Saikogenin A acts on the hypothalamic-pituitary-adrenal (HPA) axis, but it is shown to increase cyclic AMP (cAMP) levels in the pituitary and adrenal glands, suggesting these as secondary messenger systems involved in its mechanism. It also potentiates the effect of ACTH on the adrenal gland.[2]
Saikogenin A directly affects inflammatory processes by inhibiting histamine release from mast cells. [2]

The DPP-IV enzyme is somewhat inhibited by saikogenin A. With a 20 μg/mL concentration, 47.6% of DPP-IV was inhibited. The Xaa-Pro dipeptide is eliminated from the amino terminus (N-terminus) of peptides and proteins by DPP-IV, a nonclassical serine aminopeptidase [1].

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Saikogenin A did not affect the spontaneous release of corticosterone from isolated rat adrenal slices. The baseline release was 4.16 ± 0.06 ng/100 mg tissue/hr, while in the presence of 0.5 mg/ml and 0.8 mg/ml of Saikogenin A, the release was 4.39 ± 0.93 and 4.51 ± 0.76 ng/100 mg tissue/hr, respectively.[2]
Saikogenin A potentiated the ACTH-induced release of corticosterone from adrenal slices. Co-incubation with ACTH (10 ng/ml) and Saikogenin A (0.8 mg/ml) significantly increased corticosterone release to 38.79 ± 2.36 ng/100 mg tissue/hr, compared to 18.73 ± 2.41 ng/100 mg tissue/hr with ACTH and vehicle alone.[2]
Saikogenin A inhibited the release of histamine from isolated rat peritoneal mast cells induced by compound 48/80 (0.5 mg/ml). The effect was dose-dependent, as shown in Figure 4.[2]

An anti-inflammatory medication known as saikogenin A is present in a crude extract of the Chinese herbal plant Chai Fu. Compared to normal rats, adrenalectomized rats showed a greater reduction in carrageenan-induced edema when saikogenin A was administered. The release of adrenocorticotropic hormone (ACTH) causes an increase in corticosterone, which in turn influences the inflammatory process and accounts for Saikogenin A's anti-inflammatory effect [2].

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In normal (sham-operated) rats, intraperitoneal (i.p.) administration of Saikogenin A (50 mg/kg) 30 minutes prior to lambda carrageenin injection reduced paw edema by approximately 48% compared to vehicle-treated controls. In adrenalectomized rats, the same treatment reduced edema by only approximately 26%, indicating a partial dependency on the adrenal glands.[2]
Saikogenin A (50 mg/kg, i.p.) administered 30 minutes prior to acetic acid (0.6%) challenge significantly inhibited vascular permeability. It reduced the leakage of intravenously administered Evan blue dye into the peritoneal cavity to 55.9 ± 7.6 g (N=8), representing a 61% inhibition compared to the vehicle-treated group (138.6 ± 13.7 g, N=8).[2]
Saikogenin A (50 mg/kg, i.p.) significantly elevated plasma adrenocorticotropic hormone (ACTH) levels in a dose-dependent manner. One hour after treatment, ACTH levels were 336.9 ± 24.7 pg/ml (for 50 mg/kg) and 527.4 ± 21.6 pg/ml (for 80 mg/kg), compared to 76.4 ± 19.8 pg/ml in the control group.[2]
Saikogenin A (50 mg/kg, i.p.) significantly increased the cyclic AMP (cAMP) content in the pituitary gland (from 1.22 ± 0.16 to 3.96 ± 0.58 nmol/g wet tissue) and adrenal gland (from 2.46 ± 0.52 to 9.25 ± 1.73 nmol/g wet tissue) one hour after administration. No significant change was observed in the hypothalamus.[2]

The content of cyclic AMP (cAMP) in isolated pituitary and adrenal glands was measured. Rats were treated with Saikogenin A (50 or 80 mg/kg, i.p.) or vehicle. One hour after treatment, the animals were sacrificed, and the pituitary and adrenal glands were rapidly dissected. The cAMP content in the tissue homogenates was determined using a specific radioimmunoassay (RIA) method. The results were expressed as nmol of cAMP per gram of wet tissue.[2]
The release of histamine from mast cells was quantified. Mast cells were isolated from the rat peritoneal cavity and incubated with compound 48/80 (0.5 mg/ml) at 37°C for 10 minutes to induce histamine release. Saikogenin A was added to the incubation mixture 5 minutes before the addition of compound 48/80. The amount of histamine released into the supernatant was measured using a spectrofluorometric assay. The inhibitory rate was calculated by comparing the histamine released in the presence of the test drug to that released in the presence of the vehicle control.[2]

