Modulation of cell death and neurogenesis by early intervention with sodium butyrate and galantamine in a streptozotocin-induced Alzheimer’s rat model

Given the multifactorial nature of Alzheimer’s disease (AD), early combination therapies targeting complementary pathways offer the most effective neuroprotection. This study investigated neuroprotective potential of sodium butyrate (NaB) combined with galantamine (Gal), focusing on cell survival and markers associated with hippocampal neurogenesis and structural maturation in a streptozotocin (STZ)-induced rat model of sporadic AD. Male Wistar rats received intracerebroventricular STZ injection to induce AD-like pathology and were treated orally with Gal (10 mg/kg), NaB (600 mg/kg), or their combination for 14 days. Spatial learning and memory were evaluated using the Morris Water Maze (MWM). Hippocampal Aβ deposition, cell death, and neurogenesis were assessed by immunofluorescence, TUNEL assay, and Western blot analyses. STZ administration induced significant cognitive impairment, increased hippocampal Aβ accumulation, elevated cell death markers, BAX/Bcl-2 ratio, and reduced neurogenesis-associated markers, doublecortin (DCX; marker of immature neurons), and βIII-tubulin (marker of early neuronal maturation). Both Gal and NaB monotherapies significantly improved behavioral and molecular outcomes compared with untreated STZ rats. Combined NaB + Gal treatment produced the most pronounced overall recovery, restoring cognitive performance to near-control levels, markedly reducing Aβ burden and cell death markers, and modulating markers associated with early neuronal structural maturation. While Gal alone showed the strongest increase in hippocampal DCX immunoreactivity, combination therapy significantly increased βIII-tubulin expression, suggesting a potential facilitation of early neuronal maturation. Conclusively, early co-intervention with NaB and Gal is associated with neuroprotection, enhanced neurogenesis, and cognitive function in STZ-induced AD rats. These findings support the potential of multi-target combination early strategies for AD treatment.