Tag Archives: Alzheimer’s disease

The role of phytochemicals in the treatment and prevention of dementia.

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Drugs & Aging

“Dementia pathologies such as Alzheimer’s disease (AD) are reaching epidemic proportions, yet they are not successfully managed by effective symptomatic treatments. Only five drugs have been developed to alleviate cognitive symptoms, and more effective and safe treatments are needed for both the cognitive symptoms and behavioural and psychological symptoms of dementia (BPSD). As two of these licensed drugs (cholinesterase inhibitors [ChEIs]) are naturally derived (galantamine and rivastigmine), the potential for plants to yield new therapeutic agents has stimulated extensive research to discover new ChEIs together with plant extracts, phytochemicals and their derivatives with other mechanistic effects relevant to dementia treatment. This review presents the potential and actual therapeutic strategies for dementia in relation to the known mechanisms of dementia pathology. Phytochemicals that have shown mechanistic effects relevant to the pathological targets in dementia are discussed, with an emphasis on those showing positive clinical trial evidence. Those phytochemicals discussed include the alkaloid physostigmine, a ChEI from the calabar bean (Physostigma venenosum), which has been used as a template for the development of synthetic derivatives that inhibit acetylcholinesterase, including the drug rivastigmine. Also discussed are other ChEI alkaloids including huperzine A, from Huperzia serrata, and galantamine, originally from the snowdrop (Galanthus woronowii); both alkaloids improve cognitive functions in AD patients.

Other phytochemicals discussed include cannabinoids (e.g. cannabidiol) from Cannabis sativa, which are emerging as potential therapeutic agents for BPSD, and resveratrol (occurs in various plants) and curcumin (from turmeric [Curcuma longa]), which have been investigated for their pharmacological activities relevant to dementia and their potential effects on delaying dementia progression. The review also discusses plant extracts, and their known constituents, that have shown relevant mechanistic effects for dementia and promising clinical data, but require more evidence for their clinical efficacy and safety. Such plants include Ginkgo biloba, which has been extensively studied in numerous clinical trials, with most outcomes showing positive effects on cognitive functions in dementia patients; however, more reliable and consistent clinical data are needed to confirm efficacy. Other plants and their extracts that have produced promising clinical data in dementia patients, with respect to cognition, include saffron (Crocus sativus), ginseng (Panax species), sage (Salvia species) and lemon balm (Melissa officinalis), although more extensive and reliable clinical data are required. Other plants that are used in traditional practices of medicine have been suggested to improve cognitive functions (e.g. Polygala tenuifolia) or have been associated with alleviation of BPSD (e.g. the traditional prescription yokukansan); such remedies are often prescribed as complex mixtures of different plants, which complicates interpretation of pharmacological and clinical data and introduces additional challenges for quality control. Evidence for the role of natural products in disease prevention, the primary but considerably challenging aim with respect to dementia, is limited, but the available epidemiological and clinical evidence is discussed, with most studies focused on ChEIs, nicotine (from Nicotiana species), curcumin, wine polyphenols such as resveratrol and G. biloba. Challenges for the development of phytochemicals as drugs and for quality control of standardized plant extracts are also considered.”

http://www.ncbi.nlm.nih.gov/pubmed/21639405

https://link.springer.com/article/10.2165%2F11591310-000000000-00000

Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders.

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“In traditional practices of medicine, numerous plants have been used to treat cognitive disorders, including neurodegenerative diseases such as Alzheimer’s disease (AD) and other memory related disorders. An ethnopharmacological approach has provided leads to identifying potential new drugs from plant sources, including those for memory disorders. There are numerous drugs available in Western medicine that have been directly isolated from plants, or are derived from templates of compounds from plant sources. For example, some alkaloids from plant sources have been investigated for their potential in AD therapy, and are now in clinical use (e.g. galantamine from Galanthus nivalis L. is used in the United Kingdom).

 Various other plant species have shown favourable effects in AD, or pharmacological activities indicating the potential for use in AD therapy.

This article reviews some of the plants and their active constituents that have been used in traditional medicine, including Ayurvedic, Chinese, European and Japanese medicine, for their reputed cognitive-enhancing and antidementia effects. Plants and their constituents with pharmacological activities that may be relevant to the treatment of cognitive disorders, including enhancement of cholinergic function in the central nervous system, anti-cholinesterase (anti-ChE), antiinflammatory, antioxidant and oestrogenic effects, are discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/12557240

Medicinal plants and Alzheimer’s disease: from ethnobotany to phytotherapy.

