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Elevation in the levels of reactive oxygen and nitrogen species (RONS), and downregulation of cellular antixoidants, have ubiquitously been reported from studies in animal models of neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD). Thus, plant-derived compounds are widely being investigated for their beneficial effects in these models. However, while studies have reported antioxidant potentials of several phytochemicals, a large number of studies have demonstrated different phytochemicals to be rather pro-oxidant and exaggerate oxidative stress (OS). One such study aimed to investigate possible ameliorative effect of Pomegranate juice (PJ) in rat model of toxin-induced parkinsonism revealed that PJ exacerbates OS, inflammation and promotes neurodegeneration. Thus, it remains to be investigated whether different constituents and metabolites of PJ are pro-oxidant or anti-oxidant. Using computational modeling, we investigated possible inhibitory potential of different constituents of PJ and their metabolites viz. delphinidin-3-glucoside, dimethylellagic acid-glucuronide, ellagic acid, ellagitannin, gallic acid, gallotannin 23, pelargonidin, punicalagin, urolithin A, urolithin A-glucuronide and urolithin B, on anti-oxidant defense system of the brain. The results indicate that the constituents of PJ have the potential to inhibit five key enzymes of the neuronal antioxidant defense system, viz. catalase, superoxide dismutase, glutathione peroxidase 4, glutathione reductase and glutathione-S-transferase. Thus, it is surmised that the constituents of PJ may contribute to OS and neurodegeneration by way of affecting antioxidant defense mechanism. This may particularly be more pronounced in neurodegenerative diseases, since neurons are known to be more vulnerable to OS. Thus, the present findings caution the use of PJ in patients prone to OS, especially those suffering from neurodegenerative diseases, and warrant further experimental studies to unveil the effects of individual components and metabolites of PJ on antioxidant defense system of brain.