A brief history of EGb 761 and its therapeutic uses.
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Animals↗
Biomedical subjects
F V DeFeudis
Publications and source records attributed to F V DeFeudis.
Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications.
The effects of EGb 761 on the CNS underlie one of its major therapeutic indications; i.e., individuals suffering from deteriorating cerebral mechanisms related to age-associated impairments of memory, attention and other cognitive functions. EGb 761 is currently used as symptomatic treatment for cerebral insufficiency that occurs during normal ageing or which may be due to degenerative dementia, vascular dementia or mixed forms of both, and for neurosensory disturbances. Depressive symptoms of patients with Alzheimer's disease (AD) and aged non-Alzheimer patients may also respond to treatment with EGb 761 since this extract has an "anti-stress" effect. Basic and clinical studies, conducted both in vitro and in vivo, support these beneficial neuroprotective effects of EGb 761. EGb 761 has several major actions; it enhances cognition, improves blood rheology and tissue metabolism, and opposes the detrimental effects of ischaemia. Several mechanisms of action are useful in explaining how EGb 761 benefits patients with AD and other age-related, neurodegenerative disorders. In animals, EGb 761 possesses antioxidant and free radical-scavenging activities, it reverses age-related losses in brain alpha 1-adrenergic, 5-HT1A and muscarinic receptors, protects against ischaemic neuronal death, preserves the function of the hippocampal mossy fiber system, increases hippocampal high-affinity choline uptake, inhibits the down-regulation of hippocampal glucocorticoid receptors, enhances neuronal plasticity, and counteracts the cognitive deficits that follow stress or traumatic brain injury. Identified chemical constituents of EGb 761 have been associated with certain actions. Both flavonoid and ginkgolide constituents are involved in the free radical-scavenging and antioxidant effects of EGb 761 which decrease tissue levels of reactive oxygen species (ROS) and inhibit membrane lipid peroxidation. Regarding EGb 761-induced regulation of cerebral glucose utilization, bilobalide increases the respiratory control ratio of mitochondria by protecting against uncoupling of oxidative phosphorylation, thereby increasing ATP levels, a result that is supported by the finding that bilobalide increases the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome oxidase. With regard to its "anti-stress" effect, EGb 761 acts via its ginkgolide constituents to decrease the expression of the peripheral benzodiazepine receptor (PBR) of the adrenal cortex.
Alzheimer Disease↗
Effects of single intraperitoneal injections of an extract of Ginkgo biloba (EGb 761) and its terpene trilactone constituents on barbital-induced narcosis in the mouse.
A mouse model of barbital-induced narcosis was used to examine the effects of single intraperitoneal injections of an extract of Ginkgo biloba (EGb 761), an extract devoid of terpene trilactones (CP 205), and three terpene trilactone constituents of the extract (ginkgolides A and B, bilobalide). Administration of sodium barbital (180 mg/kg, IP) to the mice caused narcosis, measured as a loss in righting reflex. Single injections of EGb 761 (25 and 50 mg/kg), given 60 min prior to sodium barbital, significantly shortened barbital-induced sleeping time, whereas these same doses of CP 205 were ineffective. Single injections of ginkgolide B (1 mg/kg) and bilobalide (2 and 5 mg/kg) significantly shortened sleeping time, whereas ginkgolide A was ineffective. The effects of ginkgolide B and bilobalide were reflected as increases in latency to onset of sleep and those of EGb 761, ginkgolide B, and bilobalide were correlated with decreases in the number of mice that slept. At the behavioral level, these potent in vivo effects of EGb 761, ginkgolide B, and bilobalide resemble those of certain antidepressants. At the molecular level, it is hypothesized that interactions with the picrotoxinin/TBPT site of GABA-regulated Cl- channels of the CNS may be involved. This information appears useful in explaining the clinically observed "vigilance-enhancing" and "antidepressant-like" actions of EGb 761.
Analysis of Variance↗
Interactions of Ginkgo biloba extract (EGb 761), diazepam and ethyl beta-carboline-3-carboxylate on social behavior of the rat.
