Exploring the Neuroprotective Potential of Polyphenolic Compounds in Mitigating Quinolinic Acid-Induced Neurotoxicity in Alzheimer's Disease.

Abstract

Background: Quinolinic Acid (QA), a neurotoxic metabolite in the kynurenine pathway, contributes to neuronal damage, oxidative stress, and neuroinflammation, playing a key role in Alzheimer's Disease (AD) pathogenesis. This study investigates the neuroprotective potential of polyphenolic compounds, particularly lycopene and a Curcumin-Zinc (Cur-Zn) complex, using in- -silico and in-vitro approaches targeting the kynurenine pathway.

Methodology: This study evaluated the neuroprotective potential of lycopene and Cur-Zn complex using in-silico and in-vitro approaches. Molecular docking was performed to assess their binding affinities with the kynurenine pathway enzymes, and in-vitro neuroprotection assays on N2a cells measured their efficacy against QA-induced oxidative stress.

Results: Docking analysis revealed strong binding affinities of Cur-Zn and lycopene to IDO1 and KMO, with fitness scores of 143.11 and 126.41, respectively, indicating their potential as enzyme- specific inhibitors. Lycopene exhibited the most potent neuroprotective effect (IC50 = 0.63 μM), followed by Cur-Zn (1.59 μM). Both compounds significantly reduced QA-induced ROS levels, as confirmed by DCFDA fluorescence imaging. Additionally, they upregulated KAT and QPRT enzymes, promoting neuroprotective metabolite production.

Discussion: Lycopene and Cur-Zn effectively modulate key kynurenine pathway enzymes while mitigating oxidative stress, supporting their potential as neuroprotective agents. Although bisabolol and bromelain exhibited some efficacy, their effects were comparatively lower.

Conclusion: Lycopene and Cur-Zn are promising candidates for AD therapy, demonstrating not only anti-oxidant activity but also a capacity to minimise the neurotoxic effects of QA, offering a dual mechanism of action. Further, in-vivo studies are needed to validate their therapeutic potential in neurodegenerative diseases.