Frontiers in Clinical Drug Research - Alzheimer Disorders: Volume 6 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Serie: Frontiers in Clinical Drug Research - Alzheimer Disorders
- Sprache: Englisch
Frontiers in Clinical Drug Research - Alzheimer Disorders is a book series concerned with Alzheimer's disease (AD) that causes dementia, or loss of brain function. The disease affects the parts of the brain that deal with memory, thought, and language. Chapters in each volume focus on (Alzheimer Disorders) drug research with special emphasis on clinical trials, research on drugs in advanced stages of development and cure for Alzheimer’s disease and related disorders.
Frontiers in Clinical Drug Research - Alzheimer Disorders will be of particular interest to readers interested in drug therapy of this specific neurodegenerative condition and related brain disorders as the series provides relevant reviews written by experts in field of Alzheimer’s Disease research.
The sixth volume of this series features chapters covering critical discussions on AD management and new therapies. The topics reviewed in this volume include:
- treatment of brain inflammation in Alzheimer’s disease with traditional medicine
- stem cell strategies for the modeling and therapy of Alzheimer’s disease
- retinal neurodegeneration in Alzheimer’s disease
- biological mass spectrometry for diagnosis of Alzheimer's disease
…and more.
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Seitenzahl: 360
Veröffentlichungsjahr: 2017
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Frontiers in Clinical Drug Research -
Alzheimer Disorders
(Volume 6)
Edited by:
Atta-ur-Rahman, FRS
BENTHAM SCIENCE PUBLISHERS LTD.
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PREFACE
The book series, “Frontiers in Clinical Drug Research – Alzheimer Disorders”, is intended to present the important advancements in the field in the form of cutting edge reviews written by experts. Volume 6 of this eBook series is a compilation of seven well written chapters contributed by prominent researchers in the field. It includes the treatment of brain inflammation, stem cell strategies, retinal neurodegeneration, pathophysiology of Alzheimer disease, and a number of other related areas.
Chapter 1 by Adams discusses the use of plant medicines as an alternative treatment to decrease the progression of Alzheimer’s disease (AD). In chapter 2, Haigang Gu describes the recent progress of stem cell strategies for AD modeling and therapy. Cordeiro et al. in chapter 3 focus on the retinal neurodegeneration in AD. The pathological similarities between AD and eye diseases are also discussed. In Chapter 4, Gupta & Jhawat highlight the pathophysiology of Alzheimer disease with respect to the current drug therapy.
In chapter 5, Abdelhamid and Wu present the use of biological mass spectrometry for the diagnosis of Alzheimer’s disease. This review also highlights the recent developments in disease diagnosis using mass spectrometry. Chapter 6 by Herrera emphasizes the structure-activity relationship of melanin as a source of energy. The last chapter by Suzuki et al., discusses the neuro-protective properties of the fungus Isaria japonica (IJ). The results showed that products derived from IJ may prevent or decrease the impact of dementia, especially AD.
The 6th volume of this book series represents the results of a huge amount of work by many eminent researchers. I am grateful to the authors for their excellent contributions. I would also like to express my gratitude to the editorial staff of Bentham Science Publishers, particularly Mr. Mahmood Alam (Director Publication), Mr. Shehzad Naqvi (Senior Manager Publications) and Ms. Fariya Zulfiqar (Assistant Manager Publications) for their hard work and persistent efforts.
List of Contributors
The Treatment of Brain Inflammation in Alzheimer’s Disease. Can Traditional Medicines Help?
James David Adams*Abstract
The blood brain barrier degenerates in many people as they age. This degeneration can lead to inflammation, amyloid accumulation, neuron loss, tangle accumulation and dementia. Damage to the blood brain barrier may involve oxygen radical production through a visfatin mediated mechanism. Several plant medicines have been traditionally used to decrease the progression of Alzheimer’s disease. Antioxidant mechanisms of action have been described for these medicines that may protect the blood brain barrier. These plant medicines provide alternative treatments for Alzheimer’s disease.
