ESPERMIDINA ATENUA DÉFICITS COGNITIVOS E NEURODEGENERAÇÃO HIPOCAMPAL POR MODULAÇÃO DE BDNF E APOPTOSE EM MODELO DE DOENÇA DE ALZHEIMER ESPORÁDICA

Abstract

Introduction: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive impairment of memory and cognition, associated with molecular, structural, and functional alterations in the central nervous system. In this context, compounds capable of modulating multiple pathophysiological mechanisms have been investigated, with emphasis on spermidine, an endogenous polyamine with neuroprotective properties described in the literature. Objective: To evaluate the effects of spermidine on behavioral, histological, molecular, and metabolic alterations in an experimental model of AD. Methodology: Male Wistar rats (n = 31) were allocated into control, AD, and spermidine-treated groups. Experimental AD was induced by intracerebroventricular administration of streptozotocin (3 mg/kg). The treated group received spermidine (50 mg/kg, oral gavage) daily for 21 days. Behavioral tests assessing learning and memory were performed, including the Morris water maze and novel object recognition test. In addition, hippocampal histomorphometric analyses and gene expression evaluation of BDNF and CASP3 by qPCR were conducted. Data were expressed as mean ± standard error of the mean (SEM) and analyzed using ANOVA followed by Newman–Keuls post hoc test, considering p ≤ 0.05 as statistically significant. Results: Initially, STZ-induced experimental AD promoted metabolic alterations associated with insulin resistance and dyslipidemia, including glucose intolerance, increased total cholesterol, triglycerides, TyG index, and Lee Index, all of which were reversed by spermidine treatment. Furthermore, the experimental model induced cognitive deficits, hippocampal structural alterations, and dysregulation of genes related to neuroplasticity and apoptosis. In the Morris water maze, AD animals showed impaired task acquisition and reduced spatial memory compared to the control group (p < 0.05), whereas spermidine treatment significantly restored these parameters (p < 0.05 vs. AD). Similarly, spermidine prevented the impairment of episodic memory observed in the novel object recognition test (p < 0.05). Histologically, reduced cellularity was observed in the dentate gyrus hilus of the AD group (p < 0.05), which was partially reversed by treatment. Moreover, spermidine increased hippocampal BDNF expression and reduced CASP3 expression compared to the AD group (p < 0.05). Conclusion: Spermidine exhibited neuroprotective effects in the experimental AD model, acting on behavioral, structural, molecular, and metabolic alterations associated with the disease. These findings reinforce its potential as a promising therapeutic strategy, although further studies are required to elucidate its mechanisms of action and clinical applicability.