The social interaction test was used to examine the effects of an extract of Ginkgo biloba (EGb 761) and its possible interactions with diazepam and ethyl beta-carboline-3-carboxylate (beta-CCE). Pairs of naive (unfamiliar) male Wistar AF rats subjected to the same treatment were placed in a novel test arena that was brightly illuminated, and the duration (in s) of social contact was observed over a 10 min period. Single injections of EGb 761 (8-16 mg/kg, i.p.), given 30 min prior to testing, or repeated oral administration of the extract (48 or 96 mg/kg/day) for 8 days, significantly decreased social contact under conditions that did not influence locomotor activity. Injection of diazepam (1 mg/kg, i.p.), 30 min before testing, significantly increased social contact. Injection of diazepam to animals that had received repeated oral treatment with EGb 761 (96 mg/kg/ day) increased social interaction to an extent greater than observed with diazepam alone. Injection of beta-CCE (2-16 mg/kg, i.p.), 15 min before testing, significantly decreased social contact. When the animals were treated with EGb 761 (48 or 96 mg/kg/day, p.o. for 8 days) and beta-CCE (4 mg/kg), both of which decreased social interaction when administered alone, the resulting level of social contact was similar to that of control animals. Interactions with certain sites of central GABAA/ benzodiazepine/Cl- channel receptor complexes could be involved in mediating these effects of EGb 761, diazepam and beta-CCE.
Animals↗
Excess EDRF/NO, a potentially deleterious condition that may be involved in accelerated atherogenesis and other chronic disease states.
1. To date, no method exists for preventing the injury-induced, accelerated atherogenesis that can occur as a "late complication" after initially successful invasive cardiovascular therapy (e.g. coronary angioplasty, endarterectomy). The problems intrinsic to some of the therapeutic approaches that are presently being developed have been analyzed, and the need for an alternative approach is evident. 2. An hypothesis is advanced, providing a novel conceptual basis for developing preventive therapy for accelerated atherogenesis, as well as for other chronic (degenerative) disease states, using agents that selectively inhibit the actions and metabolic transformations of excessive amounts of endogenously-derived and/or exogenously-acquired nitric oxide (NO). 3. It is considered that excess NO can damage tissue by enhancing the formation of hydroxyl radicals (OH.) via the peroxynitrite pathway and alpha-hydroxynitrosamines via nitrosation processes, and that it can stimulate cell proliferation by activating guanyl cyclase. These actions would facilitate the process of accelerated atherogenesis. 4. Selectivity for opposing the effects and metabolic handling of excess NO, regardless of its origin (endogenous via the action of constitutive or inducible NO synthase, or exogenous), rather than selectivity for inhibiting the activity of inducible versus constitutive NO synthase, is considered to be the key element required of candidate therapeutic agents. 5. The vitamin C derivative, 2-O-octadecylascorbic acid, which could protect that part of the NO mechanism that is essential for normal function by scavenging superoxide anion-radicals (O2-., while preventing the formation of OH. and potentially toxic nitrosamines via metabolic reactions involving excess NO, represents a model compound for developing effective therapy.
Animals↗
Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761) on cerebral glucose utilization in the rat: an autoradiographic study.
1. The autoradiographic method based on 2-deoxy-D[1-14C]glucose ([14C]DG) was used to determine glucose utilization in 49 discrete structures of rat brain under control conditions and after the animals had received repeated treatment with an extract of Ginkgo biloba (EGb 761). 2. Oral administration of EGb 761 (50 or 150 mg/kg/day) to adult male rats for 15 days did not modify body weight, mean arterial blood pressure, the concentrations of glucose or hemoglobin in blood, blood gases or arterial pH. 3. EGb 761 treatments produced only slight-to-moderate changes in glucose utilization in the various brain structures; i.e. decreases to an extent not exceeding 18.4% at the 50 mg/kg dose or 11.7% at the 150 mg/kg dose. 4. Glucose utilization was significantly decreased only in the frontoparietal somatosensory cortex, nucleus accumbens, cerebellar cortex and pons and only with the 50 mg/kg dose of EGb 761. 5. Although the four brain structures affected by EGb 761 treatment do not, in themselves, constitute a specific functional system of the CNS, these effects appear useful in explaining mechanisms underlying the clinical use of EGb 761 in treating problems associated with deficient somatosensory processing (e.g. impairment of "vigilance") and vestibular mechanisms (e.g. vertiginous syndromes).
Administration, Oral↗
Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761), bilobalide and ginkgolide B on the electrical activity of pancreatic beta cells of normal or alloxan-diabetic mice: an ex vivo study with intracellular microelectrodes.
