Cinnamaldehyde protects against aluminum oxide nanoparticle-induced cognitive dysfunction in male Swiss mice by attenuating hippocampal ERK/p38 hyperphosphorylation and enhancing.

Aluminum exposure has been implicated in neurodegenerative disorders, and aluminum-based nanoparticles exhibit greater neurotoxicity than bulk aluminum, highlighting the need to identify protective agents. Cinnamaldehyde, a major bioactive compound of cinnamon, has demonstrated neuroprotective effects in experimental models. The present study investigated whether cinnamaldehyde could attenuate cognitive deficits induced by aluminum oxide nanoparticles (ALNP) and examined the involvement of hippocampal MAPK signaling and neurotrophic pathways. Adult male Swiss mice received ALNP (10 mg/kg, oral gavage) alone or in combination with cinnamaldehyde (100, 200, or 300 mg/kg, i.p.) for five days. Novel object recognition memory was evaluated using the novel object recognition (NOR) test, and hippocampal levels of phosphorylated and total ERK and p38, as well as BDNF, were measured by western blotting. ALNP exposure impaired recognition memory and increased phosphorylation of ERK and p38 without altering total protein levels. Cinnamaldehyde improved cognitive performance in a dose-dependent manner, with significant effects observed at 300 mg/kg. Cinnamaldehyde administered alone (300 mg/kg) did not alter cognitive performance, indicating selective protection against ALNP-induced deficits. This effective dose normalized ERK and p38 phosphorylation and significantly increased hippocampal BDNF expression. Total exploration time did not differ between any groups, indicating that behavioral effects were not attributable to locomotor alterations. These findings suggest that ALNP-induced cognitive impairment is associated with stress-related activation of MAPK signaling, and that cinnamaldehyde mitigates these neurotoxic effects, possibly through restoration of kinase signaling balance and enhancement of neurotrophic support. Collectively, the results identify intracellular signaling dysregulation as a potential mechanism of nanoparticle-induced cognitive dysfunction and support cinnamaldehyde as a candidate warranting further investigation for mitigating aluminum nanoparticle neurotoxicity.