Kukoamine A

Kukoamine A, a spermine alkaloid, is an orally active and brain-penetrant component found in the root barks of Lycium chinense (L. chinense) Miller. Kukoamine A inhibits purified Crithidia fasciculata trypanothione reductase and soybean lipoxygenase, activates μ-opioid receptor. Kukoamine A can inhibt cancer cell proliferation, migration and invasion, cause G0/G1 phase cell cycle arrest and induce apoptosis. Kukoamine A exerts neuroprotective effect and can induce autophagy . Kukoamine A inhibits LPS (HY-D1056)-induced NO, ROS, PGE₂, TNF-α, IL-1β, IL-6 production and COX-2 activity. Kukoamine A reverses palmitic acid-induced insulin resistance, lipid accumulation, and oxidative stress via downregulation of Srebp-1c. Kukoamine A can be used for the research of cancer, infection, inflammation, metabolic and neurological disease, such as glioblastoma and Parkinson's disease^{[1][2][3][4][5][6]}[7]. IC50 & Target:Ki: 1.8 μM (Trypanothione reductase)^[1] In Vitro:Kukoamine A (1-10 μM; ~0.5-2.0 times its estimated K_i) potently inhibits purified Crithidia fasciculata trypanothione reductase as a mixed inhibitor with a K_i of 1.8 μM and K_ii of 13 μM for enzyme-substrate complex, while displaying no significant inhibition of human glutathione reductase^[1].
Kukoamine A (0.1 mM; 20-60 min) shows high DPPH free radical scavenging activity, with 96% reducing activity at 0.1 mM after 20 min and 60 min incubation in a cell-free system^[2].
Kukoamine A potently inhibits cell-free soybean lipoxygenase, with an IC₅₀ of 9.5 μM^[2].
Kukoamine A (0.1 mM) inhibits AAPH-induced linoleic acid lipid peroxidation by 72% at 0.1 mM^[2].
Kukoamine A reverses palmitic acid-induced insulin resistance, lipid accumulation, and oxidative stress in AML-12 cells via downregulation of Srebp-1c, as these protective effects are abrogated by Srebp-1c overexpression^[3].
Kukoamine A (10-80 μg/mL; 1-5 days) selectively inhibits the viability of human glioblastoma U251 and WJ1 cells in a time- and dose-dependent manner, with IC₅₀ values of 73.4 μg/mL and 22.1 μg/mL respectively at day 5, and has minimal effect on human normal liver LO2 cells and rat glioma C6 cells^[4].
Kukoamine A (5-20 μg/mL; 12 days) inhibits the clonogenicity of human glioblastoma U251 and WJ1 cells in a dose-dependent manner^[4].
Kukoamine A (10-80 μg/mL; 48 h) induces apoptosis in human glioblastoma U251 and WJ1 cells in a dose-dependent manner, downregulating 5-LOX and antiapoptotic Bcl-2 protein expression, and upregulating proapoptotic Bax and active caspase-3 protein expression^[4].
Kukoamine A (5-20 μg/ml; 48 h) induces G0/G1 phase cell cycle arrest in human glioblastoma U251 and WJ1 cells in a dose-dependent manner^[4].
Kukoamine A (10-80 μg/mL；24 h) inhibits the migration and invasion of human glioblastoma U251 and WJ1 cells in a dose-dependent manner^[4].
Kukoamine A (10-40 μM; 4 h pre-incubation, followed by 24 h co-incubation with MPP⁺) dose-dependently protects SH-SY5Y cells from MPP⁺-induced injury, inhibits apoptosis and preserves mitochondrial membrane potential^[5].
Kukoamine A (10-40 μM; 4 h pre-incubation, followed by 24 h co-incubation with MPP⁺) dose-dependently reduces Bax/Bcl-2 ratio, p-JNK and p-p38 levles and increases p-AKT, p-ERK levels in SH-SY5Y cells^[5].
Kukoamine A (10-40 μM; 4 h) dose-dependently induces autophagy in SH-SY5Y cells, inducing visible autophagosomes at the highest concentration, increasing the LC3-II/LC3-I ratio, Beclin-1 and decreasing p62 ^[5].
Kukoamine A binds to human μ-opioid receptors expressed in HEK293T cell membranes with high affinity, with a K_i value of 1.3 ± 0.18 μM and an EC₅₀ value of 5.6 ± 0.65 μM^[6].
Kukoamine A (5-40 μM; 24 h) does not reduce the viability of RAW 264.7 macrophage cells^[7].
Kukoamine A (5-40 μM; 24 h) significantly inhibits LPS (HY-D1056)-induced NO, ROS, PGE₂, TNF-α, IL-1β, and IL-6 production in RAW 264.7 macrophage cells in a concentration-dependent manner^[7].
Kukoamine A (5-40 μM) significantly inhibits LPS-induced COX-2 activity in RAW 264.7 macrophage cells^[7]. In Vivo:Kukoamine A (0.01 mmol/kg; i.p.; single dose) inhibits Carrageenan (HY-125474)-induced rat paw edema by 43%^[2].
Kukoamine A (5-20 mg/kg; i.p.; daily; 4 weeks) dose-dependently attenuates high fat diet-induced insulin resistance, fatty liver, inflammation, and oxidative stress in mice by inhibiting Srebp-1c and its downstream target gene expression^[3].
Kukoamine A (10-40 mg/kg; i.p.; 5 times weekly; 4 weeks) inhibits in vivo glioblastoma growth in a dose-dependent manner, achieving up to 55.3% tumor inhibition at 40 mg/kg, while maintaining mouse body weight, via apoptosis induction and epithelial-mesenchymal transition attenuation mediated by downregulating 5-LOX and C/EBPβ expression^[4].
Kukoamine A (5-20 mg/kg; i.g.; daily; 12 days) exerts dose-dependent neuroprotective effects in MPTP (HY-W114750)-induced Parkinson's disease mice by improving motor function, reducing neuronal apoptosis, lowering α-synuclein levels, preserving dopaminergic neurons, and enhancing autophagy, without affecting MAO-B activity^[5].
Kukoamine A (5-20 mg/kg; i.g.; daily; 12 days) enhances autophagy in the SN and Str of healthy mice by regulating autophagy-related proteins, without inducing apoptosis or altering MAO-B activity^[5].
Kukoamine A (25-50 mg/kg; p.o.; daily; 5 days) exerts Concentration-dependent anti-inflammatory and antioxidant effects in rats with carrageenan-induced acute inflammation, reducing paw edema, proinflammatory cytokine levels, and oxidative stress markers while enhancing liver antioxidant enzyme activity^[7].