Galantamine–Escitalopram Combination Therapy in Alzheimer’s Comorbid Depression Model in Mice: Role of BDNF/KYN Pathways, Neuroinflammation, and Oxidative Stress

Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for more than two-thirds of cases in older adults. AD is associated with neuropsychiatric symptoms such as depression, anxiety, and sleep disturbances. The coexistence of AD with depression, in particular, poses serious challenges and often results in suboptimal outcomes with conventional therapies. The present study therefore aimed to investigate the therapeutic potential of escitalopram (ESC; SSRI) in combination with galantamine (GAL; AChE inhibitor) on key pathological pathways, including the neurotrophic system, hypothalamic-pituitary-adrenal (HPA) axis, kynurenine pathway, inflammation, and oxidative stress, in an animal model of AD comorbid with depression. Swiss albino mice were subjected to chronic mild stress (CMS) for 21 days and received intrahippocampal administration of amyloid-β peptide to mimic AD-depression comorbidity. Subsequently, ESC (10 mg/kg) combined with GAL (5 mg/kg) was administered orally for 20 days alongside the CMS protocol, followed by behavioral, biochemical, and histopathological assessments. The combined GAL + ESC treatment significantly alleviated depressive symptoms and improved working and spatial memory in CMS and amyloid-β-exposed mice. Furthermore, the therapy normalized hippocampal levels of BDNF, proinflammatory cytokines (IL-6, TNF-α), kynurenine metabolites (3-HK, QUIN), and oxidative stress markers toward those observed in the sham group. Histopathological analysis further confirmed the preservation of hippocampal integrity with combined therapy. Overall, the findings highlight the potential of ESC as an adjunct to GAL in ameliorating depressive symptoms and cognitive deficits, underscoring its promise for further clinical evaluation in the management of AD comorbid with depression.