By the year 2021, an estimated 1m people in the UK will be affected by dementia. The cost of treating them has been put at £23bn/year – more than five times the current cost of cancer or heart disease. Despite this prognosis, only a handful of drugs have been approved to alleviate cognitive symptoms. Two of these drugs – galantamine (Nivalin, Razadyne) and rivastigmine (Exelon) – involve chemicals associated with plants: snowdrop and daffodils; and the African leguminous plant Physostigma venenosum, respectively (Drugs Aging, 2011, 28(6), 439).
Many more drug leads from plants await discovery. ‘In the past 25 years more than 50% of newly introduced drugs have come from natural sources – not necessarily the original chemical but some kind of analogues,’ says Elaine Perry, a plant scientist and emeritus professor at Newcastle University, UK. About 40% of prescribed drugs, meanwhile, come from or are synthesised from a plant chemical.
Perry and coworkers, along with a number of scientists, have been studying a class of phytochemicals thought to protect against, or treat symptoms of, dementia known as alkaloids, which includes galantamine, nicotine from tobacco plants and physostigmine from the seeds of P. venenosum.
‘Almost 50% of the plant-derived natural products that are pharmaceutically and biologically significant are alkaloids,’ according to Melanie-Jayne Howes, a research pharmacist at the Royal Botanic Gardens, Kew, London, UK, who has worked with Perry on a number of plant projects including the recent analysis of the lemon-scented herb Melissa officinalis. ‘Although other classes of phytochemicals have been lead chemical structures for drug development, numerous alkaloids have provided template chemical structures important for drug discovery; therefore plant families that contain alkaloids are of interest as potential sources of new pharmaceuticals.’
In the case of Alzheimer’s disease (AD), which accounts for more than half of all dementia cases, plant-derived phytochemicals have been identified and shown promising activity for treating all three pathological mechanisms: the deposition of amyloid plaques, formation of tangles of tau protein filaments, and particularly in addressing deficits of acetylcholine and other key nerve signalling molecules or neurotransmitters in the brain.
Rivastigmine, for example, licensed for the treatment of mild to moderate dementia in AD or Parkinson’s disease, is a safer and more effective synthetic analogue of the plant alkaloid physostigmine. Galantamine and rivastigmine both inhibit the enzyme acetylcholinesterase (AChE), which catalyses the hydrolysis of the neurotransmitter acetylcholine, so the action of acetylcholine is prolonged in the brain by these drugs (Nat. Prod. Rep., 2011, 28, 48). Cholinergic deficits, including low levels of acetylcholine, are a hallmark of Alzheimer’s disease. Rivastigmine also inhibits another cholinesterase enzyme, butyrylcholinesterase. Only one drug currently approved for treating dementia – memantine – does not act as a cholinesterase inhibitor but is a glutamate receptor antagonist.
Discovering new drug leads from plants has the advantage that, in many cases, these compounds have been tried and tested for years; or as Perry phrases it: ‘riding on the back of age old legacies of safety as for most plant medicines has obvious advantages.’
But there are also problems. One of the biggest of these concerns a lack of research funding, because of a lack of financial incentive for companies to pursue complex mixtures of plant chemicals that cannot be patented, Perry explains. A typical plant oil or extract will contain thousands of chemicals, from which the key active ingredient – as in the case of galantamine – must be isolated, identified and evaluated for safety and efficacy for patenting.
Sustainability, biodiversity conservation and intellectual property concerns are other issues that need to be addressed if plants are to be harvested for their phytochemicals at scale, according to Howes. And there are also technical challenges, she adds, ‘such as inadequate yields of required chemicals from plant sources, expense and time to purify and isolate required chemicals, which may be impractical to synthesise, and potential difficulties with patenting’.
