By Vince Giuliano
Like the previous two blog entries Dietary factors and dementia – Part 1: important recent researchandDietary factors and dementia Part 2: possible interventions, this blog entry is focused on research during the last two years relating dietary substances and supplements to late-onset dementias including Alzheimer’s disease, and to the potential roles of such substances for prevention or treatment of dementia. The Part 1 blog entry deals with research on a variety of subtopics such as the value of the relationship of dementia to diabetes, the role of oxidative stress in AD and, generally when and how diet can make a difference. The Part 2 blog entry describes research on possible interventions that could delay, prevent or cure dementia or Alzheimer’s disease including ingesting fatty acids and following a Mediterranean diet. This present blog entry describes research during the last three years on how sixteen different plant-derived substances have been shown in-vitro and in transgenic mouse models to inhibit the formation of or enhance the clearance of beta amyloid or to reverse other symptoms of Alzheimer’s disease. It also describes how supplementation with a specific combination of such supplements has been shown to clear up symptoms of Alzheimer’s disease in a transgenic mouse model.
At least sixteen plant-derived substances have been shown in-vitro and in transgenic mouse models to inhibit the formation of or enhance the clearance of beta amyloid or to reverse other symptoms of Alzheimer’s disease, including fermented papaya, L-3-n-butylphthalide, olive oil, tetrahydrocurcumin, aged garlic extract, green tea, cinnamon extract , the mushroom Hericium erinaceus, olive bark, piperine, bacopa monnieri, purple rice berry, oroxylin A, silymarin, silibinin, and resveratrol.
The 2010 publication Applications and bioefficacy of the functional food supplement fermented papaya preparation reports: “Fermented papaya preparation (FPP) (a product of yeast fermentation of Carica papaya Linn) is a food supplement. Studies in chronic and degenerative disease conditions (such as thalassemia, cirrhosis, diabetes and aging) and performance sports show that FPP favorably modulates immunological, hematological, inflammatory, vascular and oxidative stress damage parameters. Neuroprotective potential evaluated in an Alzheimer’s disease cell model showed that the toxicity of the β-amyloid can be significantly modulated by FPP. Oxidative stress trigger apoptotic pathways such as the c-jun N-terminal kinase (JNK) and p38-mitogen activated protein kinase (MAPK) are preferentially activated by pro-inflammatory cytokines and oxidative stress resulting in cell differentiation and apoptosis. FPP modulated the H₂O₂-induced ERK, Akt and p38 activation with the reduction of p38 phosphorylation induced by H₂O₂. FPP reduces the extent of the H₂O₂-induced DNA damage, an outcome corroborated by similar effects obtained in the benzo[a]pyrene treated cells. No genotoxic effect was observed in experiments with FPP exposed to HepG2 cells nor was FPP toxic to the PC12 cells. Oxidative stress-induced cell damage and inflammation are implicated in a variety of cancers, diabetes, arthritis, cardiovascular dysfunctions, neurodegenerative disorders (such as stroke, Alzheimer’s disease, and Parkinson’s disease), exercise physiology (including performance sports) and aging. These conditions could potentially benefit from functional nutraceutical/food supplements (as illustrated here with fermented papaya preparation) exhibiting anti-inflammatory, antioxidant, immunostimulatory (at the level of the mucus membrane) and induction of antioxidant enzymes.”
The 2011 publication L-3-n-butylphthalide improves cognitive impairment and reduces amyloid-beta in a transgenic model of Alzheimer’s disease reports “Alzheimer’s disease (AD) is an age-related, progressive neurodegenerative disorder that occurs gradually and results in memory, behavior, and personality changes. L-3-n-butylphthalide (L-NBP), an extract from seeds of Apium graveolens Linn (Chinese celery), has been demonstrated to have neuroprotective effects on ischemic, vascular dementia, and amyloid -beta (Abeta)-infused animal models. — In the current study, we examined the effects of L-NBP on learning and memory in a triple-transgenic AD mouse model (3xTg-AD) that develops both plaques and tangles with aging, as well as cognitive deficits. Ten-month-old 3xTg-AD mice were given 15 mg/kg L-NBP by oral gavage for 18 weeks. L-NBP treatment significantly improved learning deficits, as well as long-term spatial memory, compared with vehicle control treatment. L-NBP treatment significantly reduced total cerebral Abeta plaque deposition and lowered Abeta levels in brain homogenates but had no effect on fibrillar Abeta plaques, suggesting preferential removal of diffuse Abeta deposits. Furthermore, we found that L-NBP markedly enhanced soluble amyloid precursor protein secretion (alphaAPPs), alpha-secretase, and PKCalpha expression but had no effect on steady-state full-length APP. Thus, L-NBP may direct APP processing toward a non-amyloidogenic pathway and preclude Abeta formation in the 3xTg-AD mice. The effect of l-NBP on regulating APP processing was further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human APP(695) (SK-N-SH APPwt). L-NBP treatment in 3xTg-AD mice also reduced glial activation and oxidative stress compared with control treatment. L-NBP shows promising preclinical potential as a multitarget drug for the prevention and/or treatment of Alzheimer’s disease.”
