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Ginsenoside RG1 and Corticosteroid Receptors in Rat Brain Rudolf Endocrinol. Japon. 1987, 34 (2), 213-220 Ginsenoside RG1 and Corticosteroid Receptors in Rat Brain E. R. DE KLOET, J. M. H. M. REUL, F. R. VAN DEN BOSCH, J. A. D. M. TONNAER1, AND H. SAITO2 Rudolf Magnus Institute for Pharmacology, Medical Faculty, University of Utrecht, Vondellaan 6, NL-3521 GD Utrecht, The Netherlands and 1) Scientific Development Group, ORGANON International, Oss, The Netherlands and 2) Experimental Station for Medicinal Plant Studies, Faculty of Phar- maceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113 Japan Abstract Old (28 months) male Wistar rats were treated chronically for two weeks with ginsenoside Rgi or with vehicle delivered via sc implanted Alzet mini- pumps (rate of ginsenoside release 2.4 ƒÊg/0.5 pl/h). The number of Type 1 corticosterone-preferring receptor sites (CR) and Type 2 glucocorticoid receptors (GR) was measured in the cytosol of hippocampus tissue of rat brain with an in vitro binding assay. In old rats the B. of Type 1 CR and Type 2 GR was reduced by 51.5% and 28.3% respectively. Following the two week treatment with Rgi the B. of Type 1 CR increased by 60% and a receptor concentration was reached which was 21% lower than that observed in the young control animals. Minor differences in affinity of steroid binding to both receptor systems were observed in the groups of rats. The possible binding of ginsenosides to brain corticosteroid receptors in vitro was investigated as well. The inclusion of a 500 fold molar excess of Rgi in hippocampus cytosol did not displace 3H-corticosterone from its soluble receptor sites. The affinity of Rgi with these sites in vitro is therefore negligible. In conclusion, the binding capacity of Type 1 CR and Type 2 GR is reduced in the hippocampal brain region of aged rats. Upon chronic infusion of ginsenoside Rgi, only Type 1 CR capacity is restored towards the level observed in young control animals. This finding suggests that in old rats the ginsenoside enhances the CORT signal via Type 1 CR on the function of the hippocampus, which is a limbic brain structure involved in cognition, mood and affect. Two distinct corticosteroid receptor sys- Veldhuis et al., 1982; Beaumont and Fane- tems have been identified in rat brain i.e. stil, 1983; Reul and de Kloet, 1985; Fun- Type 1 (mineralocorticoid-like) and Type 2 der, 1986). The Type 1 receptors can be (glucocorticoid) receptors (de Kloet et al., divided into two subtypes (de Kloet and 1975; Moguilevski and Raynaud, 1980; Veldhuis, 1984; Fun der, 1986; McEwen et al., 1986a). One subtype is the Type 1 Received July 2, 1986 CORT preferring receptor (CR), which re- Endocrinol. Japon. 214 DE KLOET et al. April 1987 sponds with stringent specificity to CORT. component of the ginseng root (Panax gin- The other subtype is the Type 1 mineralo- seng C. A. Meyer) (Takagi, 1974), selectively corticoid receptor (MR), which responds to increases the binding capacity of this Type ALDO in the regulation of salt appetite 1 CR towards the level observed in young (McEwen et al., 1986b). Type 1 CR is control animals. almost exclusively localized in hippocampus neurons (McEwen et al., 1968; Reul and de Kloet 1985; 1986). Type 1 CR is in- Materials and Methods volved in the regulation of aspects of adap- tive behaviour (Bohus and de Kloet, 1981) Animals and surgery and of hippocampus-associated neurotrans- Old (28 months) and young (3 months) male mission (de Kloet et al., 1986a; McEwen et Wistar rats were supplied by TNO, Zeist, The al., 1986a). Type 1 CR is 80% or more Netherlands. The animals were housed singly occupied by endogenous CORT under all in cages under standard lighting (lights on from conditions of intact adrenocortical function. 6.00-20.00 h) and temperature conditions (23•Ž). Type 1 CR mediates an activating and Food and water were given ad libitum. Six old rats were treated for two weeks with the gin- synchronizing influence of CORT on cir- senoside Rgi and a group of six old rats and cadian-driven brain processes and contributes one of six young rats were treated with vehicle. to proper expression of the stress response Alzet minipumps (model 2002) were used to (de Kloet and Reul, in press). deliver the ginsenosides. The minipumps were implanted sc under anesthesia with Nembutal The Type 2 glucocorticoid receptors (40 mg/kg body weight). The rate of release of (GR) have a widespread localization in ginsenoside Rgi was 2.4ƒÊg/0.5ƒÊl/h for 14 days. neurons and glial cells as shown by auto- The vehicle was 0.9% saline containing 1.7% radiography of in vitro