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“The use of complementary medicines, such as plant extracts, in dementia therapy varies according to the different cultural traditions. In orthodox Western medicine, contrasting with that in China and the Far East for example, pharmacological properties of traditional cognitive- or memory-enhancing plants have not been widely investigated in the context of current models of Alzheimer’s disease. An exception is Gingko biloba in which the gingkolides have antioxidant, neuroprotective and cholinergic activities relevant to Alzheimer’s disease mechanisms. The therapeutic efficacy of Ginkgo extracts in Alzheimer’s disease in placebo controlled clinical trials is reportedly similar to currently prescribed drugs such as tacrine or donepezil and, importantly, undesirable side effects of Gingko are minimal. Old European reference books, such as those on medicinal herbs, document a variety of other plants such as Salvia officinalis (sage) and Melissa officinalis (balm) with memory-improving properties, and cholinergic activities have recently been identified in extracts of these plants. Precedents for modern discovery of clinically relevant pharmacological activity in plants with long-established medicinal use include, for example, the interaction of alkaloid opioids in Papaver somniferum (opium poppy) with endogenous opiate receptors in the brain. With recent major advances in understanding the neurobiology of Alzheimer’s disease, and as yet limited efficacy of so-called rationally designed therapies, it may be timely to re-explore historical archives for new directions in drug development. This article considers not only the value of an integrative traditional and modern scientific approach to developing new treatments for dementia, but also in the understanding of disease mechanisms. Long before the current biologically-based hypothesis of cholinergic derangement in Alzheimer’ s disease emerged, plants now known to contain cholinergic antagonists were recorded for their amnesia- and dementia-inducing properties.”

http://www.ncbi.nlm.nih.gov/pubmed/10411211

Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease.

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“A placebo-controlled crossover design to investigate effects of dronabinol (THC) in patients with a diagnosis of probable Alzhemer’s disease who were refusing food. 

These results indicate that dronabinol is a promising novel therapeutic agent which may be useful not only for treatment of anorexia but also to improve disturbed behavior in patients with Alzheimer’s disease.”

http://www.ncbi.nlm.nih.gov/pubmed/9309469

Intact cannabinoid CB1 receptors in the Alzheimer’s disease cortex.

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“The cannabinoid CB1 receptor has gained much attention as a potential pharmacotherapeutic target in various neurodegenerative diseases including Alzheimer’s disease (AD). Our study suggests that CB1 receptors are intact in AD and may play a role in preserving cognitive function.

 Therefore, CB1 receptors should be further assessed as a potential therapeutic target in AD.”

http://www.ncbi.nlm.nih.gov/pubmed/21034788

Molecular reorganization of endocannabinoid signalling in Alzheimer’s disease

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“CB1 cannabinoid receptor expression is unchanged in Alzheimer’s disease

Therefore, endocannabinoid signalling networks may represent novel targets to reinstate the precision of synaptic communication under neurodegenerative conditions associated with cognitive deficit.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069704/

Cannabinoid system in neurodegeneration: new perspectives in Alzheimer’s disease.

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“Alzheimer’s disease is a chronic and progressive neurodegenerative disorder. The presence of functional cannabinoid CB2 receptors in central nervous system (CNS) has provoked that this receptor and its agonist ligands are now considered as promising pharmacological targets for neurological diseases. Herein, we review the evidences supporting the potential role of the ECS as a therapeutic target, focused on CB2 receptor and its ligands, for the treatment of Alzheimer’s disease.”

http://www.ncbi.nlm.nih.gov/pubmed/19456285

Alzheimer’s disease and inflammation: a review of cellular and therapeutic mechanisms.

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“1. Of the neurodegenerative diseases that cause dementia, Alzheimer’s disease (AD) is the most common. Three major pathologies characterize the disease: senile plaques, neurofibrillary tangles and inflammation. We review the literature on events contributing to the inflammation and the treatments thought to target this pathology. 2. The senile plaques of AD consist primarily of complexes of the beta-amyloid protein. This protein is central to the pathogenesis of the disease. 3. Inflammatory microglia are consistently associated with senile plaques in AD, although the classic inflammatory response (immunoglobulin and leucocyte infiltration) is absent. beta-Amyloid fragments appear to mediate such inflammatory mechanisms by activating the complement pathway in a similar fashion to immunoglobulin. 4. Epidemiological studies have identified a reduced risk of AD in patients with arthritis and in leprosy patients treated with anti-inflammatory drugs. Longitudinal studies have shown that the consumption of anti-inflammatory medications reduces the risk of AD only in younger patients (< 75 years). 5. There is a considerable body of in vitro evidence indicating that the inflammatory response of microglial cells is reduced by non-steroidal anti-inflammatory drugs (NSAID). However, no published data are available concerning the effects of these medications on brain pathology in AD. 6. Cyclo-oxygenase 2 enzyme is constitutively expressed in neurons and is up-regulated in degenerative brain regions in AD. Non-steroidal anti-inflammatory drugs may reduce this expression. 7. Platelets are a source of beta-amyloid and increased platelet activation and increased circulating beta-amyloid have been identified in AD. Anti-platelet medication (including NSAID) would prevent such activation and its potentially harmful consequences. 8. Increased levels of luminal beta-amyloid permeabilizes the blood-brain barrier (BBB) and increases vasoconstriction of arterial vessels, paralleling the alterations observed with infection and inflammation. Cerebral amyloidosis is highly prevalent in AD, compromising the BBB and vasoactivity.