“Oleic acid is a fatty acid that occurs naturally in various animal and vegetable fats. It is an odorless, colourless oil, although commercial samples may be yellowish. In chemical terms, oleic acid is classified as a monounsaturatedomega-9fatty acid. — The term “oleic” means related to, or derived from, oil or olive, the oil of which is predominantly derived from oleic acid(ref).” The May 2011 publication Oleic acid ameliorates amyloidosis in cellular and mouse models of Alzheimer’s disease reports: “Several lines of evidence support protective as well as deleterious effects of oleic acid (OA) on Alzheimer’s disease (AD) and other neurological disorders; however, the bases of these effects are unclear. Our investigation demonstrates that amyloid precursor protein (APP) 695 transfected Cos-7 cells supplemented with OA have reduced secreted amyloid-beta (Aβ) levels. — An early-onset AD transgenic mouse model expressing the double-mutant form of human APP, Swedish (K670N/M671L) and Indiana (V717F), corroborated our in vitro findings when they were fed a high-protein, low-fat (18% reduction), cholesterol-free diet enriched with OA. These mice exhibited an increase in Aβ40/Aβ42 ratio, reduced levels of beta-site APP cleaving enzyme (BACE) and reduced presenilin levels along with reduced amyloid plaques in the brain. The decrease in BACE levels was accompanied by increased levels of a non-amyloidogenic soluble form of APP (sAPPα). Furthermore, the low-fat/+OA diet resulted in an augmentation of insulin-degrading enzyme and insulin-like growth factor-II. These results suggest that OA supplementation and cholesterol intake restriction in a mouse model of AD reduce AD-type neuropathology.”
Another relevant publication is the August 2011 item Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against amyloid-β-induced toxicity. Involvement of the NF-κB signaling which relates: “Alzheimer’s disease (AD) is the most common form of dementia. Recently, a number of epidemiological studies have evidence that some dietary factors such as low antioxidants and vitamins intake could increase the risk of AD. In the opposite, diets rich in unsaturated fatty acids, in polyphenols, vitamins and antioxidants were identified as preventive factors. Several studies have reported that adherence to the Mediterranean diet (MeDi) was associated with a reduction in incident of dementia. The beneficial effect of MeDi may be the result of the association of some individual and non-identified food components and high consumption of olive oil. In this study we have investigated the protective effects of two components of olive oil, tyrosol (Tyr) and hydroxytyrosol (OH-Tyr), against Aβ-induced toxicity. In cultured neuroblastoma N2a cells, we found that Aβ(25-35) (100 µg/ml) treatment induced a decrease of glutathione (GSH) and the activation of the transcription factor NF-κB and cell death. Our results demonstrated that the number of cell death decreased when cells were co-treated with Aβ and Tyr or OH-Tyr. However, neither of these phenolic compounds was able to prevent the decrease of GSH induced by H(2)O(2) or Aβ. We found that the increase in the nuclear translocation of the NF-κB subunits after Aβ exposure was attenuated in the presence of Tyr or OH-Tyr. These results identified two individual food components of the MeDi as neuroprotective agent against Aβ and their potential involvement in the beneficial effect of the MeDi for the prevention of AD.”
