Candesartan Mitigates Perioperative Neurocognitive Disorders by Modulating Hypertension-Linked Neuroinflammatory...

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Perioperative neurocognitive disorders (PND) are associated with neuroinflammation, a condition also linked to hypertension.
• The causal link between hypertension and PND, and potential therapeutic targets, remain underexplored.

Purpose of the Study:

• To investigate if hypertension is a risk factor for PND.
• To identify neuroinflammatory targets associated with hypertension and PND.
• To determine if candesartan, an angiotensin receptor blocker (ARB), can improve cognitive function in PND mouse models by modulating these targets.

Main Methods:

• Mendelian randomization (MR) analysis to assess hypertension as a risk factor for cognitive dysfunction.
• Bioinformatics and machine learning to identify neuroinflammatory biomarkers (Bdkrb1, Ccr1, Thbs1).
• In vivo studies using a PND mouse model, assessing cognitive function and hippocampal molecular changes (RT-qPCR, Western blotting, ELISA) after candesartan treatment.

Main Results:

• MR analysis confirmed hypertension as a risk factor for cognitive dysfunction (OR=1.0767, P=0.0057).
• Bdkrb1, Ccr1, and Thbs1 were identified as key biomarkers for PND associated with hypertension.
• Candesartan treatment improved cognitive function in PND mice, reduced neuroinflammation (decreased IL-1β, IL-6, TNF-α, microglial activation), and modulated target gene expression in the hippocampus.

Conclusions:

• Hypertension is a significant risk factor for PND.
• Candesartan demonstrates therapeutic potential for PND by mitigating neuroinflammation and improving cognitive function through modulation of Bdkrb1, Ccr1, and Thbs1.
• Targeting hippocampal immune responses with ARBs like candesartan may offer a novel strategy for managing PND.