1. The effects of repeated (5-day) treatments with an extract of Ginkgo biloba leaves (EGb 761), bilobalide, and ginkgolide B on the in vitro electrical activity of insulin-secreting pancreatic beta cells of mice have been examined using intracellular microelectrodes. 2. EGb 761 (200 mg/kg/day, p.o.) protected beta cells against the toxic effects of alloxan (50 mg/kg, i.v.), an effect characterized by a restoration of membrane potential (Vr) and an increase in spike frequency (Fs/30), an indicator of insulin secretion. 3. Treatment of non-diabetic mice with EGb 761 (200 mg/kg/day, p.o.) increased Fs/30 of their beta cells, as tested by in vitro exposure of the cells to 11.1 mM glucose, an effect that also occurred with bilobalide (8 mg/kg/day, i.p.) but not with ginkgolide B (4 mg/kg/day, i.p.). 4. Since bilobalide and ginkgolide B caused opposite effects on the sensitivity of beta cells to glucose, the stimulatory effect of EGb 761 on Fs/30 may be attributed to its content of bilobalide. 5. In contrast to its ex vivo effect, the direct in vitro effect of EGb 761 (10 and 25 micrograms/ml) on beta cells favors a decrease in electrical activity, indicating that its in vivo action might be indirect (e.g. via the formation of an active metabolite).
Action Potentials↗
Demonstration of the "anti-stress" activity of an extract of Ginkgo biloba (EGb 761) using a discrimination learning task.
1. Young (4-month-old) and old (20-month-old) rats, maintained under water restriction, were trained to discriminate to obtain a small amount of drinking water as a reward. Each animal had to learn to press a lever corresponding to a light that was randomly distributed on the left or right. 2. Introduction of an auditory perturbation ("stress") during the discriminative phase of learning modified the capacity and rate of acquisition in both young and old animals, changes that were correlated with increases in plasma concentrations of epinephrine, norepinephrine and corticosterone. 3. Stress-induced detrimental changes in both discrimination learning and plasma hormones were suppressed by 20 days of oral treatment with an extract of Ginkgo biloba leaves (EGb 761; 50 or 100 mg/kg/day) in both young and old rats, effects that became statistically significant by the third day of learning (time of maximal acquisition rate). 4. EGb 761 treatment was less effective in increasing the percentage of efficient lever presses in old than in young rats, but more effective in decreasing the number of inefficient lever presses and reaction time in the older animals. 5. These results indicate that EGb 761 can facilitate behavioral adaptation despite adverse environmental influences, a property that supports its clinical use in treating cognitive impairment, especially in elderly patients.
Age Factors↗
Coronary atherosclerosis: current therapeutic approaches and future trends.
Invasive cardiovascular procedures, such as percutaneous translumenal coronary angioplasty (PTCA) and aorto-coronary bypass surgery (ACBS), that are currently employed in treating the coronary stenosis or occlusion caused by atherosclerosis represent a major therapeutic advance for managing coronary heart disease (CHD). However, the cellular proliferative response and associated intimal hyperplasia that can follow the damage to blood vessels that occurs with these procedures leads to late complications which cannot be effectively controlled by presently available drugs. Hence, a new approach is required for managing these complications, termed "restenosis" (in the case of PTCA) or "stenosis" (in the case of ACBS). Existing drug therapy is reviewed and some new approaches to this problem are provided herein. Further studies of growth factors and other substances that influence the cellular proliferative response that follows injury to the blood vessel wall could lead to the development of effective therapy. Inhibition of intimal hyperplasia and/or acceleration of endothelial cell re-growth provide a basis for such new approaches. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), as well as endothelium-derived relaxing factor(s) (EDRF) and calcitonin gene-related peptide (CGRP) are among the substances discussed. Modification of certain currently available drugs (e.g. Ca(2+)-antagonists) could also be of value in meeting this therapeutic demand.
Calcitonin Gene-Related Peptide↗
Pharmacological studies of somatostatin and somatostatin-analogues: therapeutic advances and perspectives.
This article is aimed at reviewing and analyzing studies that are related to the possible therapeutic use of a potent and ubiquitously-distributed hormone--somato-statin (SS-14), and its analogues. Administration of these substances has provided beneficial effects in treating acromegaly, gastro-intestinal hemorrhagic and hypersecretory disorders, acute pancreatitis, diabetes mellitus, and certain types of cancer. Further studies with SS-14-analogues might provide new therapies for treating certain life-threatening disorders of man.