The May 2011 report Olive oil reduces oxidative damage in a 3-nitropropionic acid-induced Huntington’s disease-like rat modelrelates: “Free radicals contribute to altered neuronal functions in neurodegenerative diseases and brain aging, by producing lipid- and other molecule-dependent modifications. The Mediterranean diet has been associated with a reduced risk of neurodegenerative disease. This study sought to verify whether extra-virgin olive oil (EVOO) exerted a brain antioxidant effect, protecting the brain against the oxidative stress caused by 3-nitropropionic acid (3NP). 3NP was administered intraperitoneally (i.p.) at a dose of 20 mg/kg body weight over four consecutive days. EVOO (representing 10% of calorie intake in the total standard daily diet of rats) and hydroxytyrosol (HT; 2.5 mg/kg body weight) were administered for 14 days. In all studied samples, 3NP caused a rise in lipid peroxides (LPO) and a reduction in glutathione (GSH) content. While the results showed that EVOO and HT reduces lipid peroxidation product levels and blocks the GSH depletion prompted by 3NP in both striatum and rest of the brain in Wistar rats. In addition, EVOO blocks and reverses the effect of 3NP on succinate dehydrogenase activity. In brief, the data obtained indicate that EVOO and HT act as a powerful brain antioxidant.”
The January 2011 publication Tetrahydrocurcumin confers protection against amyloid β-induced toxicity reports: “Amyloid plaques and neurofibrillary tangles are the hallmarks of Alzheimer’s disease. Amyloid β, a primary component of the amyloid plaques, is neurotoxic. Considerable attention has been directed toward identifying compounds with neuroprotective properties. Using rat primary hippocampal cultures, we show that tetrahydrocurcumin (THC), a metabolite of curcumin, shows a protective effect against oligomeric amyloid-β-induced toxicity. We further show that THC reduces amyloid-β-induced (i) increase in the level of reactive oxygen species, (ii) decrease in mitochondrial membrane potential, and (iii) caspase activation. In addition, we show that THC protects human neurons from oligomeric amyloid-β-induced toxicity as well. Thus, THC confers protection against amyloid-β-induced toxicity, and the antioxidant activity may contribute to its protective effect.”
The August 2010 blog entry Neurogenesis, curcumin and longevity is specifically concerned with the impact of the dietary supplement curcumin on neurogenesis in the hippocampus and the impact of curcumin neural plasticity. A number of research reports quoted there relate to the neural protective effects of curcumin and how curcumin can increase neurogenesis under conditions of stress.
A January 2011 publication Revisiting dietary antioxidants, neurodegeneration and dementia comments editorially “Epidemiological studies suggest there is marginal benefit that dietary antioxidants reduce risk of Alzheimer type of dementias. Yet cumulative biological evidence indicates oxidative and nitrosative stresses are precursors of neurodegenerative and neurovascular processes. Different dietary flavonoids and polyphenols found in fruits, vegetables, and spices such as curcumin offer neuroprotection through different mechanisms. A study in this volume shows that tetrahydrocurcumin confers protection against amyloid [beta]-induced toxicity by reducing reactive oxygen species and retaining mitochondrial membrane potential. Alzheimer’s disease is a complex disorder. A single target through use of antioxidants may be effective in some but multiple approaches for its control seem to be necessary.”
Aged garlic extract
The May 2011 publication Oxidative insults to neurons and synapse are prevented by aged garlic extract and S-allyl-L-cysteine treatment in the neuronal culture and APP-Tg mouse model reports: “Alzheimer’s disease (AD) is one of the most common forms of dementia in the elderly. In AD patients, β-amyloid peptide (Aβ) plaques and neurofibrillary tangles are common features observed in the CNS. Aβ deposition results in the production of reactive oxygen species (ROS) leading to the hyperphosphorylation of tau that are associated with neuronal damage. Cholinesterase inhibitors and a partial NMDA receptor antagonist (memantine) have been identified as potential treatment options for AD. However, clinical studies have found that these drugs fail to prevent the disease progression. From ancient times, garlic (Allium sativum) has been used to treat several diseases. By ‘aging’ of garlic, some adverse reactions of garlic can be eliminated. Recent findings suggest that ‘aged garlic extract’ (AGE) may be a therapeutic agent for AD because of its antioxidant and Aβ lowering properties. To date, the molecular properties of AGE have been sparsely studied in vitro or in vivo. The present study tested specific biochemical and molecular effects of AGE in neuronal and AD rodent models. Furthermore, we identified S-allyl-L-cysteine (SAC) as one of the most active chemicals responsible for the AGE-mediated effect(s). We observed significant neuroprotective and neurorescue properties of AGE and one of its ingredients, SAC, from ROS (H(2)O(2))-mediated insults to neuronal cells. Treatment of AGE and SAC were found to protect neuronal cells when they were independently co-treated with ROS. Furthermore, a novel neuropreservation effect of AGE was detected in that pre-treatment with AGE alone protected ∼ 80% neuronal cells from ROS-mediated damage. AGE was also found to preserve pre-synaptic protein synaptosomal associated protein of 25 kDa (SNAP25) from ROS-mediated insult. For example, treatment with 2% AGE containing diet and SAC (20 mg/kg of diet) independently increased (∼70%) levels of SNAP25 and synaptophysin in Alzheimer’s amyloid precursor protein-transgenic mice, of which the latter was significantly decreased in AD. Taken together, the neuroprotective, including preservation of pre-synaptic proteins by AGE and SAC can be utilized in future drug development in AD.”
