Features and outcomes of drugs for combination therapy as multi-targets strategy to combat Alzheimer's disease

• Published in: Journal of ethnopharmacology 2018-04, Vol.215, p.42-73
• Main Authors: Sahoo, Atish Kumar, Dandapat, Jagnehswar, Dash, Umesh Chandra, Kanhar, Satish
• Format: Article
• Language: English
• Subjects: Acetyl cholinesterase; Alzheimer's disease; Amphotericin B (PubChem CID: 5280965); Amyloid-β peptide; Arecoline (PubChem CID: 2230); Azithromycin (PubChem CID: 447043); Berberine (PubChem CID: 2353); Bexarotene (PubChem CID: 82146); Clioquinol (PubChem CID: 2788); Crocin (PubChem CID: 5281233); Curcumin (PubChem CID: 969516); Cytisine (PubChem CID: 10235); Desferrioxamine (PubChem CID: 2973); Donepezil (PubChem CID: 3152); E2020 (PubChem CID: 3152); Eptastigmine (PubChem CID: 65872); Galanthamine (PubChem CID: 9651); Ganstigmine (PubChem CID: 89594); Ginsenoside Rg1 (PubChem CID: 441923); Honokiol (PubChem CID: 72303); Huperzine A (PubChem CID: 1253); Idebenone (PubChem CID: 3686); Imatinib (PubChem CID: 5291); Ladostigil (PubChem CID: 208907); Lobeline (PubChem CID: 3945); Lu 25–109 (PubChem CID: 178030); LY450139 dihydrate (PubChem CID: 9843750); Magnolol (PubChem CID: 72300); Memantine (PubChem CID: 4054); Metformin (PubChem CID: 4091); Metrifonate (PubChem CID: 5853); Minocycline (PubChem CID: 54675783); Neramexane (PubChem CID: 6433106); Neurodegenerative disease; Neurofibrillary tangles; Nicergoline (PubChem CID: 34040); Nicotine (PubChem CID: 89594); Nilvadipine (PubChem CID: 4494); Nimodipine (PubChem CID: 4497); Paclitaxel (PubChem CID: 36314); Phenserine (PubChem CID: 192706); Physostigmine (PubChem CID: 5983); Propentofylline (PubChem CID: 4938); Puerarin (PubChem CID: 5281807); Quetiapine (PubChem CID: 4494); Resveratrol (PubChem CID: 445154); Rifampin (PubChem CID: 6913622); Rivastigmine (PubChem CID: 77991); Rutaecarpine (PubChem CID: 65752); Silibinin (PubChem CID: 31553); Sinapic acid (PubChem CID: 637775); Sitoindoside IX (PubChem CID: 189586); Sitoindoside X (PubChem CID: 189702); Tacrine (PubChem CID: 1935); Talsaclidine (PubChem CID: 6918244); Tanshinones (PubChem CID: 164676); Tetracycline (PubChem CID: 54675776); Thalidomide (PubChem CID: 5426); Velnacrine maleate (PubChem CID: 5702293); Withaferin A (PubChem CID: 265237); Withanolide A (PubChem CID: 11294368); Xanomeline (PubChem CID: 60809); Zanapezil (PubChem CID: 198752); ZT-1 (PubChem CID: 101344572); τ-proteins
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2017.12.015

Alzheimer's disease (AD), a deleterious neurodegenerative disorder that impairs memory, cognitive functions and may lead to dementia in late stage of life. The pathogenic cause of AD remains incompletely understood and FDA approved drugs are partial inhibitors rather than curative. Most of drugs are synthetic or natural products as galanthamine is an alkaloid obtained from Galanthus spp. Huperzine A, an alkaloid found in Huperzia spp., gingkolides a diterpenoids from Gingko biloba and many ethnobotanicals like Withania somnifera (L.) Dunal., Physostigma venenosum Balf., Bacopa monnieri (L.) Wettst., Centella asiatica (L.) Urb. have been used by traditional Indian, Chinese, and European system of medicines in AD. Clinical significance opioid alkaloid in Papaver somniferum has shown another dimension to this study. Over exploitation of medicinal plants with limited bioactive principles has provided templates to design synthetic drugs in AD e.g. rivastigmine, phenserine, eptastigmine based on chemical structure of physostigmine of Physostigma venenosum Balf. Even ZT-1 a prodrug of Hup A and memogain a prodrug of galantamine has achieved new direction in drug development in AD. All these first-line cholinesterase-inhibitors are used as symptomatic treatments in AD. Single modality of “One-molecule-one-target” strategy for treating AD has failed and so future therapies on “Combination-drugs-multi-targets” strategy (CDMT) will need to address multiple aspects to block the progression of pathogenesis of AD. Besides, cholinergic and amyloid drugs, in this article we summarize proteinopathy-based drugs as AD therapeutics from a variety of biological sources. In this review, an attempt has been made to elucidate the molecular mode of action of various plant products, and synthetic drugs investigated in various preclinical and clinical tests in AD. It also discusses current attempts to formulate a comprehensive CDMT strategy to counter complex pathogenesis in AD. Information were collected from classical books on medicinal plants, pharmacopoeias and scientific databases like PubMed, Scopus, GoogleScholar, Web of Science and electronic searches were performed using Cochrane Library, Medline and EMBASE. Also published scientific literatures from Elsevier, Taylor and Francis, Springer, ACS, Wiley publishers and reports by government bodies and documentations were assessed. 60 no. of natural and synthetic drugs have been studied with their significant bioactivities. A de