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

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

Cannabis May Offer Alzheimer’s Hope, Study Says

“Marijuana compounds offer an alternative approach for treating the neurodegeneration associated with Alzheimer’s disease (AD)…

Investigators at the Trinity College, Institute for Neuroscience, in Dublin report that cannabinoids have been shown to protect neurons from the deleterious effects of amyloid plaque – the primary pathological hallmark of Alzheimer’s. Cannabinoids also demonstrate a propensity to reduce oxidative stress and inflammation, while also promoting neurogenesis (the birth of new neuronal cells), authors report.

Authors write: “In recent years the proclivity of cannabinoids to exert a neuroprotective influence has received substantial interest as a means to mitigate the symptoms of neurodegenerative conditions. … [C]annabinoids offer a multi-faceted approach for the treatment of Alzheimer’s disease by providing neuroprotection and reducing neuroinflammation, whilst simultaneously supporting the brain’s intrinsic repair mechanisms by augmenting neurotrophin expression and enhancing neurogenesis. … Manipulation of the cannabinoid pathway offers a pharmacological approach for the treatment of AD that may be efficacious than current treatment regimens.”

Preclinical studies have demonstrated that cannabinoids can delay disease progression in animal models of several neurodegenerative diseases, including multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrig’s disease).”-

Paul Armentano, NORML  http://norml.org/news/2007/09/20/cannabis-may-offer-alzheimers-hope-study-says

Full text of the study, “Alzheimer’s disease; taking the edge off with cannabinoids?” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2190031/

Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease.

“Microglial activation is an invariant feature of Alzheimer’s disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in vitro and in vivo… the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms…

Cannabinoids, whether plant-derived, synthetic, or endocannabinoids, exert their functions through activation of cannabinoid receptors, two of which have been well characterized to date: CB1 and CB2. Cannabinoids are neuroprotective against excitotoxicity and acute brain damage, both in vitro and in vivo. Several mechanisms account for the neuroprotection afforded by this type of drug such as blockade of excitotoxicity, reduction of calcium influx, antioxidant properties of the compounds, or enhanced trophic factor support. A decrease in proinflammatory mediators brought about by cannabinoids may be also involved in their neuroprotection… Cannabidiol (CBD), the major plant-derived nonpsychotropic constituent of marijuana, is of potential therapeutic interest in different disease conditions (e.g., inflammation)…

…this kind of drug with neuroprotective and anti-inflammatory effects may be of interest in the prevention of AD inflammation, in particular CB2-selective agonists, which are devoid of psychoactive effects…

Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo…

CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD.

Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102548/

Regulation of cannabinoid CB1 receptors in the central nervous system by chronic cannabinoids.

“The potential therapeutic benefits of certain cannabinoid-mediated effects, as well as the use of marijuana for its psychoactive properties, has raised interest in understanding the cellular adaptations produced by chronic administration of this class of drugs.”

http://www.ncbi.nlm.nih.gov/pubmed/14977366

The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells.

“Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. A massive accumulation of beta-amyloid (Abeta) peptide aggregates has been proposed as pivotal event in AD. Abeta-induced toxicity is accompanied by a variegated combination of events including oxidative stress… Cannabidiol, a non-psychoactive marijuana component, has been recently proposed as an antioxidant neuroprotective agent in neurodegenerative diseases. Moreover, it has been shown to rescue PC12 cells from toxicity induced by Abeta peptide. Here, we report that cannabidiol inhibits hyperphosphorylation of tau protein in Abeta-stimulated PC12 neuronal cells, which is one of the most representative hallmarks in AD… These results provide new molecular insight regarding the neuroprotective effect of cannabidiol and suggest its possible role in the pharmacological management of AD, especially in view of its low toxicity in humans.”

http://www.ncbi.nlm.nih.gov/pubmed/16389547

 

Cannabis and Alzheimer’s disease

“‘Clearly in the test tube cannabinoids have the ability to block at least one of the probable causal mechanisms in Alzheimer’s disease and so become a potential treatment or preventative agent that needs to be tested in humans.”