INTRODUCTION
Alzheimer’s disease (AD) involves neurodegeneration induced by amyloidβ. This neurodegeneration results in loss of neurons, plaque and tangle formation and ultimately in dementia. Many AD patients are treated with acetylcholinesterase inhibitors to slow the progression of mild AD. Eventually, most AD patients die from pneumonia and not neurodegeneration.
The current consensus is that AD is caused by amyloidβ toxicity in the brain [1]. It is clear that extracellular amyloidβ is toxic to neurons. Amyloidβ aggregates into fibrils, sheets and plaques. Some intermediate amyloid protein aggregates in the plaque formation process are toxic to neurons.
The role of inflammation in the pathophysiology of AD is well established [1]. Inflammation in AD can be secondary to amyloidβ accumulation. In other words, amyloidβ causes inflammation in the brain. Inflammation can also occur early in
the disease process and initiate amyloidβ accumulation and AD pathology [2]. This inflammation involves microglial cells, astrocytes, perivascular macrophages and monocytes that infiltrate into the brain [2]. There are a number of different inflammatory molecules that are produced in the brain in this inflammatory process and as a consequence of amyloidβ production including chemokines, complement molecules, cytokines, inflammatory and acute phase proteins, cyclooxygenase-2, and free radicals [2-5].
Tau phosphorylation leading to tangle formation may occur as the result of amyloidβ oligomer toxicity [1]. Microglial and astrocytic activation are also involved in alteration of tau phosphorylation [1]. Neurofibrillary tangles are frequently found in AD brains.
The question that remains unanswered is why does amyloidβ production increase in the brains of people who will develop AD? This question can be avoided by claiming that 100% of people will develop AD if they live long enough. In other words, amyloidβ accumulation is a natural process in the brain that cannot be avoided. However, many very old people do not develop AD.
Anti-inflammatory Agents in AD
Several epidemiological studies have examined the use of anti-inflammatory drugs in patients and have found that the use of these drugs may decrease the induction of AD. These studies have been critically reviewed [2, 5, 6]. The use of indomethacin was reported to slow the progression of AD [7]. This finding was later disputed [8]. Patients suffering from arthritis have a decreased risk of developing AD, perhaps because of their use of anti-inflammatory agents [9]. Several other reports have failed to show a protective effect of anti-inflammatory agents in the progression or development of AD. In addition, several attempts to slow the progression of AD with various anti-inflammatory drugs have failed to show an effect. It must be remembered that oral nonsteroidal anti-inflammatory agents (NSAIDs) are very toxic, especially to the elderly. NSAIDs have effects on prostaglandins, lipoxins, resolvins, thromboxanes and other lipid metabolites. NSAIDs cause strokes, heart attacks, kidney damage and ulcers. They cause 42,000 or more deaths in the US every year. NSAIDs should be avoided in trials that hope to delay the progression of AD. Steroids damage the hippocampus and should also be avoided [10]. Perhaps the choice of anti-inflammatory agent has been inappropriate so far. In addition, the doses chosen may have been inappropriate in past studies. The doses chosen were probably too high and induced too much toxicity.
Risk Factors for Developing AD
If all people get AD with age, then the only risk factor for developing AD should be age. However, there are other risk factors that increase the chance of developing AD. The risk factors for developing AD are age, head trauma, high blood pressure, high blood cholesterol, diabetes, cardiovascular disease, atrial fibrillation, apolipoprotein E4, thrombosis, peripheral inflammatory factors, decreased muscle mass and high alcohol consumption [11-13]. Women are more likely to develop AD than men [11-13]. Brain trauma can cause gliosis, inflammation and deleterious changes to the brain that may be important in AD. Peripheral inflammatory factors cause high blood pressure, high blood cholesterol, type 2 diabetes, cardiovascular disease, atrial fibrillation and thrombosis [14]. These peripheral inflammatory factors include adipokines made in visceral and ectopic fat that are released into the blood. Inflammatory adipokines include visfatin, leptin, resistin, tumor necrosis factor α, IL-6 and others.