The January 2012 publication The importance of the multiple target action of green tea polyphenols for neuroprotection reports: “–Brain aging and neurodegenerative diseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation. Thus, it is not surprising that a large amount of drugs/agents in therapeutic use for these conditions are antioxidants/metal complexing, bioenergetic and anti-inflammatory agents. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. — Human epidemiological and new animal data suggest that green and black flavonoids named catechins, may help protecting the aging brain and reduce the incidence of dementia, AD and PD. This review will present salient features of the beneficial multi-pharmacological actions of black and green tea polyphenols in aging and neurodegeneration, and speculate on their potential in drug combination to target distinct pathologies as a therapeutic disease modification approach.”
The January 2011 report Orally administrated cinnamon extract reduces β-amyloid oligomerization and corrects cognitive impairment in Alzheimer‘s disease animal models reports: “An increasing body of evidence indicates that accumulation of soluble oligomeric assemblies of β-amyloid polypeptide (Aβ) play a key role in Alzheimer’s disease (AD) pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice. Several reports have documented the inhibition of Aβ plaque formation by compounds from natural sources. Yet, evidence for the ability of common edible elements to modulate Aβ oligomerization remains an unmet challenge. Here we identify a natural substance, based on cinnamon extract (CEppt), which markedly inhibits the formation of toxic Aβ oligomers and prevents the toxicity of Aβ on neuronal PC12 cells. When administered to an AD fly model, CEppt rectified their reduced longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aβ in their brain. Furthermore, oral administration of CEppt to an aggressive AD transgenic mice model led to marked decrease in 56 kDa Aβ oligomers, reduction of plaques and improvement in cognitive behavior. Our results present a novel prophylactic approach for inhibition of toxic oligomeric Aβ species formation in AD through the utilization of a compound that is currently in use in human diet.”
The mushroom Hericium erinaceus
The February 2011 publication Effects of Hericium erinaceus on amyloid β(25-35) peptide-induced learning and memory deficits in micereports: “The mushroom Hericium erinaceus has been used as a food and herbal medicine since ancient times in East Asia. It has been reported that H. erinaceus promotes nerve growth factor secretion in vitro and in vivo. Nerve growth factor is involved in maintaining and organizing cholinergic neurons in the central nervous system. These findings suggest that H. erinaceus may be appropriate for the prevention or treatment of dementia. In the present study, we examined the effects of H. erinaceus on amyloid β(25-35) peptide-induced learning and memory deficits in mice. Mice were administered 10 µg of amyloid β(25-35) peptide intracerebroventricularly on days 7 and 14, and fed a diet containing H. erinaceus over a 23-d experimental period. Memory and learning function was examined using behavioral pharmacological methods including the Y-maze test and the novel-object recognition test. The results revealed that H. erinaceus prevented impairments of spatial short-term and visual recognition memory induced by amyloid β(25-35) peptide. This finding indicates that H. erinaceus may be useful in the prevention of cognitive dysfunction.”
The January 2011 publication Neuroprotective effects of Eucommia ulmoides Oliv. Bark on amyloid beta(25-35)-induced learning and memory impairments in mice reports: “In the present study, we examined whether aqueous extract of Eucommia ulmoides Oliv. Bark (EUE) with graded doses exerted its neuroprotective effects on amyloid beta(25-35) (Aβ(25-35))-induced learning and memory impairments in mice. Mice received a single intracerebroventricular (i.c.v.) injection of Aβ(25-35) 6 nmol as the critical factor in Alzheimer’s disease (AD), cognition was evaluated using Y-maze, passive avoidance, and Morris water maze tests. EUE significantly improved the Aβ(25-35)-induced memory deficit in the Y-maze test. Also, EUE increased step-through latency time with Aβ(25-35)-induced learning and memory deficits in the passive avoidance test. In addition, EUE decreased the escape latencies with Aβ(25-35)-induced cognitive impairments in the Morris water maze test. In the probe trial session, EUE increased time spent in the target quadrant. In the in vitro study, EUE was found to inhibit acetylcholinesterase (AChE) activity in a dose-dependent manner (IC50 value; 172 μg/ml). Ex vivo study, EUE significantly inhibited AChE activity in the hippocampus and frontal cortex. These results demonstrate that EUE possesses potent neuroprotective effects and that its beneficial effects are mediated, in part, by AChE inhibition, and therefore, might be a potential candidate in neurodegenerative diseases such as AD.”
