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Neuroprotective and metabolic effects of resveratrol: Therapeutic implications for Huntington's disease and other neurodegenerative disorders
Abstract
Resveratrol is a naturally occurring polyphenolic compound associated with beneficial effects on aging, metabolic disorders, inflammation and cancer in animal models and resveratrol is currently being tested in numerous clinical trials. Resveratrol may exert these effects by targeting several key metabolic sensor/effector proteins, such as AMPK, SIRT1, and PGC-1α. Resveratrol has also received considerable attention recently for its potential neuroprotective effects in neurodegenerative disorders where AMPK, SIRT1 or PGC-1α may represent promising therapeutic targets. A recent study published in Experimental Neurology (Ho et al., 2010) examined the therapeutic potential of a micronised proprietary resveratrol formulation, SRT501 in the N171-82Q transgenic mouse model of Huntington's disease (HD). HD is a progressive and devastating genetic neurodegenerative disorder that is associated with downregulation of PGC-1α activity. The Ho et al. study found that SRT501 treatment did not lead to significant improvement in weight loss, motor performance, survival and striatal atrophy. However, other studies have reported neuroprotective effects of resveratrol and a distantly related polyphenol, fisetin, in HD models. HD has been associated with diabetes mellitus. Interestingly, evidence from the Ho et al. study suggests a resveratrol formulation induced beneficial anti-diabetic effect in N171-82Q mice. This commentary summarizes the pertinent outcomes from the Ho et al. study and discusses the further prospects of resveratrol and other polyphenols, including novel grape-derived polyphenols, in the treatment of HD and other neurodegenerative disorders.
... Inhibition of misfolded proteins, antineuroinflammation, antioxidative stress EAE mice (300 mg/kg) AD [210,212,214], PD [211], MS [215] Gallic acid [259,260,263,[268][269][270], PD [271][272][273][274][275][276], HD [256,277,278], ALS [281], MS [282][283][284] 11 Oxidative Medicine and Cellular Longevity the nonflavonoids mainly include phenolic acids, phenolic alcohols, stilbenes, lignans, curcuminoids, and coumarins ( Figure 6) [142]. ...
... Resveratrol, known as 3,4,5-trihydroxystilbene, belongs to stilbenes, which is widely investigated and found to be abundant in dietary plants, including grapes, raspberries, mulberries, and peanuts [253]. Increasing studies suggest that resveratrol exerts antiageing and neuroprotective effects [254][255][256][257]. At present, the phase II clinical trials of resveratrol for AD patients are ongoing [258]. ...
... Meanwhile, resveratrol alleviates the pathology of Drosophila and R6/2 mice via activating the ERK signaling pathway [277]. In addition, resveratrol protects the normal function of mitochondrial and improves the motor coordination and learning ability in YAC128 mice and N171-82Q transgenic mice through the AMPK, SIRT1, and peroxlsome proliferator-activated receptor-γ coactlvator-1α (PGC-1α) pathways [256,278]. In thimerosal-induced SH-SY5Y and VSC4.1 cells overexpressing mutant SOD1-G93A, resveratrol increases the cell viability via the upregulation of SIRT1 [279,280]. ...
Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), are characterized by the progressive degeneration of neurons. Although the etiology and pathogenesis of neurodegenerative diseases have been studied intensively, the mechanism is still in its infancy. In general, most neurodegenerative diseases share common molecular mechanisms, and multiple risks interact and promote the pathologic process of neurogenerative diseases. At present, most of the approved drugs only alleviate the clinical symptoms but fail to cure neurodegenerative diseases. Numerous studies indicate that dietary plant polyphenols are safe and exhibit potent neuroprotective effects in various neurodegenerative diseases. However, low bioavailability is the biggest obstacle for polyphenol that largely limits its adoption from evidence into clinical practice. In this review, we summarized the widely recognized mechanisms associated with neurodegenerative diseases, such as misfolded proteins, mitochondrial dysfunction, oxidative damage, and neuroinflammatory responses. In addition, we summarized the research advances about the neuroprotective effect of the most widely reported dietary plant polyphenols. Moreover, we discussed the current clinical study and application of polyphenols and the factors that result in low bioavailability, such as poor stability and low permeability across the blood-brain barrier (BBB). In the future, the improvement of absorption and stability, modification of structure and formulation, and the combination therapy will provide more opportunities from the laboratory into the clinic for polyphenols. Lastly, we hope that the present review will encourage further researches on natural dietary polyphenols in the treatment of neurodegenerative diseases.
