Research on the improvement of cognitive impairment, endoplasmic reticulum stress and neuroinflammation in Alzheimer's disease by emodin

doi:10.3969/j.issn.1674-8115.2025.06.007

Abstract

Abstract:

Objective ·To explore the effects and potential mechanisms of emodin on Alzheimer's disease (AD). Methods ·Wild-type C57BL/6J mice and 3×Tg-AD mice were divided into 6 groups: Control group (C57BL/6J mice), AD group (3×Tg-AD mice), Emodin 25 mg/kg group (3×Tg-AD mice + Emodin 25 mg/kg), Emodin 50 mg/kg group (3×Tg-AD mice + Emodin 50 mg/kg), Emodin 100 mg/kg group (3×Tg-AD mice + Emodin 100 mg/kg) and Donepezil group (3×Tg-AD mice + Donepezil 3 mg/kg). The Morris water maze test was used to evaluate the learning and memory abilities of mice. The expression of glial fibrillary acidic protein (GFAP), glucose-regulated protein 78kDa (GRP78), and inositol-requiring enzyme 1α (IRE1α) was detected by immunohistochemistry. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in brain tissue were measured by enzyme-linked immunosorbent assay (ELISA). Western blotting was used to detect the expression of NF-κB p65, p-NF-κB p65, p38, and p-p38 proteins. Results ·Compared with the control group, mice in the AD group showed impaired cognition, increased GFAP expression, elevated levels of TNF-α, IL-1β and IL-6, and increased expression of GRP78 and IRE1α, along with enhanced phosphorylation of NF-κB p65 and p38. Compared with the AD group, emodin improved cognitive impairment of AD mice, inhibited astrocyte overactivation and neuroinflammation, and decreased the expression of GRP78, IRE1α, phosphorylated NF-κB p65, and phosphorylated p38 in brain tissue. Conclusion ·Emodin can effectively improve cognitive impairment in AD mice, which may be related to the inhibition of endoplasmic reticulum stress-mediated neuroinflammation in astrocytes.

Key words: Alzheimer's disease (AD), emodin, neuroinflammation, endoplasmic reticulum stress

CLC Number:

R741.02

YANG Le, ZHOU Yi, WANG Keyun, LAI Yali. Research on the improvement of cognitive impairment, endoplasmic reticulum stress and neuroinflammation in Alzheimer's disease by emodin[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 727-734.

