)
and the hydroxyl radical (OH.) are aggressive chemical
compounds that can induce tissue injury, e.g. by peroxidation
of polyunsaturated fatty acids in cell membranes or directly
by DNA damage. Many pathological conditions are in part caused
by ROS. There are various biological defense systems directed
towards radicals: specific enzymes, e.g. superoxide dismutase
or glutathion peroxidase; nonessential antioxidants, e.g. the
plasma proteins and uric acid; and the essential antioxidants,
e.g. Vitamin-C, vitamin D and carotenoids. This review focuses
on various clinical conditions where ROS are of major
pathogenetic significance: ageing, cancer, stroke, hematologic
disorders, adult respiratory distress syndrome (ARDS) and
organ preservation in transplantation medicine. Moreover, the
complementary system of the vitamins C and E in defense
against ROS is shortly discussed and the need for further
studies about the effects of antioxidant treatment, such as
interventional studies, proposed. The chronic exposure of the
organism to ROS is an important factor for tissue injury in
the process of ageing. Lipofuscin is a typical product of
lipid peroxidation and inversely correlates with longevity of
an organism. The ingestion of higher doses of antioxidative
vitamins was recently shown to be protective for the
development of cataracts, a degenerative disorder of the eye.
The impairment of the immune system in elderly people might be
prevented by a higher intake of multivitamin supplements.
Whether supplementation with antioxidative vitamins can extend
the life span in humans, as was shown in experimental animals,
remains unanswered. High intake of vegetables and fruits is
associated with a significantly lower incidence of cancer, in
particular of lung, but also of laryngeal, esophageal and
colorectal cancer, which might be attributed to higher intake
of antioxidant vitamins. As discussed in this issue of the
journal by Gey et al., there is an inverse correlation between
plasma status of antioxidant vitamins and coronary mortality
due to prevention of atherosclerosis. There is also an inverse
correlation between the risk of suffering from a fatal stroke
and the plasma concentrations of antioxidant vitamins.
Supplementation with vitamin E in some hematologic disorders
such as beta-thalassemia and
glucose-6-phosphatase-dehydrogenase deficiency showed an
improvement of hemolysis. ARDS, a common cause of respiratory
failure in severly ill patients, is a 'classical free radical
disease'. Interventional studies with antioxidant vitamins for
the treatment of ARDS are so far lacking. Reperfusion injury
by a 'radical burst' may be a major cause for performance of
organ transplants such as the kidney. The treatment with
multivitamin preparations containing Vitamin-C and E was
associated with better transplant performance in kidney
transplants in a recent study. In conclusion, 'optimal' plasma
concentrations of essential antioxidants are a primary aim in
the prevention of disease such as ischemic heart disease,
stroke and cancer. This is achieved by intake of higher doses
of dietary antioxidants (as compared with RDAs) or, if
necessary, by vitamin supplements.
Vitamin E consumption and the risk of coronary
disease in women
Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B,
Willett WC
Channing Laboratory, Boston, MA 02115.
New Engl. J. Med. (USA), 1993, 328/20
(1444-1449)
Background. Interest in thdocumented 552 cases of major
coronary disease (437 nonfatal myocardial infarctions and 115
deaths due to coronary disease).
Results. As compared with women in the lowest fifth of the
cohort with respect to vitamin E intake, those in the top
fifth had a relative risk of major coronary disease of 0.66
(95 percent confidence interval, 0.50 to 0.87) after
adjustment for age and smoking. Further adjustment for a
variety of other coronary risk factors and nutrients,
including other antioxidants, had little effect on the
results. Most of the variability in intake and reduction in
risk was attributable to vitamin E consumed as supplements.
Women who took vitamin E supplements for short periods had
little apparent benefit, but those who took them for more than
two years had a relative risk of major coronary disease of
0.59 (95 percent confidence interval, 0.38 to 0.91) after
adjustment for age, smoking status, risk factors for coronary
disease, and use of other antioxidant nutrients (including
multivitamins).