... Another study found that 3-NPactivated mouse mental impairments were reversed by resveratrol. Resveratrol may have neuroprotective effects due to its potential as a cancer-preventative agent [300]. The fact that resveratrol inhibits Ku70 acetylation via extending polyQ of ataxin-3 (Q79C) has also been explained [301]. ...
... analogues should be discovered before being tried in animal models [300]. Two polyphenols, resveratrol in vitro and fisetin in vivo, have been shown in a recent study to have neuroprotective effects in HD animals. ...
A neurodegenerative disorder (ND) refers to Huntington's disease (HD) which affects memory loss, weight loss, and movement dysfunctions such as chorea and dystonia. In the striatum and brain, HD most typically impacts medium-spiny neurons. Molecular genetics, excitotoxicity, oxidative stress (OS), mitochondrial, and metabolic dysfunction are a few of the theories advanced to explicit the pathophysiology of neuronal damage and cell death. Numerous in-depth studies of the literature have supported the therapeutic advantages of natural products in HD experimental models and other treatment approaches. This article briefly discusses the neuroprotective impacts of natural compounds against HD models. The ability of the discovered natural compounds to suppress HD was tested using either in vitro or in vivo models. Many bioactive compounds considerably lessened the memory loss and motor coordination brought on by 3-nitropropionic acid (3-NP). Reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and enhanced mitochondrial energy generation have profoundly decreased the biochemical change. It is significant since histology showed that therapy with particular natural compounds lessened damage to the striatum caused by 3-NP. Moreover, natural products displayed varying degrees of neuroprotection in preclinical HD studies because of their antioxidant and anti-inflammatory properties, maintenance of mitochondrial function, activation of autophagy, and inhibition of apoptosis. This study highlighted about the importance of bioactive compounds and their semi-synthetic molecules in the treatment and prevention of HD.
... Additionally, considerable interest has been focused on the neuroprotective effects of polyphenols (natural substances with variable phenolic structures which are found enriched in vegetables, fruits, grains, bark, roots, tea, and wine) [12]. In particular, resveratrol (3,5,4′-trihydroxytrans-stilbene, RSV), a stilbenoid phenol found in red wine, was shown to exert a protective effect in experimental models of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), ischemia, Huntington's disease (HD), and traumatic brain injury, among other conditions [12][13][14][15][16][17][18]. ...
... Exposure of astrocyte cultures to a pathological concentration of ammonia (5 mM, for 24-48 h) was previously shown to increase cell swelling ( [6] and references therein). We examined whether resveratrol, a potent polyphenol, which has been shown to exert a protective effect against many conditions in vivo [12][13][14][15][16][17][18], as well as its protective effect post-cell injury in various conditions in vitro [49][50][51][52][53], would also reduce astrocyte cell volume post-ammonia treatment. ...
Swelling of astrocytes represents a major component of the brain edema associated with many neurological conditions, including acute hepatic encephalopathy (AHE), traumatic brain injury (TBI) and ischemia. It has previously been reported that exposure of cultured astrocytes to ammonia (a factor strongly implicated in the pathogenesis of AHE), oxygen/glucose deprivation, or to direct mechanical trauma results in an increase in cell swelling. Since dietary polyphenols have been shown to exert a protective effect against cell injury, we examined whether resveratrol (RSV, 3,5,4′-trihydroxy-trans-stilbene, a stilbenoid phenol), has a protective effect on astrocyte swelling following its exposure to ammonia, oxygen–glucose deprivation (OGD), or trauma in vitro. Ammonia increased astrocyte swelling, and pre- or post-treatment of astrocytes with 10 and 25 µM RSV displayed an additive effect, while 5 µM did not prevent the effect of ammonia. However, pre-treatment of astrocytes with 25 µM RSV slightly, but significantly, reduced the trauma-induced astrocyte swelling at earlier time points (3 h), while post-treatment had no significant effect on the trauma-induced cell swelling at the 3 h time point. Instead, pre- or post-treatment of astrocytes with 25 µM RSV had an additive effect on trauma-induced astrocyte swelling. Further, pre- or post-treatment of astrocytes with 5 or 10 µM RSV had no significant effect on trauma-induced astrocyte swelling. When 5 or 10 µM RSV were added prior to, or during the process of OGD, as well as post-OGD, it caused a slight, but not statistically significant decline in cell swelling. However, when 25 µM RSV was added during the process of OGD, as well as after the cells were returned to normal condition (90 min period), such treatment showed an additive effect on the OGD-induced astrocyte swelling. Noteworthy, a higher concentration of RSV (25 µM) exhibited an additive effect on levels of phosphorylated forms of ERK1/2, and p38MAPK, as well as an increased activity of the Na+–K+–Cl− co-transporter-1 (NKCC1), factors known to induce astrocytes swelling, when the cells were treated with ammonia or after trauma or ischemia. Further, inhibition of ERK1/2, and p38MAPK diminished the RSV-induced exacerbation of cell swelling post-ammonia, trauma and OGD treatment. These findings strongly suggest that treatment of cultured astrocytes with RSV enhanced the ammonia, ischemia and trauma-induced cell swelling, likely through the exacerbation of intercellular signaling kinases and ion transporters. Accordingly, caution should be exercised when using RSV for the treatment of these neurological conditions, especially when brain edema is also suspected.