As people age, visceral and ectopic fat deposits develop. Toxic lifestyles, including lack of exercise and over eating, cause fat accumulation. Ectopic fat is fat that surrounds arteries, infiltrates muscles and other sites. Visceral fat accumulates in the peritoneal cavity. Therefore risk factors for AD are probably high blood levels of inflammatory adipokines released by visceral and ectopic fat. Obesity has increased greatly since the 1980s as reported by the Centers for Disease Control (www.cdc.gov). The incidence of AD has also increased greatly since 1980, in parallel with the increase in visceral obesity [15]. According to the Centers for Disease Control, among the entire US population, 93,500 people died while affected with AD in 2014. The entire US population, age adjusted death rate from AD increased by 39% from 2000 through 2010.
Several studies found the incidence of AD decreased over the last 25 years or more by about 25% [16-19], in spite of the increases in obesity and type 2 diabetes. These studies were done in selected populations and point to better education and better treatment of heart disease as ways to prevent AD. This indicates that patients who are educated enough about risk factors for AD to seek out better health care and other healthy lifestyle practices have a decreased risk. Weight reduction can be part of a healthy lifestyle. All of these studies advise that patients who practice healthy lifestyles have a decreased risk of developing AD. Is the incidence of AD actually decreasing in the US? The answer is clearly that the incidence of AD is increasing in the total US population.
Apolipoprotein E4 transports lipids inside the brain, including cholesterol and triglycerides. When triglycerides accumulate, the alternative fat ceramide is made in greater amounts. Apolipoprotein E4 is made in astrocytes and transports lipids to neurons by interacting with receptors in the low density lipoprotein receptor family. Since apolipoprotein E4 is a risk factor for developing AD, lipids are probably important in the mechanism of induction of AD.
Muscles produce myokines such as adiponectin, irisin, IL-6, IL-8 and IL-15 [20]. These myokines stimulate lipolysis, decrease atherosclerosis and are anti-inflammatory. Muscle is also responsible for clearing some insulin and glucose from the blood. Loss of muscle tissue causes insulin levels to increase leading to insulin resistance, also known as type 2 diabetes. Loss of anti-inflammatory myokines may be important in the induction of AD.
Alcohol consumption leads to visceral fat and ectopic fat accumulation since alcohol activates sterol regulatory element binding protein [21]. Alcohol is an obesogen and can cause alcohol induced dementia, which is very similar to AD. In order to live long enough to develop AD, patients must not drink enough to result in death from a heart attack, stroke or cirrhosis.
Prevention of AD
Factors that decrease the onset and progression of AD include: regular physical activity, coffee consumption, moderate wine consumption, smoking and diets low in fat, high in fruit and vegetables [12, 22-24]. Diets high in fruit and vegetables have a major effect on gut bacteria that have a major effect on health.
Physical activity decreases visceral fat, ectopic fat in the muscles, increases glucose and insulin clearance from the blood and promotes heart health. Muscle health improves with physical activity. Healthy muscles secrete anti-inflammatory myokines. Exercise also stimulates stem cell growth in every organ including the adult human brain [25].
It is not entirely clear why coffee decreases the likelihood of developing AD. Caffeine has been shown to be neuroprotective in patients older than 65 [26]. Moderate wine consumption can improve heart health that may decrease the chances of developing AD. It is not clear why smoking decreases AD. Nicotine is toxic to the heart and arteries, and stimulates atherosclerosis. A study found that smoking may actually increase the risk of developing AD [27]. However, nicotine is also an appetite suppressant. Perhaps smokers have less visceral and ectopic fat than nonsmokers. It is also possible that smokers die of other things, like cancer and heart disease, before they develop AD. Nicotine has been shown to be neuroprotective in laboratory animal experiments [28].
