Effect and mechanism of Donepezil hydrochloride on Alzheimer’s disease

Abstract

Objective: To explore the effect and mechanism of donepezil hydrochloride on Alzheimer’s disease (AD).

Methods: Thirty-six 3-month-old SD rats were selected as the research subjects and randomly divided into a normal control (NC) group and a model group. The model group was given continuous intraperitoneal injection of D-galactose solution (120 mg/kg/d) combined with aluminum trichloride (10 mg/kg/d) by gavage for 60 days. Morris water maze test was conducted to test the learning and memory abilities of the rats, and AD rats were selected. After modeling, AD rats were divided into a normal saline (NS) group and a drug treatment (DT) group. The DT group was given donepezil hydrochloride (1.0 mg/kg) by gavage intervention, and the NC group and the NS group were given equal volumes of physiological saline by gavage. After 4 weeks of intervention, Morris water maze test was conducted to detect the escape latency, the number of platform crossings and residence time in the target quadrant, the rats were euthanized, with serum and hippocampal tissues collected, and hippocampal tissue homogenate (10%) was prepared by using NS. Enzyme linked immunosorbent assay (ELISA) was used to detect the inflammatory and oxidative stress indicators in rat hippocampal tissues and serum, and hematoxylin eosin (HE) staining was used to observe pathological damage in rat hippocampal tissues.

Results: Compared with the NC group, the NS group showed a significant increase in escape latency (p<.05), a significant decrease in the number of platform crossings and residence time in the target quadrant (p<.05), and a significant decrease in the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in serum and hippocampal tissues (p<.05). The content of malondialdehyde (MDA) was significantly increased (p<.05), and the levels of interleukin-6 (IL-6) and tumor necrosis factor-α(TNF-α) were significantly increased (p<.05). Compared with the NS group, the DT group can significantly reduce the escape latency (p<.05), increase the number of platform crossings and residence time in the target quadrant (p<.05), significantly increase the activities of SOD and GSH-Px in serum and hippocampal tissues and reduce the content of MDA (p<.05) and the levels of IL-6 and TNF-α (p<.05). After intervention with donepezil hydrochloride, the number of neurons in the hippocampus were significantly increased.

Conclusions: Donepezil hydrochloride can improve the learning and memory abilities of rats, reduce the levels of oxidative stress and inflammation in the brain and serum, and improve pathological damage in the hippocampus.

Keywords

Donepezil hydrochloride / Alzheimer’s disease / Ability to learn and remember / Oxidative stress / Inflammation

References

[1] Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet. 2021; 397(10284): 1577-1590. PMid:33667416. https://doi.org/10.1016/S0140-6736(20)32205-4

[2] GBD 2019 Dementia Forecasting Collaborators. Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022; 7( 2): e105-e125.

[3] Wang C, Pei L, Zhu H. Clinical effect of Angelica paeonia powder combined with donepezil tablets in the treatment of elderly Alzheimer’s disease. Chinese Medical Innovations. 2023; 20(18): 99-102.

[4] Jin H, Peng Y, Rao G, et al. Research progress in drug therapy for Alzheimer’s disease. Journal of International Neurology and Neurosurgery. 2023; 50(01): 87-92.

[5] Jurcău MC, Andronie-Cioara FL, Jurcău A, et al. The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer’s Disease: Therapeutic Implications and Future Perspectives. Antioxidants (Basel). 2022; 11(11): 2167. PMid:36358538. https://doi.org/10.3390/antiox11112167

[6] Yang WN, Han H, Hu XD, et al. The effects of perindopril on cognitive impairment induced by d-galactose and aluminum trichloride via inhibition of acetylcholinesterase activity and oxidative stress. Pharmacol Biochem Behav. 2013; 114-115: 31-36. PMid:24201055. https://doi.org/10.1016/j.pbb.2013.10.027

[7] Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. Neuroscience Methods. 1984; 11: 47-60. PMid:6471907. https://doi.org/10.1016/0165-0270(84)90007-4

[8] Brandeis R, Brandys Y, Yehuda S. The use of the Morris water maze in the study of memory and learning. International Journal of Neuroscience. 1989; 48(1-2): 29-69. PMid:2684886. https://doi.org/10.3109/00207458909002151

[9] Wang YJ, Wang XY, Hao XY, et al. Ethanol Extract of Centipeda minima Exerts Antioxidant and Neuroprotective Effects via Activation of the Nrf 2 Signaling Pathway. Oxid Med Cell Longev. 2019; 2019: 9421037. PMid:31139305. https://doi.org/10.1155/2019/9421037

[10] Liang B. Effect of donepezil hydrochloride on rats with Alzheimer’s disease. Chinese Journal of Gerontology. 2020; 40(05): 1060-1062.

[11] Sinyor B, Mineo J, Ochner C. Alzheimer’s Disease, Inflammation, and the Role of Antioxidants. J Alzheimers Dis Rep. 2020; 4(1): 175-183. PMid:32715278. https://doi.org/10.3233/ADR-200171

[12] Dionisio-Santos DA, Olschowka JA, O’Banion MK. Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease. J Neuroinflammation. 2019; 16(1): 74. PMid:30953557. https://doi.org/10.1186/s12974-019-1453-0

[13] Deng L, Zhang J, Han F. Research on the role and treatment of transcription factor NRF2 in Alzheimer’s disease. Chinese Bulletin of Life Science. 2022; 34(9): 1090-1100.

[14] Wang Z, Sun Y, Huang H. Pathological relationship between oxidative stress and Alzheimer’s disease and intervention strategies. Chinese Bulletin of Life Science. 2023; 35(04): 519-528.

[15] Wici´nski M, Socha M, Malinowski B, et al. Liraglutide and its Neuroprotective Properties-Focus on Possible Biochemical Mechanisms in Alzheimer’s Disease and Cerebral Ischemic Events. Int J Mol Sci. 2019; 20(5): 1050. PMid:30823403. https://doi.org/10.3390/ijms20051050

[16] Bennett JP. Medical hypothesis: Neurodegenerative diseases arise from oxidative damage to electron tunneling proteins in mitochondria. Med Hypotheses. 2019; 127: 1-4. PMid:31088629. https://doi.org/10.1016/j.mehy.2019.03.034

[17] López-Navarro ME, Jarquín-Martínez M, Sánchez-Labastida LA, et al. Decoding Aging: Understanding the Complex Relationship among Aging, Free Radicals, and GSH. Oxid Med Cell Longev. 2020; 2020: 3970860. PMid:33110472. https://doi.org/10.1155/2020/3970860

[18] Pavlovic D, Pekic S, Stojanovic M, et al. Traumatic brain injury: neuropathological, neurocognitive and neurobehavioral sequelae. Pituitary. 2019; 22(3): 270-282. PMid:30929221. https://doi.org/10.1007/s11102-019-00957-9

[19] Dorostkar MM, Zou C, Blazquez-Llorca L, et al. Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities. Acta Neuropathol. 2015; 130(1): 1-19. PMid:26063233. https://doi.org/10.1007/s00401-015-1449-5