Neurobehavioral, cholinergic and histopathological alterations induced by copper oxide nanoparticles in male mice

Copper is an essential element involved in metabolic processes in both plants and animals. However, in its nanoparticle form, copper is widely used in industrial and biomedical applications, raising concerns about its potential health risks. This study aimed to evaluate the impact of CuO-NPs on cognitive and memory functions in mice, with a particular focus on the cholinergic system and oxidative stress pathways. Adult male mice were exposed to CuO-NPs at different doses (0, 5, and 10 mg/kg bw) via intraperitoneal administration over a period of 21 days. Behavioral assessments, including the open field test (OF), novel object recognition test (NORT), and Morris water maze (MWM), revealed significant impairments in spatial learning, short-term memory, and recognition ability in the group treated with 10 mg/kg CuO-NPs. In contrast, no alterations in memory or anxiety-like behaviors were observed at the low dose (5 mg/kg) compared to controls. Biochemical analyses of brain tissues showed increased lipid peroxidation and altered antioxidant and cholinesterase activities, while qRT-PCR analysis revealed significant downregulation of cholinergic-related genes in mice exposed to the high dose (10 mg/kg) compared with controls. Additionally, histopathological examination confirmed pronounced neuronal damage, particularly in the hippocampus and cortex, indicating severe neuropathological lesions at the highest dose. Importantly, no significant toxic effects were observed at the 5 mg/kg dose. These findings suggest that CuO-NPs are relatively safe at lower doses; however, higher exposure may impair cognitive and memory functions by disrupting cholinergic neurotransmission and inducing oxidative stress, emphasizing the need for caution in their widespread application.