Diets high in fruit and vegetables and low in fat can help decrease the likelihood of developing visceral fat [29]. Eating a good diet in combination with regular exercise is the basis of living in balance, a traditional concept. Living in balance allows the body to heal itself [30].
Prevention of AD with education, proper diet, proper weight and regular exercise is the best medicine for AD. As people age, exercise becomes more difficult due to loss of muscle tissue, a normal aspect of aging. However, gentle exercise such as walking can still be done. During aging, the body switches from making subdermal fat to making visceral and ectopic fat. Eating less and eating better food becomes critical at this time. Aging patients, after the age of 60 or so, should weigh less than when they were 20 or so, due to loss of muscle tissue. Aging causes loss of muscle, brain and bone tissue. Prevention of AD should become the normal medicine for everyone.
Ceramide and AD
Lipids and lipid metabolites can be pharmacologically active. Ceramide is a lipid that is pharmacologically active and becomes much more abundant in the body during visceral obesity [14]. High serum ceramide levels increase the risk of developing AD [31]. Ceramide levels are high in AD brain compared to control brain [32]. Ceramide increases in astrocytes and microglial cells in proximity to capillary amyloid deposits in AD [33]. Amyloidβ activates the production of ceramide in some neurons, which implies that ceramide may be involved in the downstream mechanism of amyloidβ toxicity [32]. Ceramide stabilizes β-secretase, the enzyme that makes amyloidβ [34]. Amyloidβ then activates sphingomyelinases to increase cellular ceramide levels even more [34]. Therefore, ceramide may cause the formation of amyloidβ, or amyloidβ may cause the formation of ceramide. It is most likely that visceral and ectopic fat increase ceramide throughout the body and the brain, leading to increased amyloidβ production.
Ceramide induces nitric oxide synthase, both the endothelial (eNOS) and inducible (iNOS) forms [14]. However, the induced iNOS and eNOS also dysfunction in the presence of ceramide leading to oxygen radical and peroxynitrite formation. This oxidative stress damages astrocytes and endothelial cells, leading to a damaged blood brain barrier that allows monocytes and neutrophils to penetrate into the brain. Ceramide increases amyloidβ in the brain that induces NADPH oxidase (NOX) on macrophages, monocytes and neutrophils that penetrate the blood brain barrier. NOX forms extracellular hydrogen peroxide that damages neuronal DNA, causes cell death and activates neutral sphingomyelinase, which makes more ceramide.
The Blood Brain Barrier and AD
The blood brain barrier is formed by endothelial cells that restrict the entry of many molecules into the brain and are joined by tight junctions. Astrocytes wrap their foot processes around the endothelial cells and are involved in maintaining the blood brain barrier. Pericytes are contractile cells involved in sustaining the blood brain barrier as well.
It is clear that atherosclerosis of arteries in the blood brain barrier and other sites increases with aging and visceral adiposity, as does the incidence of AD [14]. Pericytes in the blood brain barrier degenerate in AD and a mouse model of AD, resulting in decreased clearance of amyloidβ from the brain [35]. The blood brain barrier becomes leaky and allows serum proteins and inflammatory cells to enter the brain. These inflammatory cells are mostly monocytes [2].
Glucose enters into the brain mostly due to the actions of glucose transporters, such as GLUT1, on endothelial cells. AD patients have decreased GLUT1 activity in their cerebral microvessels [36]. This means there is diminished glucose entry into the brain in AD. Decreased GLUT1 causes the induction of sterol regulatory element binding protein2 in the brain, which decreases amyloidβ clearance from the brain [36].
Visfatin and AD
How does the blood brain barrier become damaged in AD? Visfatin is an inflammatory adipokine that increases in AD patients [37]. Blood born visfatin and xanthine dehydrogenase found on endothelial cells of the blood brain barrier catalyze the formation of oxygen radicals and hydrogen peroxide at the blood brain barrier [37]. This and ceramide induced oxygen radical formation damage endothelial cells and pericytes. Some plant derived compounds, such as quercetin and resveratrol, inhibit the release of visfatin from adipocytes [38]. This may decrease blood brain barrier damage.