Mast cells were collected from the peritoneal cavity of rats for the histamine release assay. These cells were incubated with compound 48/80 (0.5 mg/ml) at 37°C for 10 minutes to trigger degranulation. Saikogenin A was added to the cell suspension 5 minutes prior to the addition of the secretagogue. The reaction was stopped, and the supernatant was collected. The concentration of histamine in the supernatant was then determined using a spectrofluorometric method. The percentage of inhibition was calculated based on the histamine released in the presence of Saikogenin A versus the vehicle control.[2]
Adrenal glands were removed from rats and sliced to study corticosterone release. The adrenal slices were perfused in a chamber with Locke-Linger solution. The effect of Saikogenin A (0.5 mg/ml and 0.8 mg/ml) on spontaneous and ACTH (10 ng/ml)-induced corticosterone release was evaluated. The perfusate was collected, and the corticosterone concentration was measured using a specific assay method. The results were expressed as ng of corticosterone released per 100 mg of adrenal tissue per hour.[2]

Rats (Wistar, 230-250 g) were used in all experiments. Saikogenin A was dissolved in 85% ethanol and then diluted with 0.9% saline. The vehicle solution was prepared similarly without the drug. All drug and vehicle solutions were prepared fresh daily.[2]
**For the anti-inflammatory (edema) assay:** Lambda carrageenin (0.1 ml, 2%) was injected into the plantar region of the right hind paw to induce inflammation. Saikogenin A was administered via intraperitoneal (i.p.) injection 30 minutes prior to the carrageenin challenge. Paw volumes were measured using a water plethysmometer immediately before and at various time points after carrageenin injection. The degree of swelling was calculated as the mean percentage increase in paw volume compared to the initial pre-injection volume. A dose-response study was performed using doses of 20, 40, 50, 75, and 95 mg/kg.[2]
**For the vascular permeability assay:** Rats were injected intravenously with 0.25% Evan blue dye. To induce vascular leakage, 0.6% acetic acid was injected intraperitoneally (i.p.). Saikogenin A (50 mg/kg, i.p.) or vehicle was administered 30 minutes before the acetic acid injection. After 30 minutes, the rats were sacrificed, and the peritoneal cavity was washed with Locke-Linger solution to collect the extravasated dye. The collected solution was measured spectrophotometrically at 610 nm to quantify the amount of dye leakage.[2]
**For the ACTH and cAMP assays:** Rats were treated with Saikogenin A (50 or 80 mg/kg, i.p.) or vehicle. One hour after treatment, they were decapitated. Trunk blood was collected for plasma ACTH measurement using an immunoradiometric assay. The hypothalamus, pituitary, and adrenal glands were rapidly dissected for the determination of cAMP content via a specific radioimmunoassay.[2]
**For the adrenalectomy study:** Rats were adrenalectomized under ether anesthesia via a dorsal approach. A sham operation was performed on control rats. The operated animals were used for experiments 96 hours (4 days) post-surgery. The anti-inflammatory effect of Saikogenin A (50 mg/kg, i.p., 30 min pre-treatment) was then evaluated in both adrenalectomized and sham-operated rats using the carrageenin-induced paw edema model.[2]