The 2010 publication Piperine, the main alkaloid of Thai black pepper, protects against neurodegeneration and cognitive impairment in animal model of cognitive deficit like condition of Alzheimer’s disease reports: “Recently, numerous medicinal plants possessing profound central nervous system effects and antioxidant activity have received much attention as food supplement to improve cognitive function against cognitive deficit condition including in Alzheimer’s disease condition. Based on this information, the effect of piperine, a main active alkaloid in fruit of Piper nigrum, on memory performance and neurodegeneration in animal model of Alzheimer’s disease have been investigated. Adult male Wistar rats (180-220 g) were orally given piperine at various doses ranging from 5, 10 and 20mg/kg BW at a period of 2 weeks before and 1 week after the intracerebroventricular administration of ethylcholine aziridinium ion (AF64A) bilaterally. The results showed that piperine at all dosage range used in this study significantly improved memory impairment and neurodegeneration in hippocampus. The possible underlying mechanisms might be partly associated with the decrease lipid peroxidation and acetylcholinesterase enzyme. Moreover, piperine also demonstrated the neurotrophic effect in hippocampus. However, further researches about the precise underlying mechanism are still required.”
The 2010 publication Cognitive enhancement and neuroprotective effects of Bacopa monnieri in Alzheimer’s disease model reports: “ETHNOPHARMACOLOGICAL RELEVANCE: Bacopa monnieri (L.) Wettst., a plant belonging to the family Scrophulariaceae, has been used in the traditional system of Ayurvedic medicine to improve intelligence and memory for a long time. Therefore, the potential of this plant to protect against Alzheimer’s disease has been raised but less supported document is available. AIM OF THE STUDY: To determine the effect of alcoholic extract of Bacopa monnieri on cognitive function and neurodegeneration in animal model of Alzheimer’s disease induced by ethylcholine aziridinium ion (AF64A). MATERIALS AND METHODS: Male Wistar rats were orally given the alcoholic extract of Bacopa monnieri at doses of 20, 40 and 80 mg/kg BW via feeding needle for a period of 2 weeks before and 1 week after the intracerebroventricular administration of AF64A bilaterally. Rats were tested for spatial memory using Morris water maze test and the density of neurons and cholinergic neurons was determined using histological techniques 7 days after AF64A administration. RESULTS: Bacopa monnieri extract improved the escape latency time (p<.01) in Morris water maze test. Moreover, the reduction of neurons and cholinergic neuron densities were also mitigated. CONCLUSION: These findings suggest that Bacopa monnieri is a potential cognitive enhancer and neuroprotectant against Alzheimer’s disease.”
Purple rice berry
The July 2011 publication Purple rice berry is neuroprotective and enhances cognition in a rat model of Alzheimer’s disease reports: “Alzheimer’s disease, a neurodegenerative disease characterized by progressive memory loss and cognitive impairment, is the most common type of dementia in aging populations due to severe loss of cholinergic neurons in a specific area. Oxidative stress is known to be involved in the pathogenesis of this condition. Therefore, the cognition-enhancing and neuroprotective effects of rice berry (Oryza sativa), a purple-pigmented rice that is rich in antioxidant substances, was evaluated. Young adult male Wistar rats, weighing 180-220 g, were orally given rice berry once daily at doses of 180, 360, and 720 mg/kg of body weight for a period of 2 weeks before and 1 week after the induction of memory deficit and cholinergic lesions with AF64A, a specific cholinotoxin, via bilateral intracerebroventricular administration. One week following AF64A administration the rats were evaluated for spatial memory, neuron density, acetylcholinesterase activity, and hippocampal lipid peroxidation products. Our results showed that rice berry could significantly prevent memory impairment and hippocampal neurodegeneration in hippocampus. Moreover, it also decreased hippocampal acetylcholinesterase activity and lipid peroxidation product formation. These results suggest that rice berry has potential as an effective agent for neurodegeneration and memory impairment in Alzheimer’s disease.”