Other adipokines are present in the blood, including monocyte chemoattractant protein-1, which causes monocytes to stick to damaged endothelial cells. Visfatin also induces monocyte chemoattractant protein-1 [39]. Monocytes secrete adhesion proteins that cause more monocytes to adhere to the blood brain barrier. These cells then penetrate into the brain and increase the inflammatory response.
Traditional Plant Medicines for AD
Before the advent of modern medicine, people suffered from AD [40]. Healers found plant medicines that helped old patients with short-term memory loss remain productive awhile longer. Table 1 presents a list of several of these plant medicines [41]. Several anti-inflammatory plant medicines are discussed below. Many people have used these plant medicines and still developed AD. These plant medicines must be used in combination with lifestyle changes to prevent or delay the progression of AD.
Angelica sinensis, Angelica pubescens and other Angelica species are used in the treatment of AD. Angelica species contain several coumarins including umbelliferone, umbelliferone 6-carboxylic acid, scopoletin, isoscopoletin, 7-methoxy coumarin, 2’-isopropyl psoralene, scoparone, scopolin and esculetin [42]. Umbelliferone 6-carboxylic acid and esculetin inhibit acetylcholinesterase and β-site amyloid precursor protein cleaving enzyme 1 also called β-secretase 1 [42]. This means that Angelica plant medicines are useful for treating AD since they may enhance brain acetylcholine and decrease brain amyloidβ. Angelica also contains ligustilide that is anti-inflammatory, decreases cortical and hippocampal nerve damage, decreases astrocyte activation and protects the blood brain barrier [43, 44]. Ferulic acid is also found in Angelica plants, inhibits amyloid fibril formation and is an antioxidant, free radical scavenger [45]. Angelica plants contain furanocoumarins that can cause photosensitivity [46]. These plants are used daily by many people in China with no reports of adverse effects. Angelica is also present in Benedictine and other liqueurs that are consumed daily by many people around the world.
Astragalus propinquus is used in China to treat AD. Astragalus extracts improve learning and memory in a mouse model of AD [47]. Astragaloside IV purified from the plant protects against amyloidβ toxicity by protecting mitochondria and protects the blood brain barrier [48, 49]. Extracts of the plant have been found to enhance telomerase activity in patients [50]. Cycloastragenol found in the plant is a telomerase activator. Telomerase lengthens telomeres. There is some evidence that telomeres may be short in AD patients. However, telomerase knock out mice are protected from amyloidβ pathology [51]. Plant medicines made from Astragalus are used daily in doses up to 40 grams with no reports of adverse effects.
Fermented Codonopsis pilosula, dang shen, can enhance learning and memory in rats [52]. Extracts of plants of the Codonopsis genus have been shown to inhibit acetylcholinesterase [53]. Codonopsis contains hesperidin and atractylenolide [54]. Hesperidin is an inhibitor of β-secretase, prevents amyloid fibril formation [55] and protects against aluminum chloride induced cognitive dysfunction [56]. Hesperidin also attenuates learning and memory deficits and suppresses inflammation by activation of Akt/Nrf2 and inhibition of RAGE/NFkB [57]. Plant medicines made from Codonopsis are used daily, safely by many people. However, the medicine can interfere with blood clotting in some patients [58].
Crocus sativus, saffron, is comparable to memantine in the treatment of moderate to severe AD [59]. It is also comparable to donepezil in the treatment of mild to moderate AD [60]. Crocin, an anti-inflammatory ingredient from the plant, increases long-term potentiation in hippocampal neurons and prevents amyloid fibril formation [61]. Crocin is also neuroprotective and anti-inflammatory by inhibition of sphingomyelinase, which decreases ceramide production [62]. This implies that Crocus plant medicines may protect the blood brain barrier by decreasing ceramide. Crocin also decreases microglial cell activation and inflammatory cytokine production in the brain through inhibition of Notch signaling [63]. Crocetin, another active ingredient, may inhibit acetylcholine-sterase [61]. Saffron is a spice that is consumed daily by many people around the world with no reports of toxicity. Plant medicines made from saffron are safe.However, consumption of 20 g of saffron can be toxic or even lethal to humans [64].
