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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
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, and lactate dehydrogenase (LDH, 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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