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Rats (Wistar, 230-250 g) were used in all experiments. Saikogenin A was dissolved in 85% ethanol and then diluted with 0.9% saline. The vehicle solution was prepared similarly without the drug. All drug and vehicle solutions were prepared fresh daily.[2]
For the anti-inflammatory (edema) assay: Lambda carrageenin (0.1 ml, 2%) was injected into the plantar region of the right hind paw to induce inflammation. Saikogenin A was administered via intraperitoneal (i.p.) injection 30 minutes prior to the carrageenin challenge. Paw volumes were measured using a water plethysmometer immediately before and at various time points after carrageenin injection. The degree of swelling was calculated as the mean percentage increase in paw volume compared to the initial pre-injection volume. A dose-response study was performed using doses of 20, 40, 50, 75, and 95 mg/kg.[2]
For the vascular permeability assay: Rats were injected intravenously with 0.25% Evan blue dye. To induce vascular leakage, 0.6% acetic acid was injected intraperitoneally (i.p.). Saikogenin A (50 mg/kg, i.p.) or vehicle was administered 30 minutes before the acetic acid injection. After 30 minutes, the rats were sacrificed, and the peritoneal cavity was washed with Locke-Linger solution to collect the extravasated dye. The collected solution was measured spectrophotometrically at 610 nm to quantify the amount of dye leakage.[2]
For the ACTH and cAMP assays: Rats were treated with Saikogenin A (50 or 80 mg/kg, i.p.) or vehicle. One hour after treatment, they were decapitated. Trunk blood was collected for plasma ACTH measurement using an immunoradiometric assay. The hypothalamus, pituitary, and adrenal glands were rapidly dissected for the determination of cAMP content via a specific radioimmunoassay.[2]
For the adrenalectomy study: Rats were adrenalectomized under ether anesthesia via a dorsal approach. A sham operation was performed on control rats. The operated animals were used for experiments 96 hours (4 days) post-surgery. The anti-inflammatory effect of Saikogenin A (50 mg/kg, i.p., 30 min pre-treatment) was then evaluated in both adrenalectomized and sham-operated rats using the carrageenin-induced paw edema model.[2]

Saikogenin A did not cause a significant change in adrenal gland weight. In rats treated with 50 mg/kg (i.p.), the adrenal weight was 15.4 ± 1.4 mg/100g body weight 3 hours post-treatment, which was not statistically different from non-treated animals (14.8 ± 1.8 mg/100g body weight, P > 0.01).[2]

[1]. Pharmaceutical application of saikogenin A. CN107375300A.

[2]. Anti-inflammatory effect of Saikogenin A. Biochem Pharmacol. 1986 Aug 1;35(15):2483-7.

According to reports, Bupleurum contains saikosaponin A, and relevant data is available for reference.

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Saikogenin A is an anti-inflammatory compound derived from the dry root of Bupleurum falcatum L. (Umbelliferae), a Chinese herbal plant known as Tsai-Fu or Saiko. It is a saponin compound (a sapogenin).[2]
The study concludes that the anti-inflammatory action of Saikogenin A is due to at least two mechanisms: 1) an indirect effect via stimulation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to increased ACTH and subsequently corticosterone release; and 2) a direct effect on the inflammatory process, such as inhibiting histamine release and reducing vascular permeability. This dual mechanism is supported by its partial efficacy in adrenalectomized rats and its direct effects on mast cells and vascular permeability in vivo.[2]

C30H48O4

472.71

472.355

5092-09-1

99651

White to off-white solid powder

1.2±0.1 g/cm3

607.4±55.0 °C at 760 mmHg

252.4±26.1 °C

0.0±3.9 mmHg at 25°C

1.586

5.38

4

4

2

34

921

9

C[C@]12CC[C@@H]([C@@]([C@@H]1CC[C@@]3([C@@H]2C=CC4=C5CC(CC[C@@]5([C@H](C[C@]43C)O)CO)(C)C)C)(C)CO)O

QGNVMEXLLPGQEV-HSFRRAFJSA-N

InChI=1S/C30H48O4/c1-25(2)13-14-30(18-32)20(15-25)19-7-8-22-26(3)11-10-23(33)27(4,17-31)21(26)9-12-28(22,5)29(19,6)16-24(30)34/h7-8,21-24,31-34H,9-18H2,1-6H3/t21-,22-,23+,24+,26+,27+,28-,29-,30-/m1/s1

(3S,4R,4aR,6aR,6bS,8S,8aS,14aR,14bS)-4,8a-bis(hydroxymethyl)-4,6a,6b,11,11,14b-hexamethyl-1,2,3,4a,5,6,7,8,9,10,12,14a-dodecahydropicene-3,8-diol

Saikogenin D Saikogenin A

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~52.89 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.29 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.29 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.29 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)