Aescine is a class of triterpenoid saponin compounds extracted from the dried, mature seeds of the horse chestnut tree (Aesculus hippocastanum), a traditional Chinese medicine. Preparations with aescine as the active ingredient mainly include sodium aescinate lyophilized powder for injection, sodium aescinate liniment, compound sodium aescinate gel, and sodium aescinate tablets. The current clinical indications for aescine preparations are cerebral edema, swelling caused by trauma or surgery, and diseases with impaired venous return. With the continuous advancement of research in recent years, intravenous aescine preparations are now widely used clinically for the treatment of diseases such as cerebral hemorrhage and cervical spondylosis. There are also reports on its use in treating edema caused by lymphatic drainage disorders, with better efficacy when used in combination with other medications.
1. Anti-inflammatory Effects and Mechanisms
The anti-inflammatory effects of aescine are similar to those of dexamethasone, but its duration of action is longer. It has no significant effect on the spleen index (SI), thymus index (TI), spleen cell proliferation capacity (PS), lymphocyte count (LC), or serum tumor necrosis factor-α (TNF-α) levels in experimental animals. aescine does not significantly increase serum corticosteroid secretion levels, nor does it promote apoptosis of immune cells in the spleen and thymus; therefore, its anti-inflammatory effect is not dependent on corticosteroid secretion.
In studies on the effect of aescine on the survival rate of mice with lipopolysaccharide-induced endotoxemia, aescine inhibited the release of high-mobility group box 1 (HMGB1) from macrophages, reduced the levels of TNF-α, IL-1β, and IL-6 in macrophages, inhibited NF-κB activation, and improved the survival rate of mice. Furthermore, the antioxidant activity of aescine enhances its anti-inflammatory capacity. aescine can increase the activities of myeloperoxidase, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), reduce the levels of inflammatory factors such as NO, TNF-α, and IL-1β in serum, increase the expression and function of glucocorticoid receptors, significantly reduce lung injury in endotoxemia mice, and prolong their survival time. Topical application of aescine significantly inhibits carrageenan-induced paw edema in rats, with a more pronounced effect after pretreatment with dexamethasone; it can significantly inhibit xylene-induced ear edema in mice, with better efficacy than dexamethasone alone; it can inhibit histamine-induced increases in skin vascular permeability, but with less efficacy than dexamethasone; it significantly inhibits cotton ball-induced subacute granulomatous inflammation, with better efficacy than dexamethasone. Experiments show that aescine can significantly inhibit the increase of inflammatory factors such as PGE2, TNF-α, and IL-1β, and its effect may be related to the involvement of glucocorticoid receptors.
aescine can significantly inhibit exudation in inflammatory tissues and reduce their permeability, showing significant effects on edema and damage in various tissues. Studies have confirmed that high-dose aescine can significantly inhibit the increase in blood-retinal barrier permeability caused by ischemia/reperfusion in rats, reduce retinal edema, and effectively inhibit retinal edema and visual impairment. The combined application of aescine and triamcinolone has a synergistic protective effect against ischemia/reperfusion injury to the blood-retinal barrier; the combination significantly reduces the permeability of the blood-retinal barrier after ischemia, while low-dose aescine or triamcinolone alone has no such effect. Furthermore, the combined application can promote the expression of the tight junction protein occludin, counteracting the damage to the blood-retinal barrier and significantly improving the therapeutic effect.
In the treatment of allergic inflammation, experiments have found that low-dose prednisone combined with aescine treatment can significantly reduce paw swelling in animal models of arthritis, reduce synovial inflammatory cell infiltration, inhibit synovial hyperplasia and bone erosion, reduce serum levels of TNF-α, IL-1β, and IL-6, and reduce the side effects of high-dose hormones. aescine can dose-dependently inhibit skin allergic reactions. In experimental animals orally administered 5 mg/kg of aescine, allergic skin reactions were significantly suppressed on day 2, with a significant reduction in the extent of skin redness and swelling. Its anti-allergic effect may be related to the glucocorticoid receptor pathway. Regarding airway allergic inflammation, sodium β-aescinate can inhibit the activation and degranulation of mast cells in mouse skin, prevent fluid infiltration into tissues, and reduce type I hypersensitivity reactions; it also inhibits lung tissue inflammation, reduces the accumulation of leukocytes, eosinophils, IL-5, and IL-13 in the alveoli, reduces airway inflammatory responses, and decreases the intensity of delayed type I hypersensitivity reactions.
