Therapeutic and medicinal effects of snowdrop (Galanthus spp.) in Alzheimer's disease: A review

The Amaryllidaceae family comprises about 85 genera and over 1100 species and is notable for its alkaloid content. Snowdrop (Galanthus spp.), a perennial bulbous member of this family, contains diverse alkaloids, among which galantamine is prominent. First isolated from Galanthus woronowii and later from G. nivalis and currently sourced from Leucojum aestivum, galantamine has been used clinically for AD since 2011. AD, a progressive neurodegenerative disorder first described in 1907, is the leading cause of dementia in the elderly and is characterized by cortical degeneration, cholinergic neuron loss, amyloid plaques, and neurofibrillary tangles. Therapeutic strategies have long targeted the cholinergic hypothesis, aiming to enhance cholinergic transmission via AChE inhibition. FDA-approved symptomatic treatments include the AChE inhibitors galantamine, rivastigmine, and donepezil, and the NMDA receptor antagonist memantine. Natural alkaloids are a rich source of cholinesterase inhibitors; galantamine uniquely offers dual action as a selective, reversible AChE inhibitor and an allosteric modulator of nicotinic acetylcholine receptors (nAChRs). This review introduces the botanical and pharmacological aspects of Galanthus and emphasizes its role in AD treatment.

- Geographical distribution: Galanthus species are distributed across Europe, Asia Minor, and the Caucasus, with some species widespread (e.g., G. nivalis) and others narrowly endemic (e.g., G. trojanus). Turkey harbors notable diversity. - AD pathology and cholinergic neurotransmission: AD features extracellular Aβ plaques and intracellular neurofibrillary tangles with synaptic loss and cholinergic deficits. In healthy neurotransmission, ~90% of synaptic ACh is rapidly hydrolyzed by AChE; deficits in AD disrupt vesicle maturation/release and receptor activation. - Alkaloids as multifunctional therapeutics: Over 27,000 alkaloids are known; several exhibit AChE/BChE inhibition relevant to AD. FDA-approved cholinesterase inhibitors include the alkaloids galantamine and rivastigmine (a physostigmine derivative). Some alkaloids (isoquinolines, piperidines, β-carbolines, tetrahydroisoquinolines) act as potent cholinesterase inhibitors. - Galantamine pharmacology: A phenanthrene-type alkaloid (C17H21NO3; MW 287.35 g/mol) with reversible, competitive AChE inhibition and allosteric potentiation of nAChRs. Structural studies show galantamine binding at the base of the AChE active-site gorge interacting with the acyl pocket and Trp-84 vicinity. - Evidence base summarized in the review: • Natural products-based approaches highlight galantamine (Nivalin/Reminyl) as a promising symptomatic AD drug. • Preclinical/biochemical reports attribute dual cholinergic action, potential anti-amyloid aggregation, neuroprotection, and antioxidant effects to galantamine. • Clinical imaging work suggests switching from donepezil to galantamine may benefit apathy/executive dysfunction via nicotinic modulation. • Meta-analyses and RCTs indicate galantamine significantly improves cognition, behavior, and global function in AD, with caution advised in clinical use. • Long-term analyses report reduced mortality and slower decline in cognition and activities of daily living in mild-to-moderate AD on galantamine, and sustained cognitive benefits up to 36 months; early initiation yields better outcomes than delayed switch from placebo. - Botanical/chemical studies within Galanthus: discovery of multiple new alkaloids (e.g., galanthindole), micropropagation and alkaloid production methods, and historical isolation/structure elucidation of galantamine from Galanthus spp. and Leucojum aestivum.

Web-based narrative review conducted in 2021. Sources searched: ISI Web of Knowledge, PubMed, Scopus, MedLib, SID, ISC, and publishers/platforms including Springer, Elsevier, John Wiley and Sons, and Taylor & Francis. Timeframe: publications from 1990 to 2021. Language: English. Keywords: "Galanthus," "galanthamine," and "Alzheimer's disease." The review compiles botanical, pharmacological, and clinical literature on Galanthus alkaloids with emphasis on AD, without reporting formal inclusion/exclusion criteria or quantitative synthesis.

- Amaryllidaceae alkaloids commonly exhibit anticholinesterase activity; Galanthus is a rich source of such compounds, with galantamine the most studied. - Galantamine is a selective, reversible, competitive AChE inhibitor and an allosteric modulator of nAChRs, producing increased synaptic ACh and enhanced nicotinic receptor function. - Structural insights: galantamine binds within the AChE active-site gorge, interacting with residues near Trp-84 and the acyl-binding pocket. - Clinical evidence summarized in the review indicates galantamine: • Significantly improves cognitive, behavioral, and global outcomes in AD (meta-analysis of RCTs). • Provides sustained cognitive benefits with continuous treatment up to 36 months; earlier initiation yields better long-term function than delayed start. • In post-hoc analyses, is associated with reduced mortality and slower decline in cognition and activities of daily living in mild-to-moderate AD. • May confer benefits related to nicotinic receptor modulation affecting apathy and executive dysfunction (imaging-supported observations). - Additional proposed benefits from preclinical literature include inhibition of amyloid-β aggregation, neuroprotection, and mitigation of oxidative damage.

This review addresses whether snowdrop (Galanthus spp.)-derived alkaloids, particularly galantamine, have therapeutic relevance for AD. Converging botanical, biochemical, structural, and clinical findings support galantamine’s role as an effective symptomatic therapy that targets the cholinergic deficit central to AD by inhibiting AChE and enhancing nicotinic receptor function. Structural data provide a mechanistic basis for its selectivity and reversible action, while clinical studies demonstrate improvements in cognition and daily function, with benefits sustained over long-term treatment and potentially reduced mortality. Compared with other AChE inhibitors, galantamine’s dual mechanism may underlie additional clinical effects (e.g., on apathy/executive domains) and suggests broader neuroprotective potential indicated by preclinical data. Nonetheless, current benefits are largely symptomatic; disease modification remains unproven, aligning with the broader limitations of cholinergic therapies in AD.

Amaryllidaceae alkaloids, notably from the Galanthus genus, possess antiviral, antitumor, and anticholinesterase activities. Among them, galantamine is the most extensively studied and is clinically used as a potent, reversible AChE inhibitor for AD and other neurological conditions. Its mechanism involves reversible AChE inhibition, increasing synaptic acetylcholine, and allosteric interaction with nicotinic acetylcholine receptors. Evidence compiled in this review supports galantamine as an effective symptomatic treatment that can delay cognitive decline over sustained use. Continued research into Galanthus alkaloids may yield additional therapeutic candidates and clarify potential multi-target effects (e.g., anti-amyloid, neuroprotection) for future AD interventions.