Synergistic effect of spermidine and ciprofloxacin against Alzheimer disease in male rat via ferroptosis modulation

Abstract Alzheimer's disease (AD) is a prevalent form of neurodegenerative disease with a complex pathophysiology that remains not fully understood, and the exact mechanism of neurodegeneration is uncertain. Ferroptosis, a programmed cell death mechanism mediated by iron, has been linked to the progression of degenerative diseases observed in clinical AD models. In this study, we aimed to explore the synergistic effects of spermidine and/or ciprofloxacin in combating Alzheimer's disease (AD). We investigated AD-related biomarkers, including neurotoxic Aβ, arginaseI, and serotonin.Spermidine demonstrated an anti-ferroptotic effect in the AD model, evident from the modulation of ferroptosis parameters such as hippocampus iron levels, reduced protein expression of transferrin receptor 1 (TRF1), and arachidonate 15-lipoxygenase (ALOX15). Additionally, the administration of spermidine led to a significant increase in protein expression of phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) and upregulation of Cystine/glutamate transporter (SLC7A11) gene expression. Moreover, spermidine notably decreased p53 protein levels, acrolein, and gene expression of spermidine/spermine N1-acetyltransferase 1 (SAT1). The histopathological examination of hippocampus tissue corroborated these results obtained from molecular biochemical inspection. Overall, our findings suggest that spermidine and/or ciprofloxacin may offer potential benefits against Alzheimer's disease (AD) by modulating ferroptosis. Furthermore, spermidine enhanced the antioxidant efficacy of ciprofloxacin and reduced its toxic effects by increasing antioxidant enzymes, thereby enhancing its potency against oxidative stress.