Conclusions. Although these prospective data do not prove a
cause-and-effect relation, they suggest that among middle-aged
women the use of vitamin E supplements is associated with a
reduced risk of coronary heart disease. Randomized trials of
vitamin E in the primary and secondary prevention of coronary
disease are being conducted; public policy recommendations
about the widespread use of vitamin E should await the results
of these trials.
Increased risk of cardiovascular disease at
suboptimal plasma concentrations of essential antioxidants: An
epidemiological update with special attention to carotene and
Vitamin-C
Gey KF, Moser UK, Jordan P, Stahelin HB, Eichholzer M, Ludin
E
Vitamin Unit, University of Berne, Switzerland.
Am. J. Clin. Nutr. (USA), 1993, 57/5 Suppl.
(787S-797S)
For the prolongation of life expectancy and reduction of
ischemic heart disease (IHD) dietary guidelines generally
recommend lowering saturated mammalian fat with partial
replacement by vegetable oils and increasing generously
vegetables, legumes, and fruits, which provide more essential
antioxidants. Plasma antioxidants as assayed in
epidemiological studies of complementary type (ie the
cross-cultural MONICA Vitamin Substudy reevaluation
considering the 'Finland-Factor', the Edinburgh Angina-Control
Study, and the Basel Prospective Study) consistently revealed
an increased risk of IHD (and stroke) at low plasma
concentrations of antioxidants, with the rank order as
follows: lipid-standardized vitamin E >> carotene =
Vitamin-C > vitamin A, independently of classical IHD risk
factors. Decreasing IHD risk through nutrition may be possible
when plasma concentrations have the following val ues: >
27.5-30.0 micromol vitamin E/L, 0.4-0.5 micromol carotene/L,
40-50 micromol Vitamin-C/L and 2.2-2.8 micromol vitamin A/L.
Thus, previous prudent regimens may now be updated, aiming at
an optimal status of all essential and synergistically linked
antioxidants.
Lipid peroxide, phospholipids, glutathione levels
and superoxide dismutase activity in rat brain after
ischaemia: Effect of ginkgo biloba extract
Seif-El-Nasr M, El-Fattah AA
Department of Pharmacology, Cairo University, Egypt.
Pharmacological Research (United Kingdom), 1995, 32/5
(273-278)
The influence of ginkgo biloba extract on the lipid
peroxide product (malondialdehyde, MDA), glutathione (GSH) and
phospholipids levels as well as superoxide dismutase (SOD,
1.15.1.1) and lactate dehydrogenase (LDH, 1.1.1.27) activities
in rat brain after occlusion of common carotid arteries was
investigated. Two experimental models were studied: 60 min
ischaemia without reperfusion and 60 min ischaemia followed by
60 min reperfusion. Compared to sham-operated animals,
ischaemia followed by reperfusion increased cytosolic LDH
activity and mitochondrial lipid peroxide content and
decreased the superoxide dismutase activity and mitochondrial
total phospholipids level. Preischaemic administration of
ginkgo biloba extract (150 mg kg-1, p.o.) could normalize the
SOD activity of the rat brain. The extract was also able to
reduce the lipid peroxide and phospholipids contents of the
mitochondrial rat brain. These effects could be explained on
the basis of the antioxidant property of ginkgo biloba extract
and suggests its beneficial role in the protection against
post-ischaemic injury.
Protection of hypoxia-induced ATP decrease in
endothelial cells by ginkgo biloba extract and
bilobalide
Janssens D, Michiels C, Delaive E, Eliaers F, Drieu K,
Remacle J
Laboratoire de Biochimie Cellulaire, Facultes Universitaires
Notre Dame de la Paix, Namur, Belgium.
