Low‐Dose Paracetamol Treatment Protects Neuronal Oxidative Stress and Neuroinflammation in D‐Galactose‐Induced Accelerated Aging Model

Aging increases the risk of neurodegenerative diseases such as Parkinson's and Alzheimer's (PD and AD) which are potentially linked to increased oxidative stress and inflammation. Paracetamol (APAP) is known for its antioxidant and anti-inflammatory properties; however, its potential neuroprotective effects against age-related oxidative stress and neuroinflammation remain inadequately investigated. Therefore, we aimed to examine whether low-dose APAP could mitigate oxidative stress and neuroinflammation in a D-galactose (D-gal)-induced aging model. In our study, fifty adult male ICR mice were divided into five groups (<i>n</i> = 10). Except for the normal control group, all mice received D-gal subcutaneous injections (200 mg/kg) and were fed vehicle, 15 or 50 mg/kg APAP, or 100 mg/kg vitamin E daily for six weeks. After treatment, liver function was assessed by serum liver enzyme analysis. The liver and brain pathologies were examined using hematoxylin and eosin staining. Brain oxidative stress was evaluated through malondialdehyde (MDA) measurement. Additionally, immunohistochemistry was used to determine levels of inflammatory cytokines (TNF-α, IL-1β, TGF-β, and IL-10) and the oxidative stress marker, NADPH Oxidase 4 (NOX4). The study found no significant changes in serum liver enzymes or liver morphology among the experimental groups. However, the D-gal group exhibited increased neuronal cell loss, along with elevated levels of MDA and NOX4 in the frontal cortex and hippocampus. Moreover, D-gal mice showed elevated levels of TNF-α, IL-1β, and TGF-β, accompanied by decreased IL-10 levels. Notably, treatment with low-dose APAP and vitamin E mitigated neuronal cell loss, decreased MDA levels, and attenuated NOX4 expression induced by D-gal injection. Furthermore, low-dose APAP, particularly at 50 mg/kg, and vitamin E reversed the alterations in TNF-α, IL-1β, and IL-10 induced by D-gal, while TGF-β was unaffected. We suggest that low-dose APAP exerts antioxidant and anti-inflammatory activities to protect against neurodegeneration in a mouse model of brain aging induced by chronic D-gal injection.