2. Antitumor Effects and Mechanisms
Increasing evidence suggests that numerous small molecules, such as various inflammatory molecules, transcription factors, adhesion molecules, activator protein 1 (AP-1), chemokines, CRP, COX-2, ILs, 5-lipoxygenase (5-LOX), MMPs, NF-κB, signal transducers and activator of transcription 3 (STAT3), TNF, and VEGF, play important roles in the development of chronic diseases such as inflammation and tumors. aescine can prevent or delay the occurrence of chronic diseases such as tumors by inhibiting these inflammatory pathways. Multiple basic studies have confirmed that aescine can kill cancer cells through various mechanisms.
2.1 Synergistic Antitumor Effects of Chemotherapy Drugs
Studies have found that aescine can enhance the antitumor effects of chemotherapeutic drugs and reverse multidrug resistance. aescine can increase the sensitivity of cancer cells to cytokines and chemotherapeutic drugs, induce cell cycle arrest, promote apoptosis in pancreatic cancer cells, enhance the growth-inhibiting effect of gemcitabine on pancreatic cancer cells, and effectively inhibit cancer cell proliferation and invasion. Its mechanism may be related to the inhibition of NF-κB activation and its regulated gene products. aescine can also enhance the efficacy of chemotherapy drugs against extrahepatic cholangiocarcinoma through the glycogen synthase kinase-3β/β-catenin (GSK3β/β-catenin) pathway, and reverse P-glycoprotein-dependent multidrug resistance.
2.2 Induction of Tumor Cell Cycle Arrest and Apoptosis aescine can increase the production of reactive oxygen species, reduce mitochondrial membrane potential, and increase cytochrome C release, thereby inducing apoptosis in bladder cancer cells and inhibiting bladder tumor growth. Furthermore, it can block the STAT3 signaling pathway, inhibit upstream JAK1 and JAK2 activation, downregulate STAT3-regulated gene products such as cyclin D1, B-cell lymphoma/leukemia-2 gene (Bcl-2), B-cell lymphoma/leukemia-XL gene (Bcl-XL), survivin, myeloid leukemia gene-1 (Mcl-1), and VEGF, promote the cleavage of poly(ADP-ribose) polymerase (PARP), inhibit the proliferation of primary liver cancer cells, and promote cancer cell apoptosis. aescine can induce apoptosis in cholangiocarcinoma cells through mechanisms such as interfering with the cell cycle and mitochondrial caspase-dependent pathways, increasing the Bax/Bcl-2 ratio, and enhancing the activity of reactive oxygen species. aescine can arrest the G2-M phase transition, increase the aggregation of cancer cells in the pre-G1 phase and annexin V binding, activate caspase-9/3, increase PARP cleavage and Bax protein levels, and decrease the levels of anti-apoptotic proteins such as Bcl-2, apoptosis inhibitory proteins, and survivin. It can also induce the generation of reactive oxygen species (ROS), leading to abnormal mitochondrial membrane potential and ultimately inducing apoptosis in human renal cell carcinoma cells.
2.3 Inhibition of Tumor Angiogenesis Sodium aescine can inhibit endothelial cell proliferation and migration, suppress endothelial cell viability, and induce endothelial cell apoptosis. Its anti-angiogenic effect is likely related to its direct action on endothelial cells. In endothelial cells, aescine can effectively induce cholesterol synthesis, leading to a decrease in the integrity of the actin cytoskeleton. This alteration significantly reduces the cellular response to TNF-α stimulation, decreases cell migration, reduces the permeability of monolayer endothelial cells, and inhibits the transcription of the NF-κB signaling pathway, thereby resulting in a decrease in the expression of TNF-α-induced effector proteins.
2.4 Inhibition of Tumor Invasion and Metastasis aescine has an inhibitory effect on the invasion and metastasis of various cancer cells, including triple-negative breast cancer. aescine can inhibit the invasion and metastasis of melanoma cells, significantly reduce the expression of phosphorylated extracellular signal-regulated kinase (p-ERK), and inhibit the expression of NF-κB and the nuclear transcription factor κB repressor (IκB). Exogenous supplementation of macrophage chemokine ligand 16 (CXCL16) can reduce the inhibitory effect of aescine on cancer cell migration. aescine can inhibit the phosphorylation of focal adhesion kinase (FAK)/serine/threonine protein kinase (Akt), reduce the activation of CXC-type chemokine receptor 6 (CXCR6)/CXCL16, decrease the expression level of CXCL16, and inhibit the expression of TM-CXCL16 induced by sCXCL16 secretion, ultimately inhibiting the migration and invasion of gastric adenocarcinoma AGS cells.