Going back to 2008 we can find the publication The effects of acute and repeated oroxylin A treatments on Abeta(25-35)-induced memory impairment in mice. “Oroxylin A is a flavonoid that is found in the roots of Scutellaria baicalensis Georgi. The aim of this study was to characterize the effects of oroxylin A on the memory impairments and pathological changes induced by Abeta(25-35) peptide in mice. The ameliorating effect of oroxylin A on memory impairment was investigated using passive avoidance and Y-maze tasks and pathological changes were identified by immunostaining and western blotting. Abeta(25-35) peptide (5nmol) was administered by intracerebroventricular injection. In the acute treatment study, a single dose of oroxylin A (5mg/kg, p.o.) treated 1h before behavioral tests was found to significantly reverse Abeta(25-35)-induced cognitive impairments based on passive avoidance and Y-maze task findings (P<0.05). Moreover, these acute effects of oroxylin A were blocked by diazepam (1mg/kg, i.p.), a GABA(A)/benzodiazepine binding site agonist (P<0.05). On the other hand, our subchronic studies revealed that oroxylin A (1 or 5mg/kg/day, p.o.) for 7 days ameliorated the memory impairment induced by Abeta(25-35) peptide. Moreover, Abeta(25-35)-induced increases in GFAP (an astroglia marker) and OX-42 (a microglia marker), and increases in iNOS positive cells in the hippocampus were found to be attenuated by subchronic oroxylin A (1 or 5mg/kg/day, i.p., P<0.05). In addition, reductions in the immunoreactivity and protein level of ChAT (a cholinergic neuronal cell marker) in the CA3 hippocampal area induced by Abeta(25-35) peptide were also attenuated by oroxylin A. Furthermore, lipid peroxidation induced by Abeta(25-35) was also reduced by oroxylin A. These results suggest that the amelioration of Abeta(25-35) peptide-induced memory impairment by oroxylin A is mediated via the GABAergic neurotransmitter system after a single administration, or by reductions in Abeta(25-35) peptide-induced astrocyte and microglia activations, iNOS expression, lipid peroxidation, and increased cholinergic neurotransmission after subchronic administration.”
The November 2010 publication Silymarin attenuated the amyloid β plaque burden and improved behavioral abnormalities in an Alzheimer’s disease mouse model reports: “Alzheimer’s disease (AD) is characterized by progressive cognitive impairment and the formation of senile plaques. Silymarin, an extract of milk thistle, has long been used as a medicinal herb for liver diseases. Here we report marked suppression of amyloid β-protein (Aβ) fibril formation and neurotoxicity in PC12 cells after silymarin treatment in vitro. In vivo studies had indicated a significant reduction in brain Aβ deposition and improvement in behavioral abnormalities in amyloid precursor protein (APP) transgenic mice that had been preventively treated with a powdered diet containing 0.1% silymarin for 6 months. The silymarin-treated APP mice also showed less anxiety than the vehicle-treated APP mice. These behavioral changes were associated with a decline in Aβ oligomer production induced by silymarin intake. These results suggest that silymarin is a promising agent for the prevention of AD.”
“Silibinin (INN), also known as silybin, is the major active constituent of silymarin, standardized extract of the milk thistle seeds, containing mixture of flavonolignans consisting of among others of silibinin, isosilibinin, silicristin and silidianin. Silibinin itself is mixture of two diastereomers Silibinin A and Silybinin B in approximately equimolar ratio(ref).” The 2008 publication Silibinin prevents amyloid beta peptide-induced memory impairment and oxidative stress in micerelates: “BACKGROUND AND PURPOSE: Accumulated evidence suggests that oxidativestress is involved in amyloid beta (Abeta)-induced cognitive dysfunction. Silibinin (silybin), a flavonoid derived from the herb milk thistle (Silybum marianum), has been shown to have antioxidative properties; however, it remains unclear whether silibinin improves Abeta-induced neurotoxicity. In the present study, we examined the effect of silibinin on the memory impairment and accumulation of oxidativestress induced by Abeta(25-35) in mice. EXPERIMENTAL APPROACH: Aggregated Abeta(25-35) (3 nmol) was intracerebroventricularly administered to mice. Treatment with silibinin (2, 20 and 200 mg.kg(-1), once a day, p.o.) was started immediately after the injection of Abeta(25-35). Locomotor activity was evaluated 6 days after the Abeta(25-35) treatment, and cognitive function was evaluated in a Y-maze and novel object recognition tests 6-11 days after the Abeta(25-35) treatment. The levels of lipid peroxidation (malondialdehyde) and antioxidant (glutathione) in the hippocampus were measured 7 days after the Abeta(25-35) injection. KEY RESULTS: Silibinin prevented the memory impairment induced by Abeta(25-35) in the Y-maze and novel object recognition tests. Repeated treatment with silibinin attenuated the Abeta(25-35)-induced accumulation of malondialdehyde and depletion of glutathione in the hippocampus. CONCLUSIONS AND IMPLICATIONS: Silibinin prevents memory impairment and oxidative damage induced by Abeta(25-35) and may be a potential therapeutic agent for Alzheimer‘s disease.” It could of course be the case that the actions of silymarin against AD are mainly due to its silibinin component.
