Tetrahydroxy stilbene glycoside alleviated inflammatory damage by mitophagy via AMPK related PINK1/Parkin signaling pathway

期刊名：International Immunopharmacology

发表日期： 19 July 2022

文章地址：https://doi.org/10.1016/j.intimp.2022.108928

Abstract

Along with the extensive application of radiation in medical, military and other fields, human beings carry a greater risk of exposure to radiation environment that causes a range of physical injure, particularly to the brain in cognition. However, the radiation-associated cognitive disability is poorly understood and there is no effective prevention or long-term treatment. Here, we demonstrate that neurogenesis and neuroinflammation disorder are primarily involved in the pathophysiological basis of irradiation-induced cognitive decline. Furthermore, we discovered that tetrahydroxy stilbene glucoside (TSG), a natural active ingredient from Heshouwu that has been well known for its unique anti-aging effect as the Chinese herb, can be a promising mitigator to improve learning-memory ability by facilitating the neurogenesis in the proliferation and differentiation of the surviving neural progenitor cells via AMPK/Tet2, and attenuating the neuroinflammation in the microglial NLRP3 inflammasomes activation via AMPK in vivo. Additionally, TSG was also revealed to activate AMPK by molecular docking and kinase enzyme system assay in vitro. Taken together, our findings identify TSG, as the AMPK activator, prevents radiation-induced cognitive dysfunction by regulating neurogenesis and neuroinflammation via AMPK/Tet2 in rodents, and represents a very promising candidate for developing drugs that can be used for radiation-associated brain injury.

2. Material and methods

2.1. Mice

Male C57BL/6J mice at 2–3 months of age were purchased fromBeijing SPF Biotechnology Co., Ltd. (Beijing, China). Tet2-/- mice wereobtained from Professors Shaorong Gao and Jiayu Chen, and back-crossed to the C57BL/6J background in our laboratory. The mice wererandomly assigned to 4 or 5 mice per cage, and kept on a 12 h light–darkcycle with free access to food and water. All tests were carried out incompliance with protocols authorized by the Animal Care and EthicsCommittee at the Fifth Medical Centre, Chinese PLA (People’s LiberationArmy) General Hospital.

2.2. Mouse models and treatment

Male C57BL/6J mice were exposed to sham irradiation as controls ora sublethal dose (6 Gy) of 60Co γ-ray ionization radiation (IR) for totalbody at a dose rate of 1.24 Gy/min for two cycles with a 2-month in-terval between the cycles. The vehicle (saline) or TSG (purity 98%)purchased from Chengdu Pufei De Biotech Co., Ltd. (Chengdu, China)was administered to mice by gavage at 40 mg, 80 mg or 120 mg per kgbody weight per day (mg/kg/d) for 5 months continuously after the first radiation. Mice were sacrificed to analyze as described below. The lit-termates of wild type as the Ctrl and age-matched male Tet2-/- mice at the age of 2 months were treated with vehicle or TSG (80 mg/kg/d)respectively by gavage for 4 months. Besides, the TSG treated Tet2-/-mice were injected with intraperitoneally dorsomorphin (Compound C,Selleck) 2HCl (10 mg/kg) every other day for last month after TSGtreatment.