Alpha‐Linolenic Acid for Mitigating Neuroinflammation and Dopaminergic Neuronal Loss in Parkinson's Disease: Insights From In Vivo and In Silico Studies

ABSTRACT Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by dopaminergic neuronal loss and chronic neuroinflammation, leading to significant motor and non‐motor deficits. This study explores the therapeutic potential of alpha‐linolenic acid (ALA), a known antioxidant and anti‐inflammatory agent, in a lipopolysaccharide (LPS)‐induced murine model of PD. Male Balb‐C mice were divided into control, LPS‐treated, LPS + ALA‐treated and ALA‐only groups. Behavioural assessments, including the pole test, rotarod test and open field test, revealed significant motor impairments in LPS‐treated mice. Co‐treatment with ALA partially ameliorated motor deficits in LPS‐treated mice compared to the healthy control group. However, no direct comparison was made with standard PD treatments such as levodopa. Immunohistochemistry analysis showed a 68% reduction in tyrosine hydroxylase‐positive (TH+) neurons in the substantia nigra pars compacta (SNpc) of LPS‐treated mice. Notably, ALA co‐treatment preserved dopaminergic neurons, demonstrating its neuroprotective effects. Western blotting and ELISA revealed heightened expression of inflammatory mediators, including TNF‐α, IL‐1β and NF‐κB, in LPS‐treated mice. ALA treatment significantly reduced these markers, indicating its capacity to mitigate neuroinflammation. Molecular docking analysis revealed moderate binding affinities of ALA to NF‐κB (−5.1 kcal/mol), TNF‐α (−5.7 kcal/mol) and IL‐1β (−3.9 kcal/mol), suggesting possible interactions with key inflammatory pathways. These interactions were comparable to known inhibitors, indicating ALA's potential for neuroprotection. This study highlights the neuroprotective and anti‐inflammatory effects of ALA in reducing dopaminergic neuronal loss and mitigating neuroinflammation in an LPS‐induced PD model. Although behavioural improvements were moderate, these findings underscore ALA's potential as an adjunct therapeutic candidate for PD and other neurodegenerative diseases. Further research is warranted to explore its translational applications in clinical settings.