... Several studies suggest that pharmacological activation of SIRT1 may represent a promising approach to prevent amyloid deposition and neurodegeneration in AD [99,149]. The relationship between SIRT1 and AD is paramount, as a study of the SIRT1 serum concentration in healthy subjects and AD patients showed a reduced serum SIRT1 concentration that correlated with the increasing age of an individual. ...
... Resveratrol has antiinflammatory functions and can inhibit Aβ-induced NF-κB signaling in microglia and astrocytes [151]. Another study showed that mice overexpressing SIRT1 exhibited reduced brain inflammation (due to its action in tau phosphorylation) and reduced cognitive defects that were specific to the APP transgenic mouse [149,150]. ...
Alzheimer's disease (AD) is a progressive and neurodegenerative disorder of the cortex and hippocampus, which eventually leads to cognitive impairment. Although the etiology of AD remains unclear, the presence of β-amyloid (Aβ) peptides in these learning and memory regions is a hallmark of AD. Therefore, the inhibition of Aβ peptide aggregation has been considered the primary therapeutic strategy for AD treatment. Many studies have shown that resveratrol has antioxidant, anti-inflammatory, and neuroprotective properties and can decrease the toxicity and aggregation of Aβ peptides in the hippocampus of AD patients, promote neurogenesis, and prevent hippocampal damage. In addition, the antioxidant activity of resveratrol plays an important role in neuronal differentiation through the activation of silent information regulator-1 (SIRT1). SIRT1 plays a vital role in the growth and differentiation of neurons and prevents the apoptotic death of these neurons by deacetylating and repressing p53 activity; however, the exact mechanisms remain unclear. Resveratrol also has anti-inflammatory effects as it suppresses M1 microglia activation, which is involved in the initiation of neurodegeneration, and promotes Th2 responses by increasing anti-inflammatory cytokines and SIRT1 expression. This review will focus on the antioxidant and anti-inflammatory neuroprotective effects of resveratrol, specifically on its role in SIRT1 and the association with AD pathophysiology.
... For example, an intravenous solution of resveratrol at a dose of up to 10 g/kg administered before and after induction of cerebral ischemia in rats reduced the area of cerebral infarction and edema and had a positive effect on the function of brain mitochondria [80]. Furthermore, resveratrol had direct neuroprotective effects both in vitro and in vivo in various neurodegenerative diseases such as Parkinson's disease [81], Alzheimer's disease [82], Huntington's disease [83] and amyotrophic lateral sclerosis [84]. Resveratrol had direct neuroprotective ability, both in vitro and in vivo [85]. ...
There is growing evidence that an active lifestyle can benefit brain health, delay the onset of neurodegenerative diseases and aging, and improve mood and cognitive function. Results seem to show that exercise-inspired or exercise-like drugs such as AICAR, metformin, GW501516, resveratrol, epicatechin, transfer plasma, platelet factor 4 and selenium effectively reduce excitotoxicity and mitochondrial dysfunction and improve neurodegenerative disease, angiogenesis and neurogenesis. The beneficial effects of exercise on the brain probably cannot be replaced by a single pill. Despite new discoveries, it is unlikely that a single molecule will ever be able to replicate all the benefits of exercise. Scientists developing drugs that mimic the effects of exercise do not aim to replace regular exercise throughout a person's life, but rather to use it in specific circumstances. However, not everyone is able to play sports due to age-related illnesses, injuries or frailty. The long-term goal is to understand how exercise increases neurogenesis and to try to develop new ways to mimic exercise-induced neurogenesis in people who cannot exercise. Identification of cellular targets activated by exercise could lead to the development of new compounds that can, to some extent, mimic the systemic and central effects of exercise. This review focuses on putative exercise mimetics such as AICAR, resveratrol, metformin, epicatechin, GW501516, transfer plasma, platelet factor 4 and selenium on brain health, neurodegenerative diseases and aging.
