Ligustilide Attenuates Neuroinflammation and Fibrosis in an Aluminum Chloride-induced Rat Model of Alzheimer's Disease via mTOR/STAT3 Signaling Inhibition.

Abstract

Alzheimer's disease (AD) affects approximately 50 million individuals worldwide and is projected to triple by 2050. Ligustilide is a naturally occurring compound with varied pharmacological actions. Ligustilide has been reported to ameliorate AD by inhibiting PKA/AKAP1 or inducing α-secretase, but no prior research has examined its ability to activate the inflammasome in AD. We aimed to investigate the potential therapeutic effects of ligustilide in rats with AD by assessing the inflammatory and fibrotic pathways. AD was induced in rats by aluminum chloride. Subsequently, some rats were orally administered 20 mg/kg of ligustilide. For structural assessment, hippocampal brain tissue sections were stained with hematoxylin/eosin and subjected to anti-mTOR and anti-phospho-tau antibody staining. The collected samples were then analyzed for gene expression and protein levels of mTOR, STAT3, TGF-β, β-catenin, NFκB, TNF-α, TLR4, and NLRP3. We found that rats treated with ligustilide displayed marked improvements in their behavior. Furthermore, microscopic analysis of hematoxylin/eosin-stained images revealed that ligustilide reduced inflamed tissues and partially dilated blood vessels, without gliosis or vacuolated neuropil. Additionally, ligustilide decreased the expression of mTOR, STAT3, TGF-β, β-catenin, NFκB, TNF-α, TLR4, and NLRP3. In conclusion, ligustilide improved AD in rats and reduced inflammation and fibrosis. This effect is attributed to ligustilide's ability to reduce mTOR and STAT3 activity, thereby suppressing NFκB, TNF-α, TLR4, and NLRP3, and inhibiting the inflammasome pathway. Consequently, this cascade results in decreased STAT3 and TGF-β levels, thereby reducing fibrosis.