Galantamine inhibits β-amyloid aggregation and cytotoxicity

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Expert Opinion on Pharmacotherapy, 2001

Galantamine is a newly available cholinergic drug that offsets reductions in central cholinergic neurotransmission in Alzheimer's disease (AD) by specifically and reversibly inhibiting acetylcholinesterase (AChE) and by allosterically modulating nicotinic cholinergic receptors. The clinical impact of this latter mechanism of action has not been fully elucidated. Galantamine has favourable pharmacokinetic features including linear elimination kinetics, a relatively short half-life and high oral bioavailability. The efficacy of galantamine has been studied in an extensive clinical development program. During randomised, double-blind, placebo-controlled trials of up to 6 months' duration, galantamine 16 and 24 mg/day consistently produced a broad spectrum of beneficial effects on cognitive and non-cognitive AD symptoms. Patients' cognition, global function and abilities to perform both instrumental and basic activities of daily living were maintained, the emergence of behavioural symptoms was postponed and apparent reductions in caregiver burden were seen. In long-term studies (≥ 12 months), galantamine maintained cognitive and functional abilities at or near baseline levels for at least 12 months. Again, these benefits were associated with decreases in caregiver burden. The incidence of adverse events, which are typically mild or moderate in severity, is generally low with galantamine. Cholinergically mediated adverse events affecting mainly the gastrointestinal system can be minimised using the recommended slow dose-escalation regimen. Galantamine may therefore help reduce the overall burden and cost involved in caring for AD patients. Being approved for the treatment of mild-to-moderately severe AD in both the US and in Europe, with trials of its efficacy in other dementia types already yielding positive results, galantamine ranks as a first-line therapy for dementia.

The search for effective treatments of Alzheimer's disease (AD) is one of the major challenges facing modern medicine. Acetylcholinesterase (AChE) inhibitors (AChEIs) are effective for the treatment of mild to moderate AD, and memantine, an N-methyl-D-aspartate ( (NMDA) inhibitor, has been approved for moderate to severe AD. Galantamine is of particular interest because it has a dual mechanism of action: it is postulated to be both an AChEI and an allosteric modulator of nicotinic receptors. Modulation of NMDA and nicotinic receptors by memantine and galantamine may provide an optimal combination therapy for AD. The cholinergic and glutamatergic neurotransmitter systems, which share a close functional relationship, may play a role in the pathogenesis of AD. Close examination of the pharmacology of the 2 compounds suggests that galantamine can augment memantine's glutamatergic noise suppression while simultaneously enhancing the physiologic glutamatergic signal. The link between these systems suggests that AD therapies, which capitalize on this relationship, may be more effective in improving cognition than approaches focusing on a single system.

European Journal of Medicinal Chemistry, 1992

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Curr Alzheimer Res, 2010

Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of-amyloid (A) peptides may cause Alzheimer's disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting A have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating A clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-A monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating A formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases,-secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of-secretase, the protease that regulates the last metabolic step generating A , have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate-secretase, the enzyme responsible for the nonamyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of A aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-A approaches in clinical testing, we will know in few years if the A hypothesis of AD is correct.

Chemico-Biological Interactions, 2007

Current therapies for Alzheimer's disease treatment rely mainly on acetylcholinesterase inhibitors, improving central cholinergic neurotransmission. Among these molecules, galantamine (GAL) has an interesting pharmacological profile as it is both a reversible acetylcholinesterase inhibitor and an allosteric potentiator of nicotinic cholinergic receptors. We investigated the effect of GAL on the metabolism of the amyloid precursor protein (APP) in differentiated SH-SY5Y neuroblastoma cells. The rationale was based on the suggestion that cholinergic activity may also be involved in the regulation of APP metabolism. We studied the acute effect on APP metabolism measuring the secretion of sAPP␣ in the conditioned medium of cells. Following 2 h treatment, GAL 10 M promoted a strong increase in the release of sAPP␣, the maximal effect approaching on average three-fold baseline value. The compound appeared to increase the release of sAPP␣, with a mechanism dependent upon an indirect cholinergic stimulation. The effect of GAL was prevented by pre-treatment with alpha-bungarotoxin (40 nM) but not low (nanomolar) atropine concentrations, suggesting the specific involvement of nicotinic cholinergic receptors.

Current Alzheimer Research, 2010

Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of -amyloid (A ) peptides may cause Alzheimer's disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting A have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating A clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-A monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating A formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, -secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of -secretase, the protease that regulates the last metabolic step generating A , have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate -secretase, the enzyme responsible for the nonamyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of A aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-A approaches in clinical testing, we will know in few years if the A hypothesis of AD is correct.

Trends in pharmacological sciences, 2002

Alzheimer's disease (AD) is a neurodegenerative age related disease in which patients of age 65 or more suffer from memory impairment problems. This disease is related to the nervous system degradation and various pathophysiological conditions have been identified such as formation of β-amyloid and plaques, nerve degeneration, neurotransmitter depletion, accumulation of toxins, oxidative stress and inflammation. Local RAS system in the brain is different from vascular RAS and play an important role in pathophysiology of AD. RAS system modulates inflammatory processes, neurotransmitter activity and amyloid and plaque formation. Angiotensin II, a vasoconstriction peptide of RAS system also induces neuronal cell loss by the process of cell senescence. Genetic polymorphism is also an important factor for pathophysiology and treatment of AD. No treatment is available which can eradicate AD completely; only prophylactic treatments are available which gives only prophylactic relief. Treatments are given which improve the pathophysiological condition of the disease and restore the brain cells activity. Treatment approach includes prevention of β amyloid and plaque formation, restoration of neurotransmitter system, prevention of oxidative stress and inflammation. Other than allopathic medicines, traditional system of medicines also have number of herbs and plants which have the property of learning and memory improvement via different mechanism of actions.

European journal of pharmacology, 2017

Alzheimer's disease (AD) is a generalized term used for the loss in memory and other intellectual abilities on levels serious enough to interfere with daily life. It accounts for 60-80% of dementia cases. The characteristic features include aggregation of Amyloid-Beta (Aβ) plaques and Tau Protein Tangles in the nervous tissue of brain. Another important aspect associated with development of AD is the decrease in levels of Acetylcholine (ACh) in brain. The conventional pharmacotherapy of AD employs the use of compounds that inhibit the enzyme acetylcholinesterase (e.g. donepezil, rivastigmine) thereby elevating the levels of Acetylcholine in nervous tissue of brain. Lately, another drug has come into picture for treatment of AD i.e.memantine. It is a Glutamatergic antagonist that protects the nervous tissue against glutamate mediated excitotoxicity. However, both these classes of drugs provide only the symptomatic relief. There has been a desperate need arising since the past few...