... Resveratrol exhibited protective effects against some neurodegenerative disorders, including Alzheimer's disease [59], Parkinson's disease [60], Huntington's disease, and amyotrophic lateral sclerosis [61]. One of the neuroprotective mechanisms attributed to resveratrol involves the activation of sirtuins, which are histone deacetylases. ...
Cancer is one of the most serious public health issues worldwide, demanding ongoing efforts to find novel therapeutic agents and approaches. Amid growing interest in the oncological applications of phytochemicals, particularly polyphenols, resveratrol—a naturally occurring polyphenolic stilbene derivative—has emerged as a candidate of interest. This review analyzes the pleiotropic anti-cancer effects of resveratrol, including its modulation of apoptotic pathways, cell cycle regulation, inflammation, angiogenesis, and metastasis, its interaction with cancer stem cells and the tumor microenvironment. The effects of resveratrol on mitochondrial functions, which are crucial to cancer development, are also discussed. Future research directions are identified, including the elucidation of specific molecular targets, to facilitate the clinical translation of resveratrol in cancer prevention and therapy.
... The third mechanism of STZ-induced pathology is the impediment of SIRT1 activity. SIRT1 activation may be a good potential strategy to counteract amyloid deposition and neurodegeneration in AD (Pasinetti et al. 2011). SIRT1 deficiency was much more prominent in AD patients (Kumar et al. 2013). ...
The prominence of autophagy in the modulation of neurodegenerative disorders has sparked interest to investigate its stimulation in Alzheimer's disease (AD). Nobiletin possesses several bioactivities such as anti-inflammation, antioxidation, and neuroprotection. Consequently, the study's aim was to inspect the possible neurotherapeutic impact of Nobiletin in damping AD through autophagy regulation. Mice were randomly assigned into: Group I which received DMSO, Groups II, III, and IV obtained STZ (3 mg/kg) intracerebroventricularly once with Nobiletin (50 mg/kg/day; i.p.) in Group III and Nobiletin with EX-527 (2 mg/kg, i.p.) in Group IV. Interestingly, Nobiletin ameliorated STZ-induced AD through enhancing the motor performance and repressing memory defects. Moreover, Nobiletin de-escalated hippocampal acetylcholinesterase (AChE) activity and enhanced acetylcholine level while halting BACE1 and amyloid-β levels. Meanwhile, Nobiletin stimulated the autophagy process through activating the SIRT1/FoxO3a, LC3B-II, and ATG7 pathway. Additionally, Nobiletin inhibited Akt pathway and controlled the level of NF-κB and TNF-α. Nobiletin amended the oxidative stress through enhancing GSH and cutting down MDA levels. However, EX527, SIRT1 inhibitor, counteracted the neurotherapeutic effects of Nobiletin. Therefore, the present study provides a strong verification for the therapeutic influence of Nobiletin in AD. This outcome may be assigned to autophagy stimulation through SIRT1/FoxO3a, inhibiting AChE activity, reducing neuroinflammation and oxidative stress.
Graphical abstract
... Polyphenol compounds exert their neuroprotective effects via myriad mechanisms. They are well known to reduce inflammation and alter redox balance 16,29,30 . Polyphenol compounds, most notably resveratrol, activate the sirtuin family of histone deacetylases, leading to altered epigenetic regulation of gene expression and altered neurobiological and behavioral plasticity 31 . ...
Opioid Use Disorder (OUD) is associated with tremendous morbidity and mortality. Despite this burden, current pharmacotherapies for OUD are ineffective or intolerable for many patients. As such, interventions aimed at promoting resilience against OUD are of immense clinical interest. Treatment with a Bioactive Dietary Polyphenol Preparation (BDPP) promotes resilience and adaptive neuroplasticity in multiple models of neuropsychiatric disease. Here, we assessed effects of BDPP treatment on behavioral and molecular responses to repeated morphine treatment in male mice. BDPP pre-treatment alters responses for both locomotor sensitization and conditioned place preference. Most notably, polyphenol treatment consistently reduced formation of preference at low dose (5 mg/kg) morphine but enhanced it at high dose (15 mg/kg). In parallel, we performed transcriptomic profiling of the nucleus accumbens, which again showed a dose × polyphenol interaction. We also profiled microbiome composition and function, as polyphenols are metabolized by the microbiome and can act as prebiotics. The profile revealed polyphenol treatment markedly altered microbiome composition and function. Finally, we investigated involvement of the SIRT1 deacetylase, and the role of polyphenol metabolites in behavioral responses. These results demonstrate polyphenols have robust dose-dependent effects on behavioral and physiological responses to morphine and lay the foundation for future translational work.