Despite the barriers, however, chemicals from plants continue to surprise. The spice saffron, for example, from the flower Crocus sativus includes carotenoid compounds called crocins – a series of sugar esters of the dicarboxylic acid crocetin – which have a range of activities linked to memory and learning. AD patients treated with saffron in two randomised controlled trials for 16 or 22 weeks were reported to show comparable improvements in cognition, with fewer adverse effects, than those administered the AChE inhibitor drug donepezil.
At Dilston Physic Garden in Northumberland alone, meanwhile, Perry estimates that there are 800 different plant species, potentially containing 160,000 chemicals – most of which have yet to be explored for their medicinal properties. Extrapolated globally, there are 260,000 species of flowering plants – potentially containing as many as 52m chemicals.
Memory boost from plants
The poisonous seeds of the native African leguminous plant, calabar beans were used historically to assess guilt of suspected criminals: if the individual died, they were deemed guilty; if they survived they were proven innocent. The main compound responsible for their toxicity is the pyrroloindole alkaloid physostigmine, a reversible inhibitor of AChE, which was originally isolated in the 19th century.
While physostigmine boosts brain functioning in animal studies, there is little evidence of its effectiveness for Alzheimer’s disease and adverse effects are common. However, the compound structure has become a useful template for the development of many other, safer, analogues, including the licensed drug rivastigmine, used for the treatment of mild to moderate dementia in Alzheimer’s and Parkinson’s diseases.
Other physostigmine analogues in development include phenserine, an inhibitor of both AChE and amyloid precursor protein; and tolserine, a C2ʹ methyl substitute of phenserine with improved selectivity for AChE.
Sage and Lemon balm
These herbs belong to the Lamiaceae family, which also includes the culinary herbs mint, rosemary and basil. Sage and lemon balm contain the active phytochemical rosmarinic acid, a phenolic carboxylic acid with a range of useful biological activities, for example, antibacterial, antiviral, antioxidant and anti-inflammatory, as well as anxiety-reducing effects.
The use of sage (Salvia species) for medicinal purposes dates back to the 16th and 17th century, and supplements for memory loss can today be bought in health food stores.
Different Salvia species have been shown to have a range of effects on the central nervous system (CNS), including memory enhancing, neuroprotective and anti-Parkinsonian activities (CNS Neurosci. & Therap., 2011, 17, 683).
Alzheimer’s patients treated with extracts of either Salvia lavandulaefolia, or S. officinalis, have been reported to show improved cognitive and memory performance, while young healthy adults also demonstrated immediate improved word recall along with other cognitive improvements as well as positive effects on mood.
Monoterpenoid compounds including 1,8-cineole and α-pinene in the Salvia extracts are known to inhibit the enzyme AChE.
Like sage, the lemon-scented leaves of the herb Melissa officinalis also have a long history as a traditional remedy, in this case to treat melancholia, neuroses and hysteria. Melissa is also acclaimed for promoting long life and restoring memory.
Essential oils from the plant have been reported to improve cognitive performance against placebo in separate clinical trials in healthy individuals and in Alzheimer’s patients treated with M. officinalis extract for four months.
The mechanism of action is believed to involve inhibition of AChE, but it also binds to receptors that suggest it may modulate the effects of other neurotransmitters, with potential to alleviate both cognitive and the behavioural and psychological symptoms of dementia. The oil has antioxidant properties and may also have some hormonal effects.
The leaves of the ancient Ginkgo biloba tree have been the subject of numerous clinical studies, with many trials in both Alzheimer’s and healthy individuals indicating a modest improvement in cognitive ability. Many studies have focused on a standardised extract of G. biloba known as EGb-761, containing flavonoid glycosides and terpenoid lactones among other constituents.
EGb-761 is known to aid blood flow to the brain, and to have favourable effects on neuronal cell metabolism and the cholinergic neuronal system. It also protects nerves from damage by nitric oxide radicals and β-amyloid induced toxicity. Other extracts improve cognition in young and old rats, short-term memory in mice and spatial learning and memory in rats with aluminium-induced brain dysfunction; and reduce cognitive impairment in brain-damaged rats.
