Ginseng And Atherosclerosis

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Atherosclerosis involves the irregular deposition of lipids such as cholesterol and triglycerides in yellowish plaques of atheroma in the subintimal layers of the inner walls of arteries and arterioles. Calcification may also occur with consequent hardening of the arteries. Atherosclerosis most commonly affects coronary arteries, cerebral arteries and peripheral arteries of the lower limbs. As a progressive condition it is particularly associatedm with old age.

Atheromatous plaques and related scarring cause narrowing of the arteries and ultimate occlusion of these vessels with ischaemia or reduction of blood supply to the structures supplied by such arteries and resultant infarction due to dead tissue formed by the lack of blood supply. According to the area involved atherosclerosis can lead to hypertension, angina pectoris, myocardial infarction, arrhythmias, paralysis, gangrene of the extremities and cerebral insufficiences leading to confusion, amnesia, personality changes or strokes.

Ginseng was suggested as a medicament for the control of cholesterol levels and for the treatment of anaemia. Experimental evidence does shew that ginseng is capable of increasing the red blood cell count, of promoting serum protein synthesis and of stimulating RNA formation in the liver and DNA synthesis in bone marrow. Cholesterol, a steroid alcohol, occurs naturally in the body and is found particularly in the bile and gall bladder and in the lipoproteins of the blood plasma. Although endogenous cholesterol can be formed in all cells of the body, blood cholesterol is usually produced in the liver, the body organ that controls the normal cholesterol level in the blood. High levels of cholesterol can occur in insulin and thyroid hormone deficient subjects or in persons consuming a high fat, high cholesterol containing diet. Dietary cholesterol, also called exogenous cholesterol, derives from foods such as milk, cream, butter, cheese, eggs, beef dripping, offal and other meats. Ginsenosides stimulate cholesterol synthesis in the liver and its conversion to other steroids as well as probable excretion in bile and faeces. At the same time, total serum cholesterol concentration falls by about 25 per cent due to reduced absorption from the gastrointestinal tract and increased rate of cholesterol metabolism in the body (Karzel, 1974).

Compounds responsible for the lowering of total serum cholesterol and low density lipoprotein (mainly cholesterol) levels occur particularly in petroleum ether extracts of ginseng root although also in aqueous extracts, lowering cholesterol and triglyceride levels in the blood, and lipogenic and cholesterol enzyme (cholesterol-7a-hydroxylase and ¡-hydroxy-^-methylglutaryl-CoA) activities in the liver (Qureshi et al., 1983). Moon et al. (1984) studied such effects during a 4-week trial of red ginseng crude saponins administered to rats fed on a diet of 2 per cent cholesterol and 10 per cent olive oil. Oral saponin treatment (150 mg/kg/day) did not affect the high density cholesterol level although the plasma total cholesterol level was lowered and the triglyceride levels markedly raised. Other workers have implicated ginsenosides Rb2 and Rc taken orally and it was noted that ginsenoside Rb2 treatment of hyperlipemic animals could result in elevated high density lipoprotein levels. High density lipoproteins comprise about 50 per cent protein with smaller concentrations of lipids and are deposited in adipose tissues. Ginsenoside Rb2 stimulated the lipolytic activity of the lipoprotein lipase causing a concomitant decrease in triglyceride levels and very low density lipoprotein-triglyceride levels in serum (Yokozawa et al., 1985a). Prednisone acetate can be employed to induce increased levels of total lipids, triglycerides and total cholesterol as well as a decrease in serum cortisol. In rabbits it has been shown that P. ginseng stem and leaf total saponins given orally (60 mg/ kg-1/day) markedly inhibited such induced changes. The total leaf saponins comprised ginsenosides Rb2, Rc, Rd, Re, Rg1, Rg2, 20(R)-Rg2, Rh1, F2 and F3, ginsenoside Re being the most important (Dou et al., 1997). Using Hep G2 liver cells cultured in a cholesterol-rich medium, Park et al. (1995b) concluded that the serum cholesterol-lowering effects of ginseng components such as total saponins, ginsenosides Rb1 and Rb2 and the non-saponifiable fraction of the ether extract could be partially attributed to increased hepatocellular acyl CoA: cholesterol acyl transferase activity. Further studies are needed using standardised preparations.

