Abstract
Copper (Cu) is essential for multiple biochemical processes, and copper sulphate (CuSO4) is a pesticide used for repelling pests. Accidental or intentional intoxication can induce multiorgan toxicity and could be fatal. Curcumin (CUR) is a potent antioxidant, but its poor systemic bioavailability is the main drawback in its therapeutic uses. This study investigated the protective effect of CUR and N-CUR on CuSO4-induced cerebral oxidative stress, inflammation, and apoptosis in rats, pointing to the possible involvement of Akt/GSK-3β. Rats received 100 mg/kg CuSO4 and were concurrently treated with CUR or N-CUR for 7 days. Cu-administered rats exhibited a remarkable increase in cerebral malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 associated with decreased GSH, SOD, and catalase. Cu provoked DNA fragmentation, upregulated BAX, caspase-3, and p53, and decreased BCL-2 in the brain of rats. N-CUR and CUR ameliorated MDA, NF-κB p65, and pro-inflammatory cytokines, downregulated pro-apoptotic genes, upregulated BCL-2, and enhanced antioxidants and DNA integrity. In addition, both N-CUR and CUR increased AKT Ser473 and GSK-3β Ser9 phosphorylation in the brain of Cu-administered rats. In conclusion, N-CUR and CUR prevent Cu neurotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis and upregulating AKT/GSK-3β signaling. The neuroprotective effect of N-CUR was more potent than CUR.
Highlights
Copper (Cu) is a redox-active metal found in many organs and tissues
CUR has shown a modulatory effect on glycogen synthase kinase-3 (GSK-3) activity [30], and we have recently reported the involvement of GSK-3β inhibition in mediating its protective efficacy against lead hepatotoxicity [20]
The ameliorative effect of CUR and N-CUR on oxidative stress in the brain of Cuexposed rats was evaluated through the assessment of malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT)
Summary
Copper (Cu) is a redox-active metal found in many organs and tissues. It is essential for a plethora of biochemical processes such as blood clotting, iron absorption, protein homeostasis, energy production, and cellular metabolism [1]. It acts as a cofactor necessary for many redox-regulating proteins [2]. Cu homeostasis is maintained within the normal level by precise regulatory mechanisms that regulate its absorption, excretion, and blood level [3]. MD is associated with a defect in Cu absorption and severe Cu deficiency, while WD results in Cu toxicity and affects several organs, including the liver, brain, and eye [2]. Chronic exposure to Cu has been implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease [6], Parkinson’s disease [7], and familial amyotrophic lateral sclerosis (ALS) [2,8]
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