Biochemical Pharmacology (United Kingdom), 1995, 50/7
(991-999)
Due to their localization at the interface between blood
and tissue, endothelial cells are the first target of any
change occurring within the blood, and alterations of their
functions can seriously impair organs. During hypoxia, which
mimics in vivo ischemia, a cascade of events occurs in the
endothelial cells, starting with a decrease in ATP content and
leading to their activation and release of inflammatory
mediators. EGb 761 and one of its constituents, bilobalide,
were shown to inhibit the hypoxia-induced decrease in ATP
content in endothelial cells in vitro. Under these conditions,
glycolysis was activated, as evidenced by increased glucose
transport, as well as increased lactate production. Bilobalide
was found to increase glucose transport under normoxic but not
hypoxic conditions. In addition, EGb and bilobalide prevented
the increase in total lactate production observed after 60 min
of hypoxia. However, after 120 min of hypoxia, the total
lactate production was similar under normoxic and hypoxic
conditions, and both compounds increased this production.
These results indicate that glycolysis slowed down between the
60th and 120th minute of hypoxia, while EGb and bilobalide
delayed the onset of glycolysis activation. In another
experimental model, both compounds were shown to increase the
respiratory control ratio of mitochondria isolated from liver
of rats treated orally. Since ischemia is known to uncouple
mitochondria, the protection of ATP content and the delay in
glycolysis activation observed during hypoxia in the presence
of EGb 761 or bilobalide is best explained by a protection of
mitochondrial respiratory activity, at least during the first
60 min of hypoxia incubation. Both products retain the ability
to form ATP, thereby reducing the cell's need to induce
glycolysis, probably by preserving ATP regeneration by
mitochondria as long as oxygen is available.
Lipid peroxidation in experimental spinal cord
injury. Comparison of treatment with Ginkgo biloba, TRH and
methylprednisolone
Koc RK, Akdemir H, Kurtsoy A, Pasaoglu H, Kavuncu I, Pasaoglu
A, Karakucuk I
Department of Neurosurgery, Erciyes University, School of
Medicine, Kayseri, Turkey.
Research in Experimental Medicine (Germany), 1995, 195/2
(117-123)
Ischaemia-induced lipid peroxidation is one of the most
important factors producing tissue damage in spinal cord
injury. In our study, the protective effects of Ginkgo biloba,
thyroid releasing hormone (TRH) and methylprednisolone (MP) on
compression injury of the rat spinal cord were investigated.
For this study 45 rats in four groups, including control, MP,
TRH and Gingko biloba, were used to determine the formation of
malondialdehyde (MDA). All the animals were made paraplegic by
the application clip method of Rivlin and Tator. Rats were
divided randomly and blindly to one of four treatment groups
(ten animals in each). MP and Ginkgo biloba treatments
significantly decreased MDA levels (F=54.138, P<0.01).
These results suggest that MP and Ginkgo biloba may have a
protective effect against ischaemic spinal cord injury by the
antioxidant effect.
Effects of natural antioxidant Ginkgo biloba
extract (EGb 761) on myocardial ischemia-reperfusion
injury
Haramaki N, Aggarwal S, Kawabata T, Droy-Lefaix MT, Packer
L
Department of Molecular and Cell Biology, University of
California, Berkeley 94720.
Free Radic. Biol. Med. (USA), 1994, 16/6
(789-794)
Recently, it was reported that Ginkgo bilboa extract (EGb
761), which is known to have antioxidant properties, also has
antiarrhythmic effects on cardiac reperfusion-induced
arrhythmias. In the present study, effects of EGb 761 on
cardiac ischemia-reperfusion injury were investigated from the
point of view of recovery of mechanical function as well as
the endogenous antioxidant status of ascorbate. Isolated rat
hearts were perfused using the Langendorff technique, and 40
min of global ischemia were followed by 20 min of reperfusion.
EGb 761 improved cardiac mechanical recovery and suppressed
the leakage of lactate dehydrogenase LDH) during reperfusion.
Furthermore, EGb 761 diminished the decrease of myocardial
ascorbate content after 40 min of ischemia and 20 min of
reperfusion. Interestingly, EGb 761 also suppressed the
increase of dehydroascorbate. These results indicate that EGb
761 protects against cardiac ischemia-reperfusion injury and
suggest that the protective effects of EGb 761 depend on its
antioxidant properties.