Anti-inflammatory medications may alleviate these problems.”

http://www.ncbi.nlm.nih.gov/pubmed/10696521

Current and future therapy in Alzheimer’s disease.

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Abstract

“Dementia is increasingly being recognized as one of the most important medical problems in the elderly. As most pharmacological research within the field of dementia is focused on Alzheimer’s dementia (AD), this review will focus on pharmacological interventions in AD. Most disease-modifying therapies are based on the amyloid hypothesis. In this hypothesis, the pathological accumulation of Abeta in the brain leads to oxidative stress, neuronal destruction and finally the clinical syndrome of AD. Following this hypothesis, secondary prevention of AD can be made by: decreasing the production of Abeta, stimulation of clearance of Abeta formed or prevention of aggregation of Abeta into amyloid plaques. First a short overview on current approved therapies for AD is given. The main part of the review will focus on potential disease-modifying therapies for AD that are currently being studied in phase I to phase III trials.”

http://www.ncbi.nlm.nih.gov/pubmed/18485144

[Therapy of Alzheimer disease].

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Abstract

“Dementia is one of the most important health problems in the aging populations. The most frequent cause of it is Alzheimer’s disease (AD) which is characterized by intracellular neuro-fibrillary tangles (NFT) and the extracellular senile plaques. The NFTs are mainly formed by the hyperphosphorylated microtubule-binding protein, the tau, while the senile plaques are composed of beta-amyloid protein cleaved from the amyloid precursor protein (APP) by the beta- and gamma-secretases. The pharmacotherapy of AD consists of symptomatic and disease-modifying therapies. The most frequently used therapeutic agents are the nootropic drugs supported by personal rather evidence based experiences. The leading-edge therapy of AD at present is the inhibition of the acetylcholine-esterase enzyme (AChEI) with mainly cognitive symptomatic and weak disease-modifying effects; they are licensed in the mild and middle stages of AD (MMSE 26-10), but their effect is proved in the severe stage of the disease and they are effective in the management of the neuropsychiatric symptoms too. Memantine (which is an inhibitor of the N-metil-D-aspartate receptor) is used in the middle and severe stages of AD and it can be effectively combined with AChEIs. The future therapy of AD will possibly be a “causative” therapy. The most frequent directions are therapies aiming to decrease the production or the deposition of beta-amyloid peptide. The active vaccination study of AN-1792 was terminated because of immunological side-effects, but several active and passive immunisation therapies are in development nowadays. It is also possible to inhibit the aggregation of the beta-amyloid peptide with peptide fragments or with Cu2+ and Zn2+ ion chelators. A promising direction is the inhibition of the enzymes responsible for the production of the beta-amyloid peptide: beta-secretase inhibitors with low molecular weight and penetrability through the blood-brain barrier are developed while the inhibitors of the gamma-secretase (some of them are the derivatives of the non-steroid anti-inflammatory drug ibuprofen) are tested in phase III trials. The inhibition of NFT formation might be promising too and inhibitors of the enzymes responsible for the hyperphosphorylation of the tau (like the glycogen synthase kinase-3) are in develo ment. Several other therapeutic methods are studied. NSAIDs and statins are useful in the prevention of the disease but they are failed in symptomatic treatment. There are promising studies in few patients using nerve growth factor therapy and some studies proved that peroxisome proliferator activated receptor (PPAR) agonist rosiglitazone (which is used to the treat diabetes mellitus) is effective in AD. The presently modest therapeutic interventions of AD will explode in the near future and together with the improved diagnostics of the disease they will cause further specialization with increased treatment and caring costs amplified by the ever growing number of the patients. This means that AD is and will be one of the most important diseases for the health care systems.”

http://www.ncbi.nlm.nih.gov/pubmed/19731816