Figures/Tables 5

Fig 1 Effect of emodin on cognitive impairment in AD mice

Fig 2 Effect of emodin on the activation of astrocytes

Fig 3 Effect of emodin on the expression of ER stress-related proteins

Fig 4 Effect of emodin on inflammatory response in AD mice

Fig 5 Effect of emodin on the inflammation signaling pathways

TrendMD

References 26

[1]	JETT S, MALVIYA N, SCHELBAUM E, et al. Endogenous and exogenous estrogen exposures: how women's reproductive health can drive brain aging and inform Alzheimer's prevention[J]. Front Aging Neurosci, 2022, 14: 831807.
[2]	ZHAO M, WANG Y C, SHEN Y X, et al. A review of the roles of pathogens in Alzheimer's disease[J]. Front Neurosci, 2024, 18: 1439055.
[3]	AVILA J, PERRY G. A multilevel view of the development of Alzheimer's disease[J]. Neuroscience, 2021, 457: 283-293.
[4]	SONG L, PIAO Z Y, YAO L F, et al. Schisandrin ameliorates cognitive deficits, endoplasmic reticulum stress and neuroinflammation in streptozotocin (STZ)-induced Alzheimer's disease rats[J]. Exp Anim, 2020, 69(3): 363-373.
[5]	LIU Y H, SHANG L R, ZHOU J B, et al. Emodin attenuates LPS-induced acute lung injury by inhibiting NLRP3 inflammasome-dependent pyroptosis signaling pathway in vitro and in vivo[J]. Inflammation, 2022, 45(2): 753-767.
[6]	陈芬,袁飞飞,李伟,等.大黄素调节AMPK/TXNIP/NLRP3信号通路对子痫前期大鼠炎症反应的影响[J]. 中国临床药理学杂志, 2024, 40(14): 2068-2072.
	CHEN F, YUAN F F, LI W, et al. Effects of emodin on inflammatory response in preeclampsia rats by regulating AMPK/TXNIP/NLRP3 signaling pathway[J]. Chinese Journal of Clinical Pharmacology, 2024, 40(14): 2068-2072.
[7]	XING M, MA X Y, WANG X, et al. Emodin disrupts the Notch1/Nrf2/GPX4 antioxidant system and promotes renal cell ferroptosis[J]. J Appl Toxicol, 2023, 43(11): 1702-1718.
[8]	ZHOU J B, LI G H, HAN G K, et al. Emodin induced necroptosis in the glioma cell line U251 via the TNF-α/RIP1/RIP3 pathway[J]. Invest New Drugs, 2020, 38(1): 50-59.
[9]	夏能银, 徐凌云, 王钰, 等. 大黄素抗小鼠阿尔茨海默病的作用及机制分析[J]. 武汉轻工大学学报, 2023, 42(6): 47-56.
	XIA N Y, XU L Y, WANG Y, et al. Study on the effects and mechanisms of emodin in the treatment of Alzheimer's disease in mice[J]. Journal of Wuhan Polytechnic University, 2023, 42(6): 47-56.
[10]	CASAS-MARTINEZ J C, SAMALI A, MCDONAGH B. Redox regulation of UPR signalling and mitochondrial ER contact sites[J]. Cell Mol Life Sci, 2024, 81(1): 250.
[11]	AJOOLABADY A, LINDHOLM D, REN J, et al. ER stress and UPR in Alzheimer's disease: mechanisms, pathogenesis, treatments[J]. Cell Death Dis, 2022, 13(8): 706.
[12]	SOUGIANNIS A T, ENOS R T, VANDERVEEN B N, et al. Safety of natural anthraquinone emodin: an assessment in mice[J]. BMC Pharmacol Toxicol, 2021, 22(1): 9.
[13]	DOROSZKIEWICZ J, MROCZKO B. New possibilities in the therapeutic approach to Alzheimer's disease[J]. Int J Mol Sci, 2022, 23(16): 8902.
[14]	MA H Y, DONG Y, CHU Y H, et al. The mechanisms of ferroptosis and its role in Alzheimer's disease[J]. Front Mol Biosci, 2022, 9: 965064.
[15]	GLASS C K, SAIJO K, WINNER B, et al. Mechanisms underlying inflammation in neurodegeneration[J]. Cell, 2010, 140(6): 918-934.
[16]	NANCLARES C, BARAIBAR A M, ARAQUE A, et al. Dysregulation of astrocyte-neuronal communication in Alzheimer's disease[J]. Int J Mol Sci, 2021, 22(15): 7887.
[17]	VERKHRATSKY A, NEDERGAARD M. Physiology of astroglia[J]. Physiol Rev, 2018, 98(1): 239-389.
[18]	FAKHOURY M. Microglia and astrocytes in Alzheimer's disease: implications for therapy[J]. Curr Neuropharmacol, 2018, 16(5): 508-518.
[19]	POTOKAR M, MORITA M, WICHE G, et al. The diversity of intermediate filaments in astrocytes[J]. Cells, 2020, 9(7): 1604.
[20]	WANG B, LIU Y, JIANG R, et al. Emodin relieves the inflammation and pyroptosis of lipopolysaccharide-treated 1321N1 cells by regulating methyltransferase-like 3-mediated NLR family pyrin domain containing 3 expression[J]. Bioengineered, 2022, 13(3): 6740-6749.
[21]	GHEMRAWI R, KHAIR M. Endoplasmic reticulum stress and unfolded protein response in neurodegenerative diseases[J]. Int J Mol Sci, 2020, 21(17): 6127.
[22]	SCHEPER W, HOOZEMANS J J M. The unfolded protein response in neurodegenerative diseases: a neuropathological perspective[J]. Acta Neuropathol, 2015, 130(3): 315-331.
[23]	RAHMAN S, ARCHANA A, JAN A T, et al. Dissecting endoplasmic reticulum unfolded protein response (UPR^ER) in managing clandestine modus operandi of Alzheimer's disease[J]. Front Aging Neurosci, 2018, 10: 30.
[24]	GRAEWERT M A, VOLKOVA M, JONASSON K, et al. Structural basis of CDNF interaction with the UPR regulator GRP78[J]. Nat Commun, 2024, 15(1): 8175.
[25]	WANG Y L, ZHOU X, LI D L, et al. Role of the mTOR-autophagy-ER stress pathway in high fructose-induced metabolic-associated fatty liver disease[J]. Acta Pharmacol Sin, 2022, 43(1): 10-14.
[26]	LIU Y Y, XU C L, GU R J, et al. Endoplasmic reticulum stress in diseases[J]. Med Comm (2020), 2024, 5(9): e701.