Stereological insights into the protective effects of agmatine on hippocampal damage induced by aluminum nanoparticles

Abstract

Background

Aluminum (Al) exposure has been implicated in neurodegenerative disorders, particularly Alzheimer’s disease (AD). Due to their small size and increased bioavailability, Al oxide nanoparticles (Al-NP) exhibit greater neurotoxicity than bulk Al, leading to hippocampal damage, neuronal loss, and cognitive decline. This study investigates whether agmatine, a polyamine with neuroprotective properties, mitigates Al-NP-induced memory impairment and hippocampal neurodegeneration.

Methods

Male Swiss mice (SWR/J) were randomly assigned to four groups: Control, Al-NP (10 mg/kg, oral), Al-NP + Agmatine (5 mg/kg or 10 mg/kg, intraperitoneal). Cognitive function was assessed using the Novel Object Recognition (NOR) test. Stereological analysis quantified hippocampal volume, as well as the volume and cell number of the CA1 and dentate gyrus (DG) sub-regions. Apoptosis was evaluated via cleaved caspase-3, Bax, and Bcl-2 expression using western blot analysis.

Results

Al-NP exposure significantly impaired memory performance, reduced hippocampal volume, and induced atrophy and neuronal loss in CA1 and DG. Molecular analysis revealed elevated cleaved caspase-3 expression, increased Bax, decreased Bcl-2, and an elevated Bax/Bcl-2 ratio, indicating activation of intrinsic apoptosis. Agmatine (10 mg/kg) effectively restored memory function, preserved hippocampal structure, and normalized apoptotic markers, suggesting its neuroprotective role.

Conclusion

Agmatine exerts potent neuroprotective effects against Al-NP-induced hippocampal toxicity by mitigating memory deficits, preventing neuronal loss, and suppressing apoptosis through downregulation of cleaved caspase-3 and modulation of Bax/Bcl-2 signaling. These structural and molecular changes may underlie its cognitive benefits. Given the role of hippocampal atrophy in AD, agmatine may be a promising candidate for preventing Al-related neurodegeneration and AD progression.