With increasing prevalence, chronic kidney disease (CKD) has become a global health problem. Due to the retention of uremic toxins, electrolytes and water, and the resultant metabolic disturbances, CKD affects several organs, including the nervous system. Thus, CKD patients suffer from several neurological complications, including dementia, cognitive impairment, motor abnormalities, depression, and mood and sleep disturbances. However, the mechanisms underlying the neurological complications are least elucidated. We have recently reported a highly reproducible mice model of CKD induced by high adenine diet, which exhibited psychomotor behavioral abnormalities and blood-brain barrier disruption. In the present study, using the mice model, we have investigated psycho-motor and cognitive behaviour, and the neurochemical and histopathological alterations in brain relevant to the observed behavioural abnormalities. The results demonstrate global loss of Acetylcholinesterase activity, and decrease in neuronal arborisation and dendritic spine density in discrete brain regions, of the CKD mice. Oxidative stress, inflammation, and mitochondrial dysfunctions were found in specific brain regions of the mice, which have been regarded as the underlying causes of the observed neurochemical and histopathological alterations. Thus, the present study is of immense importance, and has therapeutic implications in the management of CKD-associated neurological complications.

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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.

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