Dipsacus asper, xuduan, is related to teasel and contains saponins such as akebia saponin D. The total saponins and akebia saponin D protect neuronal cells from amyloidβ toxicity [65]. Akebia saponin D also attenuates the loss of memory in rats, injected intracerebroventricularly (ICV) with amyloidβ [67]. The saponin appears to alter Akt and NFkB pathways [66]. A saponin has been found to protect the blood brain barrier [67]. Although an extract of Dipsacus has been shown to have procoagulant effects on isolated platelets, there are no reports of clot problems in humans that use the medicine [68].
Glycyrrhiza glabra, licorice, water extract protects mice from ICV amyloidβ toxicity [69]. 2,2',4'-Trihydroxychalcone, an active ingredient in the plant, is an inhibitor of β-secretase, improves memory and decreases plaque formation in a mouse AD model [70]. Liquiritin, a flavanone glucoside from the plant, is neuroprotective through modulation of ERK and AKT/GSK-3β pathways [71]. Glycyrrhizic acid is neuroprotective by inhibition of oxidative stress and voltage gated sodium channels in the hippocampus and protects the blood brain barrier [72, 73]. Licorice is a food, candy and spice that is consumed daily by many people with no safety problems. Consumption of very large amounts of licorice results in hypertension and hypokalemia [74].
Heteromeles arbutifolia, toyon or California holly, is a traditional medicine used in the treatment of AD [40, 41]. The plant contains betulin, icariside E4, farrerol and other active compounds [40]. Farrerol protects endothelial cells in the blood brain barrier [75]. Other flavonoids in the plant, such as catechin, stimulate the nonamyloidogenic cleavage of amyloid precursor protein [76]. Betulin prevents sterol regulatory element binding protein activation [77], which may help control perivascular fat in the brain. Icariside compounds protect the blood brain barrier, prevent inflammatory cells from entering the brain and prevent neuronal damage [78]. Toyon is a food that can be consumed in large amounts daily with no adverse reactions.
Indigofera tinctoria, true indigo, extracts prevent neuronal death in the hippocampus after ICV injection of amyloidβ into mice [79]. A plant extract improves memory in scopolamine treated mice and has antioxidant activity [80]. Gallic acid, quercitrin and myricetin are found in the plant [81]. Gallic acid, catechin and similar compounds decrease amyloid fibril deposition and decrease brain inflammation in a mouse model of AD [82]. Myricetin, a flavonoid, inhibits β-secretase [83] and is neuroprotective. Some flavonoids have been found to protect the blood brain barrier [84]. The plant medicine made from Indigo is widely used in Africa where it is considered a safe remedy. However, the plant medicine was reported to cause multiple organ failure and death in a child [85].
Lycium barbarum, goji berry, extracts protect cultured neurons from amyloidβ toxicity [86]. Polysaccharides may be the protective compounds present in the berries [87] and have been shown to decrease tau phosphorylation [88]. Hyperphosphorylation of tau may lead to tangle formation in AD. Goji berries have been used for centuries in China to treat diseases of old age. The plant medicine made from Lycium is safe and is used daily by many people. However, extracts of the plant can cause hypoglycemia in experimental animals [89]. This suggests that diabetics should use the plant medicine with caution if at all.
