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

TL;DR

Combining escitalopram and galantamine may help treat Alzheimer's-related depression by improving brain function and reducing harmful stress markers.

Contribution

The study introduces a novel combination therapy for Alzheimer's comorbid depression and identifies key biological pathways involved.

Findings

Combined therapy improved depressive symptoms and memory in mice with Alzheimer's and depression.

The treatment normalized brain levels of BDNF, cytokines, kynurenine metabolites, and oxidative stress markers.

Hippocampal integrity was preserved with the combination therapy.

Abstract

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.

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