When I compiled my list of potentially relevant publications in early January prior to generating these blog entries, I expected to find resveratrol on the list of phytosubstances shown to be active against AD. But surprisingly there were no citations to that effect in the long list I had compiled. Sure enough though, a bit of last-minute searching turned up two very-recent publications indicating that my hunch was correct. The December 2011 publicationResveratrol Protects Rats from Aβ-induced Neurotoxicity by the Reduction of iNOS Expression and Lipid Peroxidation reports: “Alzheimer disease (AD) is an age-dependent neurodegenerative disease characterized by the formation of β-amyloid (Aβ)-containing senile plaque. The disease could be induced by the administration of Aβ peptide, which was also known to upregulate inducible nitric oxide synthase (iNOS) and stimulate neuronal apoptosis. The present study is aimed to elucidate the cellular effect of resveratrol, a natural phytoestrogen with neuroprotective activities, on Aβ-induced hippocampal neuron loss and memory impairment. On adult Sprague-Dawley rats, we found the injection of Aβ could result in a significant impairment in spatial memory, a marked increase in the cellular level of iNOS and lipid peroxidation, and an apparent decrease in the expression of heme oxygenase-1 (HO-1). By combining the treatment with Aβ, resveratrol was able to confer a significant improvement in spatial memory, and protect animals from Aβ-induced neurotoxicity. These neurological protection effects of resveratrol were associated with a reduction in the cellular levels of iNOS and lipid peroxidation and an increase in the production of HO-1. Moreover, the similar neurological and cellular response were also observed when Aβ treatment was combined with the administration of a NOS inhibitor, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME). These findings strongly implicate that iNOS is involved in the Aβ-induced lipid peroxidation and HO-1 downregulation, and resveratrol protects animals from Aβ-induced neurotoxicity by suppressing iNOS production.”
A report dated January 2012 Resveratrol, a neuroprotective supplement for Alzheimer’sdisease relates: “The polyphenolic compound resveratrol (3,4′,5-trihydroxystilbene) is a naturally occurring phytochemical which has been found in more than 70 plant species, including herbs and human food products such as grapes, berries, and peanuts. Resveratrol was first isolated in 1940; however, little attention was paid to it until its benefits in coronary heart disease were studied in 1992. Since then, increasing evidence has indicated that resveratrol may be useful in treating cardiovascular diseases, cancers, pain, inflammation, tissue injury, and in reducing the risk of neurodegenerative disorders, especially Alzheimer’sdisease (AD). AD is characterized by a progressive dementia, and is one of the most common neurodegenerative disorders in the elderly. It has been reported that resveratrol exhibits neuroprotective benefits in animal models of AD. Resveratrol promotes the non-amyloidogenic cleavage of the amyloid precursor protein, enhances clearance of amyloid beta-peptides, and reduces neuronal damage. Despite the effort spent trying to understand the mechanisms by which resveratrol functions, the research work in this field is still incomplete. Many concerns such as bioavailability, biotransformation, synergism with other dietary factors, and risks inherent to its possible pro-oxidant activities still need to be addressed. This review summarizes and discusses the neuroprotective effects of resveratrol on AD, and their potential mechanisms.”
A combination of dietary supplements in the anti-aging firewall ameliorates the symptoms and neuropathy of Alzheimer’s disease in a transgenic mouse model.