Several open clinical studies have indicated the potential value of ginseng in the prophylaxis of atherosclerotic or arteriosclerotic conditions although no large scale placebo controlled double blind studies have as yet been reported (Sonnenborn, 1987). Joo et al. (1982) noted that ginseng saponins stimulated phospholipid (very low density lipoprotein) biosynthesis and also that in cholesterol-fed rabbits the ginseng saponins reduced the penetration of cholesterol into the aortic tissue. Therefore a potential preventative action against atheroma formation was indicated. Using standardised ginseng extract G115 (Pharmaton S.A., Lugano, Switzerland) and rhesus monkeys (Macaca muletta), Dixit et al. (1991) confirmed that lowering of serum triglycerides and cholesterol occurred in hyperlipidemic animals and a 34-72 per cent reduction was reported. The high density lipoprotein-cholesterol/ total cholesterol ratio was increased and the reduction in low density lipoprotein and very low density lipoproteins again prompted the suggestion that ginseng G115 preparations might have beneficial effects as antiatherogenic agents. Saponins from Jilin ginseng rhizome, from ginseng stems and leaves and from P. quinquefolium white ginseng were found, in rats, to inhibit the formation of thrombi, decrease osmotic pressure, decrease volume swelling of erythrocytes and increase the fluidity of erythrocytic membranes, factors of value in countering atherosclerosis and ageing (Yang et al., 1992).

Ginseng saponins have also been incorporated in formulations and patented preparations (see Chapter 9) intended to reduce blood clotting in thrombosis cases. Ginseng has antiplatelet action. The blood platelets or thrombocytes are formed by fragmentation of megakaryocytes, a large type of white blood cell formed in the bone marrow. The platelets, round or oval discs about 2 microns in diameter, pass into the blood circulation and play an important role in the blood clotting mechanism. Normal blood contains 200,000 to 400,000 platelets per cubic millimetre and the platelets function to activate the blood clotting mechanism and to plug damage to the blood vessels. When in contact with damaged vascular surfaces e.g. collagen fibres in the vascular wall or damaged endothelial cells, the platelets swell, adopt irregular shapes with projecting processes, and become sticky, adhering to the collagen fibres. Secretion of adenosine diphosphate (ADP) and enzymes leads to the formation of thromboxane A in the plasma and the combination of ADP and thromboxane A activates more platelets to become adhesive and to accumulate and coalesce to form platelet plugs that can effectively block small rents and tears in vessel walls. Greater vascular damage requires the larger structure of the thrombus or clot. As the platelet plug blocks the smaller tears, vasoconstrictor substances are released constricting the blood vessel and initiating clot formation. The prothrombin activator secreted catalytically converts prothrombin to thrombin which enzymatically converts the soluble plasma protein fibrinogen to insoluble fibrin threads that make a meshwork trapping blood cells, platelets and plasma so forming the blocking blood clot.

Total saponins from P. quinquefolium roots were shewn to significantly decrease platelet aggregation rates and to increase superoxide dismutase activity in hyperlipidaemic rats (Li et al., 1996). Protopanaxatriol-derived saponins were isolated from Sanchi ginseng (P. notoginseng) and included ginsenosides Re, 20-gluco-Rf, Rg1, Rg2, Rh1 and F1 and notoginsenosides R1, R2, R3 and R6. Such triol saponins (1-4 mg/mL) inhibited ADP, collagen and arachidonic acid induced rabbit platelet aggregation in vitro. In addition, in vivo in rats the protopanaxatriol-derived saponins (75-300 mg/Kg intraduodenally) dose dependently inhibited platelet aggregation, platelet thromboxane A2 release and experimental thrombosis. Thus the anti-thrombotic mechanism was concluded to be mediated by inhibition of platelet aggregation and thromboxane A2 release (Su et al., 1996). Such results indicated potential value in the prevention and treatment of atherosclerosis.

