Study of the possible effect of sacubitril/valsartan combination versus valsartan on the cognitive function in Alzheimer's disease model in rats

Abstract

Objectives: Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder. The proportion of elderly individuals at risk for AD and cardiovascular problems increases by raising life expectancy. The present study was designed to investigate the effect of the sacubitril/valsartan combination compared to that of valsartan alone in a rat model of AD. Methods: 72 male adult Wistar rats were divided into seven groups; control untreated rats received saline, control valsartan-treated rats received valsartan orally, control sacubitril/valsartan treated rats received sacubitril/valsartan orally, model rats received aluminum chloride i.p., model valsartan treated rats received aluminum chloride i.p. and valsartan orally and model sacubitril/valsartan treated rats received aluminum chloride i.p. and sacubitril/valsartan combination orally. All previous treatments continued on a daily basis for 6 weeks. At the second, fourth, and sixth weeks of the experiment, behavioral changes were evaluated using the Morris water maze and novel object recognition tests, and systolic blood pressure was measured. In the end, rat brain malondialdehyde and amyloid-beta 1-42 levels were measured, and the isolated hippocampus was evaluated histopathologically. Results: Valsartan improved AD symptoms in the aluminum-induced rat model, while the sacubitril/valsartan combination significantly worsened all tested parameters in both control and model rats compared with untreated and valsartan-treated animals. Conclusion: Based on the current study's findings, valsartan did not increase the risk for AD development in control rats and improved AD symptoms in a rat model, while sacubitril/valsartan combination increased the risk of AD in control rats and worsened the condition in a rat model.

Keywords: Alzheimer’s disease; amyloid-beta 1–42; sacubitril/valsartan; valsartan.

Figure 1.

Rat brain malondialdehyde (MDA) in different studied groups. Number of animals: 12 rats per each group (Val: Valsartan, ARNI: angiotensin receptor-neprilysin inhibitor = sacubitril/valsartan). *Statistically significant compared with the previous record within the same group (p < .05). a: Statistically significant compared with control group in the same week (p < .05). b: Statistically significant compared with Val group in the same week (p < .05). c: Statistically significant compared with model group in the same week (p < .05). d: Statistically significant compared with model + Val group in the same week (p < .05).

Figure 2.

Rat brain amyloid beta 1-42 (Aβ 1–42) in different studied groups. Number of animals: 12 rats per each group (Val: Valsartan, ARNI: angiotensin receptor-neprilysin inhibitor = sacubitril/valsartan). *Statistically significant compared with the previous record within the same group (p < .05). a: Statistically significant compared with control group in the same week (p < .05).b: Statistically significant compared with Val group in the same week (p < .05). c: Statistically significant compared with model group in the same week (p < .05). d: Statistically significant compared with model + Val group in the same week (p < .05).

Figure 3.

Mean systolic blood pressure at beginning, second, fourth, and sixth week in different studied groups. Number of animals: 12 rats per each group (Val: Valsartan, ARNI: angiotensin receptor-neprilysin inhibitor = sacubitril/valsartan). *Statistically significant compared with the previous record within the same group (p < .05). a: Statistically significant compared with control group in the same week (p < .05). b: Statistically significant compared with Val group in the same week (p < .05). c: Statistically significant compared with model group in the same week (p < .05). d: Statistically significant compared with model + Val group in the same week (p < .05).

Figure 4.

Photomicrograph of a section in the hippocampus of an albino rat in different studied groups (H&E, x100). (a) Group I (Control untreated Group): Neurons with large rounded vesicular nuclei with prominent nucleoli (arrowheads), few dark irregular shrunken cells (spiral arrow). (b) Group II (Control Valsartan Treated Group): Neurons with large rounded vesicular nuclei with prominent nucleoli (arrowheads). (c) Group III (Control Sacubitril/valsartan Treated Group): Many neurons present large rounded vesicular nuclei with prominent nucleoli (arrow heads) some possess shrunken pyknotic nuclei (arrows). (d) Group IV (Model Group): Neurons possess irregular shrunken pyknotic nuclei (spiral arrows). (e) Group V (Model Valsartan Treated Group): Neurons with large rounded vesicular nuclei with prominent nucleoli (arrowheads), some of the neurons possess shrunken pyknotic nuclei. (f) Group VI (Model Sacubitril/valsartan Treated Group): Most neurons in the Pyramidal layer showed shrunken pyknotic nuclei with vacuolated cytoplasm (arrow).

Figure 5.

The mean number of pyknotic nuclei of neurons in hippocampus region in different studied groups. GI: Control untreated Group, GII: Control Valsartan Treated Group, GIII: Control Sacubitril/valsartan Treated Group, GIV: Model Group, GV: Model Valsartan Treated Group, GVI: Model Sacubitril/valsartan Treated Group. *significant when compared to the control. ●significant when compared to the model. β significant when compared group VI.