Acromegaly↗
Studies on endothelium-dependent vasorelaxation.
Recent studies on endothelium-dependent vasorelaxation have been briefly reviewed and analyzed. This mechanism, which might involve the release of metabolite(s) termed "endothelium-derived relaxing factor(s)" (EDRF), could play a major role in the regulation of vascular tone.
Animals↗
Effects of antidepressants on receptor-activated and Ca2+-activated contractions of rabbit isolated aorta.
Helically-cut strips of rabbit aorta were used to examine the inhibitory effects of some antidepressants on the contractile responses produced by norepinephrine (NE), serotonin (5-HT) or K+. The order of potency of antidepressants in antagonizing 5-HT-induced responses was: mianserin greater than amitriptyline greater than imipramine (IMI) greater than desipramine greater than or equal to nomifensine. With NE as agonist, the order of potency was: amitriptyline greater than mianserin greater than IMI greater than desipramine greater than or equal to nomifensine. Viloxazine (10(-5) M) was ineffective on 5-HT- or NE-induced contractions. For K+-induced contraction (which is mediated by Ca2+ entry into smooth muscle cells) tricyclic antidepressants were about equipotent with mianserin; nomifensine and viloxazine were relatively ineffective. These results indicate that certain antidepressants have multiple effects on arterial smooth muscle. Such effects could underlie not only the side-effects, but also the therapeutic actions of these agents.
Animals↗
Possible relationship between the syntheses of endothelium-derived relaxing factor (EDRF) and PAF-acether.
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Animals↗
Verapamil as an apparent competitive antagonist of the serotonin receptor of rabbit isolated aorta.
The actions of four Ca2+-antagonists (verapamil, diltiazem, nifedipine and flunarizine) were tested on serotonin- (5-HT-) induced contraction of rabbit isolated aorta. Verapamil produced a dose-dependent, parallel shift to the right of the concentration-response curve for 5-HT (pA2 approximately equal to 7.13; Schild slope approximately equal to 1.01), indicative of competitive antagonism. The effects of diltiazem, nifedipine and flunarizine were much less pronounced and best characterized as non-competitive interactions. The effect of verapamil, which likely involves its antagonism of smooth muscle 5-HT2-receptors, might be useful in explaining its therapeutic actions and/or its side-effects.
Animals↗
Endothelium-derived relaxing factor (EDRF).
Recent studies on endothelium-dependent vasorelaxation have been briefly reviewed and analyzed. The following processes appear to subserve this mechanism: In the endothelial cell: receptor activation, activation of phospholipases, mobilization of intracellular Ca2+, synthesis and release of 'endothelium-derived relaxing factor(s) (EDRF); In the smooth muscle cell: activation of guanyl cyclase and protein kinase, protein phosphorylation/dephosphorylation, relaxation. Alterations of this mechanism could be involved in certain cardiovascular disorders.
Animals↗
Comparison of the contractile effects of an extract of Ginkgo biloba and some neurotransmitters on rabbit isolated vena cava.
Dose-related contractions were elicited in strips of rabbit isolated vena cava by norepinephrine (NE, IC50 approximately equal to 2.3 X 10(-7) M), dopamine (IC50 approximately equal to 6.9 X 10(-6) M), histamine (IC50 approximately equal to 2.1 X 10(-6) M) and extract of Ginkgo biloba (Gb, IC50 approximately equal to 86 micrograms/ml). Serotonin and tyramine elicited very weak contractile effects in this preparation. Phenoxybenzamine (10(-7) M) abolished the contractions elicited by NE, and blocked the effect of Gb by about 50%. Further support is provided for the therapeutic action of Gb in cardiovascular disorders.
Animals↗
Are vascular mechanisms involved in antidepressant action?
Recent studies of the mechanisms of action of certain antidepressants, anti-migraine agents, and Ca2+ entry blockers have been briefly reviewed and analyzed. It is postulated that a thorough explanation of the therapeutic effects of antidepressants should include discussion of their actions on the cardiovascular (cerebrovascular) system. The inhibitory actions of antidepressants on Ca2+- and serotonin (5-HT)-mediated processes of vascular smooth muscle seem to be particularly important.
Animals↗