The November 2010 publication Formulation of a medical food cocktail for Alzheimer’s disease: beneficial effects on cognition and neuropathology in a mouse model of the disease reports: ”BACKGROUND: Dietary supplements have been extensively studied for their beneficial effects on cognition and AD neuropathology. The current study examines the effect of a medical food cocktail consisting of the dietary supplements curcumin, piperine, epigallocatechin gallate, α-lipoic acid, N-acetylcysteine, B vitamins, vitamin C, and folate on cognitive functioning and the AD hallmark features and amyloid-beta (Aβ) in the Tg2576 mouse model of the disease. PRINCIPAL FINDINGS: The study found that administering the medical food cocktail for 6 months improved cortical- and hippocampal- dependent learning in the transgenic mice, rendering their performance indistinguishable from non-transgenic controls. Coinciding with this improvement in learning and memory, we found that treatment resulted in decreased soluble Aβ, including Aβ oligomers, previously found to be linked to cognitive functioning. CONCLUSION: In conclusion, the current study demonstrates that combination diet consisting of natural dietary supplements improves cognitive functioning while decreasing AD neuropathology and may thus represent a safe, natural treatment for AD.”
In my treatise ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY, I suggest a number of supplemental substances likely to mitigate against aging or key phenomena of aging. It is interesting that all of the mentioned substances in the “medical food cocktail” are in my combined anti-aging supplement firewall. The big question of course is whether the cocktail works to halt or neutralize human Alzheimer’s disease. If so, that would be very big news. The study report has to say “The current study provides evidence that a combination diet of dietary supplements, individually known to be beneficial, can not only improve cognitive functioning in a transgenic mouse models of AD but also decreases Aβ levels and oligomerization. As yet there is an unmet need for effective treatments and preventative strategies for AD, and the fastest route to human patients involves the use of either existing medications, or the formulation of known safe remedies. Given that human AD is far more complex than we can effectively model in mice, which develop AD related pathology and cognitive decline but lack extensive neuronal loss, we must formulate treatments that attack not just the symptoms seen in these mice, but also those which we predict will show benefits downstream of pathology that occur in humans. Our formulation here has been designed to alter APP processing through reductions in both Aβ production, as well as aggregation, but also to prevent downstream pathologies such as excessive oxidative damage and inflammation. It is our hope that such a strategy will slow disease progression in humans. — Our rationale is that the individual components of the medical food cocktail work synergistically to produce cognitive and pathological benefits, and together have larger effects than any single component alone. In order to take the step from formulation to human administration we have tested the medical food cocktail in a well-described transgenic mouse model of AD. Serving as a proof of principal we saw cognitive recovery, as well as reduction of Aβ. Our results here show that combination approaches to the treatment of AD are effective in mouse models of AD, and have high translation potential for the human disorder(ref).”
We don’t know if this particular combination of supplements would work in humans as it does in the TG mice. Only a clinical trial would tell us convincingly, but who would spend the millions necessary to fund such a clinical trial?
The field of Alzheimer’s disease research is very large and very messy with many dark corridors and corners. Much of this research happens in pharma companies and is yet unpublished. These blog entries cover only a fraction of the research that is going on. On the other hand, Part 2 of this three-part blog series identified a half-dozen pharmacological agents shown in vitro or small-animal models to be capable of halting or reversing symptoms of dementia or Alzheimer’s disease. Above in this blog entry, sixteen plant-derived substances are identified that can do the same. These include several of the “usual suspect” supplement substances that act against cancers and have other positive qualities, like curcumin, green tea and resveratrol. And without doubt there are many more. And one dietary supplement combination of such substances appears to reverse the AD phenotype in a transgenic mouse model of AD. Yet the conventional wisdom in clinical practice is that nothing can be done either to avert or treat AD.
Something appears to be seriously wrong with this picture. Given the costs to our society of AD of billions or trillions of dollars, why are there not massive efforts to take some of the substances known to be safe and efficacious with small animals, try them in larger more systematic controlled experiments, and rush the best of these through clinical trials? Why are there not public education campaigns on the roles of exercise and diet in averting dementia? Why is there such a persistent fog about what can be done about dementia despite all the research that is out there?
Perhaps the answer lies in part in the nature of our healthcare system. In medical practice, substances are not regarded to be legitimate treatments unless they have gone through clinical trials and are certified by the FDA as being pharmaceuticals that are safe, efficacious and controlled. But what drug company would be willing to fund a clinical trial of a combination of off-the-shelf plant-derived substances? One viewpoint is that they can’t make money that way.
On the other hand the clinicaltrials.gov database on Alzheimer’s disease clinical trials does show 853 studies in various stages of completion. And a few of these are concerned with testing phytosubstances, albeit in many cases proprietary combinations of these. Perhaps there is hope.