Dr Richard Harvey, research director of the Alzheimer’s Society

Read more: http://www.alzheimers.org.uk/site/scripts/news_article.php?newsID=123

Cannabis May Cut Alzheimer’s Risk – Discovery News

“For those who have inhaled, there may be some good news: Marijuana use may cut the risk of developing Alzheimer’s disease by reducing inflammation in the brain…

The findings may explain studies showing those who regularly used marijuana in the 1960s and 1970s are now less likely to develop Alzheimer’s disease than their non-smoking contemporaries.

Under a National Institutes of Health grant, researchers used a synthetic drug similar to marijuana to treat rats with brain inflammation typically associated with Alzheimer’s disease, a form of dementia that afflicts 4.5 million people in the United States alone.”

Read more: http://dsc.discovery.com/news/2006/10/19/marijuana_hea.html

Marijuana Ingredient May Help Alzheimer’s – WebMD

“Chemical Counters Brain Problems in Alzheimer’s Disease, Says Spanish Study.
New clues about Alzheimer’s disease have emerged from a Spanish study of marijuana. The drug’s active ingredients — cannabinoids — help prevent brain problems seen in Alzheimer’s, say the scientists.

The findings showed that “cannabinoids work both to prevent inflammation and to protect the brain,” says researcher Maria de Ceballos in a news release. That “may set the stage for [cannabinoids’] use as a therapeutic approach for [Alzheimer’s disease].”

The cannabinoids completely prevented activation of cells that trigger inflammation. These cells gather near plaque and are believed to be involved in the development of Alzheimer’s disease.

“Our results indicate that cannabinoid receptors are important in the pathology of Alzheimer’s disease and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease,” write the researchers in the journal.”

Read more: http://www.webmd.com/alzheimers/news/20050223/marijuana-ingredient-may-help-alzheimers

Marijuana May Slow Alzheimer’s – WebMD

“Key Marijuana Compound Beats Current Alzheimer’s Drugs in Test-Tube Study.
THC, the key compound in marijuana, may also be the key to new drugs for Alzheimer’s disease.”While we are certainly not advocating the use of illegal drugs, these findings offer convincing evidence that THC possesses remarkable inhibitory qualities, especially when compared to [Alzheimer’s drugs] currently available to patients,” Janda says in a news release.

“Although our study is far from final, it does show that there is a previously unrecognized molecular mechanism through which THC may directly affect the progression of Alzheimer’s disease.”

“THC and its analogs may provide an improved [treatment for] both the symptoms and progression of Alzheimer’s disease,” the researchers conclude”

Read more: http://www.webmd.com/alzheimers/news/20061006/marijuana-may-slow-alzheimers

Marijuana may help stave off Alzheimer’s – NBCNews

“Active ingredient in pot may help preserve brain function.

Good news for aging hippies: smoking pot may stave off Alzheimer’s disease.

New research shows that the active ingredient in marijuana may prevent the formation of deposits in the brain associated with the degenerative disease.

Researchers at the Scripps Research Institute in California found that marijuana’s active ingredient, delta-9-tetrahydrocannabinol, or THC, can prevent an enzyme called acetylcholinesterase from accelerating the formation of “Alzheimer plaques” in the brain more effectively than commercially marketed drugs.

THC is also more effective at blocking clumps of protein that can inhibit memory and cognition in Alzheimer’s patients, the researchers reported in the journal Molecular Pharmaceutics.

The researchers said their discovery could lead to more effective drug treatment for Alzheimer’s, the leading cause of dementia among the elderly.

Those afflicted with Alzheimer’s suffer from memory loss, impaired decision-making, and diminished language and movement skills. The ultimate cause of the disease is unknown, though it is believed to be hereditary.

Marijuana is used to relieve glaucoma and can help reduce side effects from cancer and AIDS treatment.”

http://www.msnbc.msn.com/id/15145917/ns/health-alzheimers_disease/t/marijuana-may-help-stave-alzheimers/