NEUROPROTECTIVE EFFECTS OF DONEPEZIL AND FLUOXETINE VIA GSK-3 PATHWAY IN A TRANSGENIC DROSOPHILA MODEL OF ALZHEIMER'S DISEASE: NEUROPSYCHIATRIC AND BEHAVIOURAL ANALYSIS

PRIYANKA LG; BHARAT B. J.; K. L. KRISHNA

doi:10.22159/ijap.2025v17i6.55475

Authors

PRIYANKA LG Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysore-570015, India
BHARAT B. J. Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysore-570015, India https://orcid.org/0009-0004-8455-7419
K. L. KRISHNA Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysore-570015, India

DOI:

https://doi.org/10.22159/ijap.2025v17i6.55475

Keywords:

Alzheimer’s disease, Drosophila melanogaster, Donepezil, Fluoxetine, GSK-3 signalling, Neuroinflammation

Abstract

Objective: This study investigates the neuroprotective effects of Donepezil and Fluoxetine in a transgenic Drosophila melanogaster model of AD, with a specific focus on modulation of the GSK-3 signalling pathway.

Methods: Transgenic Drosophila flies expressing the UAS-ELAV-GAL4 system were divided into four groups: (1) Normal, (2) Disease Control, (3) Donepezil 100 µM (DPZ), and (4) Fluoxetine 10 µM (FLX), treated for 21 d. Behavioural assays (negative geotaxis, open field) were conducted to assess locomotor function. Biochemical analyses, including oxidative stress markers (CAT, MDA, GSH) and neurotransmitters (dopamine, serotonin, acetylcholine), were measured. Immunohistochemistry was used to qualitatively assess the expression of Aβ, GSK-3, and neuroinflammatory cytokines (IL-6, IL-1β, TNF-α) in fly brains.

Results: Transgenic Drosophila melanogaster expressing AD pathology exhibited elevated levels of oxidative stress markers, neurotransmitter deficits, and marked neuroinflammation. Donepezil and Fluoxetine significantly (p≤0.05) reduced MDA levels and restored CAT and GSH levels, indicating improved antioxidant defence. Both treatments also reversed reductions in dopamine, serotonin, and acetylcholine levels significantly (p≤0.05) when compared to the control group, suggesting neurochemical restoration. Immunohistochemistry revealed decreased Aβ, GSK-3, and pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) following treatment, with Fluoxetine demonstrating comparatively greater modulation. Histological analysis confirmed improved neuronal integrity, particularly in the Fluoxetine-treated group, indicating superior neuroprotective efficacy.

Conclusion: Donepezil and Fluoxetine confer neuroprotection by enhancing locomotor function, reducing oxidative stress, restoring neurotransmitter balance, and attenuating neuroinflammation. Notably, Fluoxetine’s modulation of serotonergic-GSK-3 signalling suggests it may augment standard AD therapy by targeting both cholinergic and non-cholinergic mechanisms, offering a promising adjunctive strategy for disease management.

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