Screening Of Natural Products For Their Effect On Kallikrein-Kinin System: Potential Implications In The Treatment Of Hereditary Angioedema

Plasma prekallikrein (PK) activation exerts both physiological and pathological effects within the cardiovascular system and central nervous system (CNS). Activated PK (kallikrein) controls cytokine release from human mononuclear cells and controls both the intrinsic blood coagulation and the alternative complement cascades. The uncontrolled activation of these cascades results in the development of pathological pain and angioedema. Increased plasma kallikrein levels are associated with hereditary angioedema (HAE) and myocardial infarction, whereby kallikrein amplifies the generation of activated factor XII (FXIIa) and bradykinin (BK) release from high molecular weight kininogen (HMWK). The primary objective of this study was to screen natural products with anti-inflammatory properties for their effects on the components namely HMWK, PK, FXIIa and FXIa. Terminalia chebula fruit, Terminalia bellirica fruit, Terminalia arjuna fruit, Terminalia brownii bark, Terminalia arjuna bark and black tea (Camellia sinensis) extracts inhibited plasma kallikrein with IC 50 values of 30, 65, 220, 240, 280 and 220 mg/ml, respectively. T. chebula fruit, T. arjuna fruit, T. bellirica fruit, T. brownii bark, T. arjuna bark and black tea extracts blocked plasma kallikrein on endothelial cells with IC50 values of 15, 20, 20, 80, 160 and 400 mg/ml, respectively. T. chebula fruit, T. bellirica fruit, T. arjuna fruit, T. arjuna bark and black tea extracts blocked FXIIa activity with IC50 values of 30, 50, 190, 190 and 27 mg/ml, respectively. Arjunoglucosed II and arjunic acid blocked FXIIa activity with IC50 values of 370 and 780 μM, respectively. T. chebula fruit, T. arjuna fruit and black tea at 50 mg/ml did not affect endothelial cells viability. While red yeast rice (RYR) extract shono inhibitory effects on plasma kallikrein, FXIIa, FXIa and rPRCP, three pure compounds blocked FXIa activity with IC50 values of 260, 270 and 400 μM, respectively. Overall, T. chebula fruit, T. arjuna fruit and black tea extracts might be useful to improve symptoms of HAE, inflammation and thrombosis. The identified inhibitors of FXIIa and FXIa could be used as a lead compound to find potent inhibitors of these coagulation factors