Safranal, a Natural Neuroprotective Compound, Modulates Plasma Iron Levels, Improves Behavioral Performance, and Demonstrates Dose-Specific Cytoprotection in Alzheimer's Disease Models

Metal dyshomeostasis contributes to Alzheimer's disease (AD) by influencing amyloid aggregation, oxidative imbalance, and impaired clearance mechanisms. Safranal, a bioactive constituent of Crocus sativus, exhibits antioxidant properties, but its metal-modulating actions remain insufficiently understood. This study investigated whether safranal modulates metal (Fe, Cu, Zn) levels in an AD rat model while evaluating its cytoprotective rescue capacity against Aβ1-42 induced neurotoxicity in differentiated SH-SY5Y cells. AD was induced in male rats via intracerebroventricular streptozotocin, followed by a four-week safranal administration (0.5 mg/kg/day, ip). Behavioral performance, plasma metal levels (ICP-MS), and cerebral total antioxidant capacity (FRAP) were evaluated alongside histological assessment. Post-treatment protocols were employed to evaluate the effects of safranal on cell viability and apoptosis in differentiated SH-SY5Y cells exposed to Aβ1-42. Longitudinal analyses revealed that safranal attenuated exploratory deficits and recognition memory impairments in AD rats. Decreased plasma iron levels in the AD group were restored by safranal, accompanied by a return of cerebral antioxidant capacity to normal. Although overt hippocampal histological alterations were absent in this early phase, post-treatment with safranal successfully offered a therapeutic rescue window, preserving cell viability and attenuating Aβ1-42-induced apoptotic features in vitro. Safranal demonstrates beneficial neuroprotective effects in AD models by improving behavioral outcomes, partially correcting plasma iron levels, and mediating cytoprotective rescue windows against Aβ1-42-induced cellular toxicity. These findings suggest that safranal represents a promising natural candidate for reducing behavioral deficits, supporting peripheral iron status, and offering functional cell survival in AD models.