labelled tissue sec- (v/v) ethanol. tions (Reul and de Kloet, 1985; 1986) and Twenty-four hours prior to killing, the animals by immunocytochemistry (Fuxe et al., 1985). were bilaterally adrenalectomized (ADX) via the dorsal approach between 9.00 and 10.00 am un- Type 2 GR is occupied in parallel with der ether anesthesia in order to deplete endo- rising plasma CORT levels during circadian genous corticosteroids. The rats were anes- variation and after stress. Type 2 GR thetized with Nembutal before killing and were mediates the glucocorticoid feedback on then perfused with ice-cold saline through the stress-activated brain processes (de Kloet heart (about 25 ml per rat). A blood sample and Reul, in press; Reul and de Kloet, was drawn for measurement of the plasma CORT 1985). level by a radioimmunoassay procedure (Veld- huis et al., 1982). All rats had a plasma CORT Previous studies have demonstrated that level below 0.2ƒÊg/100 ml. The antiserum to the senescent rat has significantly fewer CORT was kindly provided by Dr. Th. J. Ben- CORT binding receptors in the hippocampus raad, University of Nijmegen, The Netherlands. The hippocampus was dissected on ice (Gispen (Rigter et al., 1984; Sapolski et al., 1983; et al., 1972) and stored until receptor assay at -80℃ 1986) than the young animals. The total . number of CORT receptors (Type 1 CR+ Type 2 GR) was determined in these pre- Receptor binding assays vious studies. We showed in the present The hippocampal tissue of six rats was pooled study that the reduction in CORT binding and homogenized in 5 mM Tris buffbr(500μl/ capacity of the senescent rat occurs in Type lobe) containing 1 mM EDTA, 1 mM 2-mercap- toethanol, 10 mM sodium molybdate and 5% 1 CR as well as in Type 2 GR. In addi- glycerol adjusted to pH 7.4 with hydrochloric tion, we show that chronic infusion of the acid (Reul and de Kloet, 1985). The homogenate ginsenoside Rgi, which is a stimulatory was centrifuged for 1 h at 2•Ž at 100 000 gay for Vol.34, No.2 GINSENG AND BRAIN CORTICOSTEROID RECEPTORS 215 preparation of cytosol. Cytosol was added to corrected for remaining traces of CBG. Type 2 previously evaporated 3H-steroids. Type 1 GR was measured with 3H-RU 28362. B. CORT-preferring sites (CR) were measured with and KD were determined from Scatchard and 3H-corticosterone (spec . act 105.0 Ci/mmol, New Woolf analysis of the binding data (Keightley et England Nuclear, Boston, USA) in a concentra- al., 1983). tion range from 0.1 to 20 nM labelled steroid in the presence of a 500 fold molar excess of RU 28362, which completely prevents the bind- Results ing of 3H-CORT to the Type 2 glucocorticoid receptors (GR) (Philibert and Moguilevski, 1983). Figure 1 depicts the Scatchard analysis Non-specific binding was determined with a 500 fold molar excess of unlabelled CORT and of 3H-CORT binding to Type 1 CR. The specific binding was corrected for traces of con- binding to Type 2 GR was blocked by ex- taminating blood transcortin (CBG), that might cess RU 28362. The Bmax of Type 1 CR possibly have remained after perfusion. Correc- was 51.5% lower in cytosol of hippocampus tion for CBG was done after the determination tissue of the old than that of the young of non-specific binding in the presence of a 500 rats. The old rats responded to treatment fold molar excess of dexamethasone (DEX). with Rgi with a 60% increase in Type 1 Type 2 GR were measured by 3H-RU28362 CR number, reaching a Bmax 21.2% below (spec. act 78 Ci/mmol, Roussel-Uclaf, Romain- ville, France) binding using a concentration range that observed in the young animals (Table from 0.5 to 20 nM in the absence or presence 1). Figure 1 also shows the Scatchard of a 500 fold molar excess of unlabeled RU analysis of 3H-RU 28362 binding to Type 2 28362 to correct for the non-specific binding. GR. The binding capacity of Type 2 GR Incubation was carried out for 3 h at 0•Ž (de in the old rats was 28.3% lower than in Kloet et al., 1975; Veldhuis et al., 1982). Separa- the young rats and was not significantly tion of bound from unbound 3H-steroids was changed (p<0.05) upon Rg1 infusion. The performed by Sephadex LH20 gel filtration and the binding data were expressed as fmoles/mg changes in the binding affinity were small. cytosol protein. A separate series of experi- Only in the case of the Type 1 CR, the ments served to measure the displacement of old animals had a slightly higher KD for 3H-CORT binding to receptors in the hippo- 3H-CORT binding , which was restored to campus cytosol by various saponins purified that observed in the young animals after from the ginseng root (Panax-ginseng C.
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