Experimental model of cerebral ischemia. Preventive
activity of Ginkgo biloba extract
Rapin JR, Le Poncin-Lafitte M
Sem. Hop. (France), 1979, 55/43-44 (2047-2050)
Unilateral embolization of the brain was performed in rats
by intracarotid injection of 4000 radioactive microspheres (50
mu). Local blood flow in hippocampus, striatum, hypothalamus
and remainder of the brain were determined using the
iodoantipyrine technique. Embolization resulted in a decrease
in blood flow and modification of lthe distribution of
microflow. Furthermore, embolization produces changes in
energy metabolism: particularly a fall in ATP and glucose
levels and an increase in lactate level. Subsequently, severe
vasogenic edema development. There was a correlation between
the number of microspheres injected and the amount of edema.
Pretreatment using an extract of Ginkgo biloba leaves
partially suppressed the effect of embolization. An
improvement of the flow in the ischemic areas associated with
an improvement of the energy metabolism explain the decrease
of the edema.
On brain protection of co-dergocrine mesylate
(Hydergine (R)) against hypoxic hypoxidosis of different
severity: Double-blind placebo-controlled quantitative EEG and
psychometric studies
Saletu B, Grunberger J, Anderer R
Division of Pharmacopsychiatry, Psychiatric University Clinic
of Vienna, Austria.
Int. J. Clin. Pharmacol. Ther. Toxicol. (Germany, Federal
Republic of), 1990, 28/12 (510-524)
Utilizing quantitative EEG and psychometric methods we
investigated in two subsequent double-blind,
placebo-controlled trials the following questions:
1) Does co-dergocrine mesylate (CDM) protect against
cerebral hypoxic hypoxidosis as objectivated by
neurophysiological and behavioral measures in man?
2) Does CDM offer protection equally both against moderate
and marked hypoxia induced experimentally by inhalation of a
gas mixture of 9.8% and 8.6% O2 (equivalent to 6000 m and 7000
m altitude, respectively)?
3) Are brain-protective effects of CDM improving by drug
administration over a longer period of time (2 weeks)?
In the first study, hypoxic hypoxidosis was induced by a
fixed gas combination of 9.8% oxygen and 90.2% N2 (equivalent
to 6000 m altitude), which was inhaled for 23 min under
normobaric conditions by 15 healthy volunteers. They received
randomized, after an adaptation session, placebo and 5 mg CDM.
Blood gases, quantitative EEG, and psychometric measures were
obtained under normoxic (21% O2) and hypoxic (9.8% O2)
conditions before as well as 2, 4, 6 and 8 h after oral drug
administration. Blood gas analysis demonstrated under hypoxia
a drop in PO2 from 91 to 37 mmHg and in PCO2 from 38 to 33
mmHg, while pH increased from 7.41 to 7.47. Computer-assisted
spectral analysis of the EEG showed an increase of
delta/theta, decrease of alpha, and an increase of
superimposed fast beta activity indicative of deterioration in
vigilance. The latter was documented at the behavioral level
by deterioration of intellectual and mnestic functions,
psychomotor activity, performance in a reaction time task,
mood, and wakefulness. CDM attenuated significantly this brain
dysfunction, as it attenuated delta/theta and increased
alpha-adjacent beta activity. Psychometric performance based
on all 11 variables deteriorated under hypoxia by 49% after
placebo, while after 5 mg CDM only by 26%. However, in a
subsequent double-blind placebo-controlled trial in 12 healthy
young volunteers, further augmentation of hypoxia induced by
inhalation of a gas combination of 8.6% O2 and 91.4% N2
(equivalent to 7000 m altitude) leading to a drop of PO2 and
PCO2 to 32 and 32 mmHg, respectively and an increase of pH to
7.46 resulted in a loss of brain protection, even when CDM was
given over 2 weeks daily. Our findings suggest that treatment
of organic brain syndromes with nootropic/antihypoxidotics
should be initiated in an early rather than a late stage.
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