It had already been recorded that the polyacetylenes panaxydol and panaxynol caused concentration-dependent haemolysis (Kim et al., 1988b) and therefore the effect on blood platelets was investigated. Ginseng was known to have an effect on platelets and panaxynol, obtained from the ethereal fraction of ginseng root extract, was considered the most potent antiplatelet factor in ginseng and its action was mainly due to the inhibition of thromboxane formation. Panaxynol caused a marked reduction of the platelet aggregation induced by collagen, arachidonic acid, ADP and thrombin. Ginsenosides from the butanol fraction of ginseng root extract had no such effect although ginsenoside Ro did inhibit adenosine triphosphate release by washed rabbit platelets. The aggregation ability of platelets after panaxydol treatment was not readily regained. In human blood plasma panaxydol prevented secondary aggregation and completely obstructed the epinephrine and ADP-induced adenosine triphosphate release from platelets. Panaxynol, but not the ginsenosides, inhibited thromboxane B2 formation by platelets although panaxynol and ginsenoside-Rb2 inhibited increase of intracellular Ca+2 caused by collagen (Teng et al., 1989).

A later report suggested that panaxynol from the ether-soluble fraction and the ginsenosides Ro, Rg1 and Rg2 from the butanol-soluble fraction were the main antiplatelet components. Panaxynol inhibited the platelet aggregation, the adenosine triphosphate release reaction and thromboxane formation in rabbit platelets but the ginsenosides Ro, Rg1 and Rg2 suppressed the release reaction only (Kuo et al., 1990). It has also been suggested that as ginsenoside Rg1 has potent antiaggregation activity in vitro and in vivo it may be useful for the prevention and treatment of thrombotic cardiovascular disorders (Yamomoto et al., 1988).

Investigation of the effects of ginseng saponins on blood coagulation was commenced by Matsuda et al. (1985). 20 (S)-ginsenoside Rg3 and 20(R)-ginsenoside Rg3 inhibited the platelet aggregation induced by collagen and ADP and 20 (S)-ginsenoside Rg3, 20(S)-ginsenoside Rh1 and 20(R)-ginsenoside Rh1 inhibited thrombin-induced conversion of fibrinogen to fibrin. Extending this work further (Matsuda et al., 1986), the action of some ginsenosides on blood coagulation and fibrinolytic mechanisms in vitro were compared with the standard anticoagulants aspirin, heparin and dextran sulphate. Ginsenoside Rg2 demonstrated marked inhibitory action on the platelet aggregation caused by collagen, endotoxin and arachidonic acid when compared against aspirin as standard at 1.0 mM concentration. Ginsenoside Ro reduced the conversion of fibrinogen to fibrin caused by thrombin at a concentration of 0.1-1.0 mM. On the basis of the action of the enzyme urokinase on plasminogen-containing fibrin plates, it was thought that the ginsenosides Rb1, Rb2, Rc, Re, Rg1, Rg2 and Ro might promote the action of that enzyme in the fibrinolytic system. Intraperitoneal injection of panaxadiol (200 mg/kg) in rats reduced the viscosity of whole blood and plasma and in rabbits (50 or 70 mg/kg intravenously) inhibited both platelet aggregation and blood coagulation (Xu et al., 1988). Other workers stated that only ginsenoside Rg1 had potent antiaggregation activity in vitro when tested against human platelets stimulated with the aggregating agents collagen and arachidonic acid and suggested that the mechanism of action was by impairment of the thromboxane-A2-mediated pathway at post-receptor sites. A dose of 50 mg of ginsenoside Rg1 given orally significantly reduced platelet aggregation (Yamamoto et al., 1988). Also working with human platelets, Kimura et al. (1988) reported that ginsenoside Rg1 alone inhibited adrenalin and thrombin-induced platelet aggregation and the release of 5-hydroxytryptamine in a concentration-dependent manner in the range 5-500 |l g/mL. Adrenalin and thrombin induce elevation of the calcium Ca++ level in the second phase of clotting but ginsenoside Rg1 reduced such cytosolic free Ca++ levels and, in turn, inhibited 5-hydroxytryptamine release and platelet aggregation. Hence the repeated suggestions that ginsenoside Rg1 may be potentially useful in the treatment of atherosclerosis and thrombotic conditions. More recently Park et al. (1994b) concluded that panaxadiol and panaxatriol did not inhibit Ca++ influx in adrenaline-stimulated human platelets although inhibiting the formation of thromboxane-A2 and thus platelet aggregation, probably by blocking the conversion of arachidonic acids to thromboxane-A2.