... Notably, resveratrol (56) exhibits diverse biological activities ranging from cancer to neurological disorders. Resveratrol (56) improves energy metabolism and mitochondrial functions by modulating several neuroprotective and neurodegenerative therapeutic targets, including AMPK, Sirtuin 1, and PGC-1α (Fig. 8B) [199,200]. Cysteamine (RP103, 57), a natural molecule with low molecular weight, has been reported to enhance the levels of BNDF and show beneficial effects in numerous animal models of HD. In phase II/III clinical trial, cysteamine (57) was found to be safe and well tolerated, but there was no evidence of efficacy in HD patients (NCT02101957) [201]. ...
Huntington's disease (HD) is a rare and fatal neurodegenerative disorder with no disease modifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) protein having expanded polyglutamine (polyQ) residues. Current HD therapeutics only offer symptomatic relief. Infact, Food and Drug Administration (FDA) approved two synthetic small-molecule VMAT2 inhibi-tors, tetrabenazine (1) and deutetrabenazine (2), for managing HD chorea and various other diseases in clinical trials. Therefore, the landscape of drug discovery programs for HD is evolving to discover disease-modifying HD therapeutics. Likewise, numerous natural products are being evaluated at different stages of clinical development and have shown the potential to ameliorate HD pathology. The inherent anti-inflammatory and antioxidant properties of natural products mitigate the mHTT-induced oxidative stress and neuroinflammation, improve mitochondrial functions, and augment the anti-apoptotic and pro-autophagic mechanisms for increased survival of neurons in HD. In this review, we have discussed HD pathogenesis and summarized the anti-HD clinical and pre-clinical natural products, focusing on their therapeutic effects and neuroprotective mechanisms.
... Dietary antioxidants have many beneficial actions and would be more likely to succeed [111], but they have poor bioavailability and must be engineered to overcome this drawback. Resveratrol is a nonflavonoid polyphenol that acts in various neurodegenerative diseases by activating metabolic sensor/effector proteins, including AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and PGC-1α [60]. Sirtuins (SIRT 1-7) are a group of NAD + (nicotinamide adenine dinucleotide)-dependent lysine deacetylases, which can initiate a series of adaptive responses and regulate the metabolic efficiency of the cell [112]. ...
Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the age of onset or disease progression rate. Research has identified various intricate pathogenic cascades which lead to neuronal degeneration, but therapies interfering with these mechanisms have been marked by many failures and remain to be validated. Exciting new opportunities are opened by the emerging techniques which target the mutant protein DNA and RNA, allowing for “gene editing”. Although some issues relating to “off-target” effects or immune-mediated side effects need to be solved, these strategies, combined with stem cell therapies and more traditional approaches targeting specific pathogenic cascades, such as excitotoxicity and bioavailability of neurotrophic factors, could lead to significant improvement of the outcomes of treated Huntington’s disease patients.
... Resveratrol appears to be an excellent neuroprotective agent against several neurodegenerative diseases (Pasinetti et al., 2011). It works by attenuating oxidative stress, mitochondrial dysfunction, metabolic abnormalities etc. (Fig. 4). ...
Among several neurodegenerative diseases, Huntington disease has posed a major threat across the world, particularly in the aged population. The disease is caused due to expansion of cytosine-adenine-guanine repeats which further triggers the formation of a mutant huntingtin protein responsible for neuronal death. Numerous pathophysiologic mechanisms have been implicated in Huntington’s disease. Striatum and cortex represent the most affected parts of the brain. Even though a wide range of medicines are available but they possess serious side effects. Therefore, the emergence of nutraceuticals derived from natural sources has received great attention in the pharmaceutical domain. Nutraceuticals are health-promoting supplements and enhance immunity in human beings. Currently, oxidative stress is the leading factor for chronic diseases that occur due to low intake of antioxidants. Herbal nutraceuticals are said to be enriched with a massive number of antioxidants. Therefore, this article throws light on various herbal nutraceuticals and their noteworthy effects on Huntington’s disease
... It is found that the mitochondrial DNA content and the expression of mitochondrial biogenesis factors are increased by GSE administration. Studies also reported that GSE and resveratrol activate the expression of PGC-1α, silent mating type information regulation 2 homolog 1 (SIRT1) and AMP-activated protein kinase (AMPK) and could prevent mitochondrial dysfunction [49,50]. As the studies show, GSE has a solid potential to attenuate PD symptoms by protecting different brain parts. ...