3. Neuroprotective Effects: aescine can also scavenge oxygen free radicals, protect ischemic/reperfusion-damaged nerve tissue, and promote its functional recovery. Sodium aescine combined with basic fibroblast growth factor can increase Bcl-2 expression, inhibit neuronal apoptosis, reduce damage to neurons, nerve axons, and myelin sheaths, promote functional recovery after spinal cord injury, improve motor function, and has a synergistic protective effect against spinal cord nerve injury. aescine can reduce the levels of TNF-α, MMP-9, COX-2, and prostaglandin E2 (PGE2), improve blood-brain barrier permeability, reduce cerebral edema, and has a good therapeutic effect on cerebral edema in mice with acute dimethoate poisoning.
4. Gastrointestinal Protective Effects: aescine can inhibit gastric acid secretion and protect the digestive tract mucosa. It can inhibit H+/K+ ATPase, reduce gastric acid secretion, increase SOD, catalase (CAT), and GSH-Px activities, increase the levels of TNF-α, P-selectin, and vascular cell adhesion molecule-1 (VCAM-1) in gastric mucosa, and protect ulcerated mucosal tissue. Li et al. found that aescine can increase the expression of the tight junction protein claudin-5, reduce endotoxin-induced liver damage and intestinal mucosal damage, and alleviate intestinal epithelial barrier dysfunction.
Furthermore, aescine can accelerate gastrointestinal motility, promote gastrointestinal transit, and reduce postoperative adhesions. Matsuda et al. found that aescine can accelerate gastrointestinal motility in mice. The mechanism may involve stimulating the synthesis of serotonin (5-HT), interacting with 5-HT2 receptors, leading to increased release of NO and endogenous prostaglandins (PGs). aescine can alleviate postoperative intestinal adhesions, inhibit acute inflammation, reduce increased vascular permeability, restore intestinal motility, accelerate gastrointestinal transit, inhibit granuloma formation, inhibit adhesion production, and promote the recovery of motor function.
5. Analgesic, antiviral, energy metabolism regulating, and vascular tone enhancement effects: Intrathecal injection of aescine can block formaldehyde-induced hyperalgesia, inhibit formaldehyde-induced increases in c-fos and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK), reduce inflammatory pain and nociceptive sensation in the dorsal horn of the spinal cord, and inhibit pain-related behaviors. aescine derivatives significantly inhibit porcine epidemic diarrhea virus, reducing its viral replication activity and exhibiting low cytotoxicity. aescine exhibits good inhibitory and even killing effects against herpes simplex virus type 1 (HSV-1), as well as enveloped negative-sense RNA viruses and enveloped positive-sense RNA viruses (such as dengue virus type 2). However, it has no effect on non-enveloped DNA viruses (such as adenovirus-5), thus possessing a broad antiviral spectrum.
aescine can inhibit gastric emptying, glucose transport from the stomach to the small intestine and within the brush border of the small intestine, thus delaying glucose absorption, but it does not lower blood glucose levels. It can also increase serum insulin levels, increase glucose utilization in insulin-sensitive tissues, and reduce the increase in blood glucose levels caused by a high-fat diet. It can lower serum leptin levels, regulate food intake and energy metabolism through central and peripheral specific receptor pathways, reduce appetite, and increase the rate of energy metabolism. By lowering free thyroxine (FT4) levels and increasing triiodothyronine (T3) levels in individuals on a high-fat diet, it reduces ATP synthesis and increases ATP consumption in thyroid hormone-dependent processes to provide energy, thereby controlling weight. Furthermore, it can increase high-density lipoprotein cholesterol (HDL-C) levels but does not affect the metabolism of serum low-density lipoprotein cholesterol (LDL-C) and triglycerides.
aescine has a significant effect on alleviating testicular edema caused by varicocele in rats. It can significantly reduce the density of polymorphonuclear leukocytes in the diseased testicular tissue, significantly increase the number of sperm, and ultimately reverse the testicular lesions caused by varicocele. It can improve extracellular Ca2+-dependent venous contraction and thus increase venous tone, but it interferes with endogenous vasoconstrictors such as α-adrenergic receptor agonists and angiotensin II (Ang II) receptor agonists as well as vasoconstriction caused by membrane depolarization. Therefore, the efficacy of long-term use in patients with varicocele may not be ideal.