Another suggestion was presented by Shi et al. (1990) who noted that, in comparison with control animals, aortic atherosclerotic plaque was reduced in rabbits treated orally with P. notoginseng total saponins (100 mg/kg/day) for 8 weeks. They observed an increase in prostacyclin (prostaglandin PGI2) in the carotid artery and decreased thromboxane A2 in blood platelets and suggested that the anti-atherosclerotic action of the total saponins might be due to correction of imbalance between prostacyclin and thromboxane-A2. Similar results were reported by Terano et al. (1994) who had administered ginsenoside Rc to arteriosclerosis and thrombosis patients for one week. Increase in prostacyclin levels in the urine occurred although the thromboxane A2 level was unchanged. Rat cell culture experiments confirmed that ginsenoside Rc enhanced the expression of the cyclooxygenase gene in the ribonucleic acid (RNA) in the blood vessel walls, promoting prostacyclin formation. In turn the prostacyclin inhibited vascular smooth muscle cell generation and platelet aggregation as well as exhibiting vasodilatory action, factors reducing thrombosis.

The Korean group of Park et al. (1995a) studied the non-saponin, lipophilic fraction extracted from red ginseng roots and noted that it inhibited in a dose-dependent manner the aggregation of human blood platelets induced by thrombin (0.1 units/ml). It also inhibited the Ca++ influx into the platelets, markedly inhibited thromboxane-A2 formation and caused a rise in cyclic guanosine monophosphate (cGMP) concentration. Therefore it was concluded that regulation of the levels of cGMP and thromboxane-A2 was the probable mechanism of inhibition of platelet aggregation due to thrombin. Further studies (Park et al., 1996) using a lipophilic fraction in corn oil prepared from P. ginseng roots as a food supplement indicated that the lipophilic fraction increased cGMP directly and cyclic adenosine monophosphate (cAMP) indirectly and thus inhibited thrombin- or collagen-induced platelet aggregation by increasing the thrombin time and the activated partial thromboplastin time for conversion of fibrinogen to the fibrin threads that trap platelets, blood cells and plasma to form clots. Therefore dietary lipophilic fraction produces an antithrombotic effect in vivo.

The value of P. notoginseng saponins in the treatment of cerebral ischaemia was demonstrated in vivo and in vitro in rats. The saponins were administered at a dosage of 200 mg/kg intraperitoneally for 1-3 days and were shewn in vivo to significantly inhibit abnormal increases of platelet aggregation and platelet adhesiveness in rats subjected to permanent occlusion of the middle cerebral artery. Platelet aggregation induced by ADP in vitro was also inhibited by P. notoginseng saponins. Therefore it was suggested that the increased fluidity of the platelets with resultant reduced platelet adhesiveness and reduced platelet aggregation accounted, at least in part, for the anti-cerebral ischaemia action of ginseng (Ma and Xiao, 1998).

Sanchi ginseng (P. notoginseng) differs from other common ginsengs in its indigenous usage as a haemostatic agent. Such action has been ascribed to a-amino-^-(oxaloamino)propionic acid, a compound also increasing the blood platelet count and obtained from Sanchi roots (Okan, 1982)) and similarly ascribed to L-dencichin (3-[(carboxy-carbonyl)amino]-L-alanine) (Zhao and Wang, 1986). A freeze-dried powder prepared from an ethanolic extract of roasted P. notoginseng roots tended to shorten whole-blood coagulation times and plasma recalcification times one hour after oral administration of 5002000 mg/kg to rats but did not alter thrombin times (Goto et al., 1987).

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