From computational screening to zebrafish testing: repurposing of doxazosin, donepezil, and dolutegravir for neuroprotective potential in Alzheimer's disease.

Amyloid-beta (Aß) plaques and neurofibrillary tangles are distinctive features of Alzheimer's disease (AD), a progressive disorder that results in considerable memory loss and decline in cognitive function. Presently available therapies, such as donepezil and other medications that inhibit acetylcholinesterase, mainly provide relief from symptoms but do not change the course of the disease. This research article intends to investigate the possible reuse of two FDA-approved medications, doxazosin and dolutegravir, discovered through computerized screening using shape similarity, docking energy, and molecular dynamics stability, for the purpose of targeting human acetylcholinesterase (AChE) in the development of disease-altering treatments. In order to mimic neurotoxicity similar to Alzheimer's disease, zebrafish (Danio rerio) were treated with aluminum chloride (AlCl₃). Various behavioral assessments, such as the open field test, mirror biting test, novel tank test, social preference test, and dark-light preference test, were carried out to assess cognitive function, movement, and anxiety-related behaviors. The results indicated that doxazosin, a drug that blocks alpha-1 adrenergic receptors, successfully decreased neuroinflammation and improved cognitive abilities. Additionally, dolutegravir, which is mainly used as an antiviral medication, showed notable benefits in protecting the nervous system. This study highlights the possibility of using doxazosin and dolutegravir as effective alternative treatments for Alzheimer's disease. Upcoming preclinical and clinical research is necessary to confirm the safety and effectiveness of AD treatment, paving the way for new opportunities in therapeutic intervention.