Ginkgo supplements are sold in Europe as an aid to memory. Cognitive activities may be due to effects on cholinergic function and by affecting other neurotransmitter systems.
Gingko extracts are widely used for many conditions, for example, tinnitus, premenstrual tension, intermittent claudication, without significant adverse side-effects. However, the use of Ginkgo with antiplatelet or anticoagulant medicines should be avoided as it may increase the risk of bleeding.
Long used as a folk medicine for memory loss and circulatory disorders, the lesser periwinkle (Vinca minor) contains a variety of alkaloid compounds reported to be helpful for the treatment of vascular dementia caused by blood supply problems. Vascular dementia is the second most common form of dementia after Alzheimer’s disease. The alkaloid vincamine found in the plant, and vincanol and vinpocetine derived from it, increase blood flow to the brain, block sodium ion channels and protect nerve cells from damage.
Patients with mild to moderate dementia who received vinpocetine over a 16-week trial period were reported to show significant benefit. Vinpocetine has also been found to improve cognitive functioning in stroke patients, although there is insufficient evidence to support its clinical use in cognitive disorders.
Daffodils and Snowdrops
Plants such as daffodils (Narcissus species) and snowdrops (Galanthus species) contain galantamine, an alkaloid licensed for the treatment of mild to moderate dementia in Alzheimer’s disease. Surprisingly, however, there is no record of their use as a traditional remedy for age-related brain and memory disorders, as the compound causes severe stomach upsets after ingestion.
Found in the plant bulbs, galantamine was probably biosynthesised as a plant defence mechanism to deter predators and target insect nervous systems, a mode of action that also explains the drug’s side-effects including nausea, vomiting and diarrhea.
Galantamine is a well documented AChE inhibitor and also affects nicotinic receptors linked to memory and learning. Numerous synthetic galantamine derivatives have been developed, including some that are even more potent AChE inhibitors. Memogain, a prodrug of galantamine, improves cognition more effectively and has fewer side effects.
The moss Huperzia serrata has been used as a traditional Chinese medicine for treating and preventing dementia. It contains the alkaloid huperzine A, a potent AChE inhibitor, which is neuroprotective and linked to reported improvements in memory and learning.
Huperzine A is claimed as eight-fold and two-fold more effective than the AD drugs donepezil and rivastigmine, respectively, in increasing levels of acetylcholine in the brain, with a more prolonged action.
It is also claimed to protect nerve cells against β-amyloid peptide toxicity and free radical damage. In several clinical trials, the compound improved memory in elderly and AD patients, with few adverse effects.
In 1996, a tablet formulation of huperzine A (Shuangyiping) was developed in China and used for symptomatic treatment of AD. The chemical is also sold as powdered H. serrata supplements for memory loss in the US.
A prodrug of huperzine A, Debio 9902 (ZT-1), was effective when administered once-daily to AD patients in a Phase 2 clinical trial.
Evidence for the benefits of the anti-ageing ‘panacea’ ginseng in dementia is mixed, though generally positive.
While some studies have shown increases in attention span, abstract thinking and information processing in healthy volunteers, others have shown no quantifiable effects on memory. This may be due to differences in the compositions tested, as ginseng refers to any one of several plants belonging to the genus Panax, which have different chemical profiles.
Phytochemicals associated with biological activities are found in the roots of Panax species, and include ginsenosides, which are triterpenoid saponins.
Numerous in vivo studies report how individual ginsenosides reduce or prevent memory deficits associated with the cholinergic system, with ginsenosides Rg1 and Rb1 in particular demonstrated to improve learning and memory in animal studies and enhance acetylcholine levels in the CNS.
Based on the results from two clinical trials, Panax ginseng may improve cognitive functions in AD patients; however, evidence for its efficacy in AD is still inconclusive.
Cath O’Driscoll is deputy editor of C&I