Paeonia alba, peony, contains paeoniflorin that is an anti-inflammatory monoterpene glycoside. Paeoniflorin decreases plaque formation, downregulates tumor necrosis factorα and interleukin-1β in the brain, decreases activation of microglia and astrocytes in a mouse AD model [90]. Paeoniflorin also protects the blood brain barrier [91]. These effects may involve inhibition of suppressor of cytokine signaling 2 [92]. Ursolic acid is present in the plant and decreases memory deficits caused by ICV injection of amyloidβ [93]. Paeonol, a phenolic compound, is anti-inflammatory due to inhibition of toll-like receptor 2 and 4 [94]. Peony also contains several antioxidant flavonoids. Peony is a very popular remedy in China that is used safely, daily by many people. It can cause mild diarrhea in some cases [95].
Rhodiola crenulata extracts are adaptogens that help balance the body. Salidroside, a monoterpene glucoside found in the plant, has antioxidant activity and protects cells from amyloidβ toxicity [96]. The compound decreases reactive oxygen species, inhibits NADPH oxidase, inhibits the expression of iNOS and COX2, and stimulates JNK and p38 MAP kinase pathways [97, 98]. Salidroside also protects the blood brain barrier [99]. Extracts of the plant protect neural stem cells by an antioxidant mechanism and improve hippocampal neurogenesis [100]. Proanthocyanidins found in the plant inhibit amyloid aggregation [101]. The use of Rhodiola plant medicine has been reported to cause occasional mild adverse reactions, such as indigestion.
Schisandra chinensis fruit contains several dibenzocyclooctadiene lignans including schisandrin, schisantherin A, schisandrin B and schisandrin C. The lignans, schisandrin B and C protect against amyloidβ toxicity and decrease reactive oxygen species in cultured neurons, and in mice injected ICV with amyloidβ [102-104]. An extract of the fruit protects against ICV amyloidβ induced memory loss in mice, inhibits β-secretase and acetylcholinesterase [105]. Schisandrin B inhibits toll like receptor 4 signaling and decreases microglia-induced neuroinflammation [106]. Schisantherin A, schisantherin B, schisandrin and schisandrin A (deoxyschizandrin), used individually, improve memory loss induced by ICV amyloidβ injection in mice, perhaps through antioxidant mechanisms [107-110]. Isocubebenol, a sesquiterpene isolated from the fruit, inhibits acetylcholinesterase and is neuroprotective [111]. Schisandra plant medicine has not been reported to cause significant adverse reactions.
The Modern Approach to Curing AD
Several drug candidates have been tested in AD clinical trials. Active vaccines against amyloidβ have failed [1]. Solanezumab, a monoclonal antibody against soluble amyloidβ, failed [112]. Another monoclonal antibody, aducanumab is in trial as of Spring, 2017. It is not clear how antibodies against amyloid could remove deposits of amyloidβ from the brain, since they do not cross the blood brain barrier. Gamma-secretase inhibitor trials have failed [1]. CHF5074, a gamma-secretase inhibitor, did not improve health in 96 patients with mild cognitive impairment [113]. The beta-secretase inhibitor, verbucestat, failed in clinical trial. Pioglitazone, a peroxisome proliferator activated receptor gamma agonist, improved cognition in 21 patients with mild AD, but suffers from hepatoxicity and can induce bladder cancer [114]. Bexarotene, a retinoid X receptor agonist, did not improve amyloid burden in AD patients [115].
Concluding Remarks
Prevention is the best medicine for AD. Many people live long lives without developing AD, perhaps because they live healthy lifestyles that prevent the disease. Plant medicines have been traditionally used for thousands of years to delay the progression of AD. These plant medicines should be used in the traditional way, as crude plant extracts, not as single purified agents. Thousands of years of experience has shown the proper way to use these medicines. Each plant has several active compounds that may work together to delay disease progression. The mechanisms of action of several plant medicines involve decreasing inflammation and protecting the blood brain barrier. However, the use of single purified drugs, derived from plants, has been successful in delaying the progression of AD, such as galantamine, an acetylcholinesterase inhibitor from Galanthus caucasicus. Many of the compounds discussed are anti-inflammatory agents that are not cyclooxygenase inhibitors and offer a better approach to the treatment of AD.
CONFLICT OF INTEREST
The author declares no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENT
Declared none.