Common neurological disorders, including neurodegenerative diseases, stroke, epilepsy, autism and psychiatric disorders, affect many people worldwide and threaten their lives and health by inducing movement disorders, behavioral disorders, or a combination of both. Oxidative stress and neuroinflammation play a central role in neuronal damage and neurological diseases induction and progression. In addition, protein homeostasis (proteostasis) impairment occurs in many neurodegenerative diseases, which plays a critical role in the progression of the pathology. Grape seed contains several flavonoids and non-flavonoids and exerts potent antioxidant and anti-inflammatory effects. In addition, polyphenols and flavanols can maintain cellular proteostasis. Since impaired proteostasis is closely involved in all amyloid diseases, particularly neurodegenerative diseases, grape seeds extract can be a valuable therapeutic agent. Therefore, this review discusses the protective and therapeutic mechanisms of grape seed against neurological disorders and, in the end, links GSE to microRNAs as future therapeutic developments.
... Over the last several decades, various biological activities have been identified with resveratrol including cardiovascular disease, diabetes, antiaging, antioxidants, chemical preventative effects, neurodegenerative and anti-inflammatory properties, antiplatelets, and antiallergy (Gambini et al., 2015;Kuršvietienė et al., 2016). Resveratrol appears to be an outstanding neurodegenerative agent in many diseases (Pasinetti et al., 2011). It functions by attenuating oxidative stress, instability of mitochondria, metabolic abnormalities, etc. (Figure 14). ...
... Over the last several decades, various biological activities have been identified with resveratrol including cardiovascular disease, diabetes, antiaging, antioxidants, chemical preventative effects, neurodegenerative and anti-inflammatory properties, antiplatelets, and antiallergy (Gambini et al., 2015;Kuršvietienė et al., 2016). Resveratrol appears to be an outstanding neurodegenerative agent in many diseases (Pasinetti et al., 2011). It functions by attenuating oxidative stress, instability of mitochondria, metabolic abnormalities, etc. (Figure 14). ...
... Over the last several decades, various biological activities have been identified with resveratrol including cardiovascular disease, diabetes, antiaging, antioxidants, chemical preventative effects, neurodegenerative and anti-inflammatory properties, antiplatelets, and antiallergy (Gambini et al., 2015;Kuršvietienė et al., 2016). Resveratrol appears to be an outstanding neurodegenerative agent in many diseases (Pasinetti et al., 2011). It functions by attenuating oxidative stress, instability of mitochondria, metabolic abnormalities, etc. (Figure 14). ...
... Neuroprotective, [202] Cardioprotective [203,204] DNA protective, Anti-inflammatory ...
Immune dysregulation, neuronal inflammation, and oligodendrocyte degradation are key causes for autoimmune disorders like multiple sclerosis (MS) and various otherimmune dysregulated neurodegenerative complications responsible for CNS-mediated immune responses.Sirtuins (SIRT-1) is nicotinamide adenosine dinucleotide (NAD)-dependent transcriptional protein thatdeacetylases and removes acetyl groups from its transcription factors like P53, FOXO, NF-Κb, PGC-1α. SIRT-1 mediates a wide range of physiological functions,including gene transcription, metabolism, neuronal apoptosis, and glucose production.SIRT-1 dysregulation targets transcription factors,and other molecular alterations such as gene expression modification influence neuronal plasticity, inhibits Th17 cells, and interleukin-1β can aggravate brain diseases.Preclinical and clinical findings show that the upregulation of SIRT-1 reduces autoimmunity, neurodegeneration, and neuroexcitation. Even though drugs are being developed for symptomatic therapies in clinical trials, there are particular pharmacological implications for improving post-operative conditions in neurodegenerativepatients where intensive care is required.Understanding the SIRT-1 signaling and identifying immune-mediated neuron deterioration can detect major therapeutic interventions that could prevent neurocomplications.Thus, in the current review, we have addressed the manifestations of disease by the downregulation of SIRT-1 that could potentially cause MS and other neurodegenerative disorders and provided data on existing available and effective drug therapies and disease management strategies.
... Resveratrol is a kind of natural antioxidant polyphenol. Various studies have shown that resveratrol has the characteristics of good health, can prevent or slow down the process of various pathological conditions, and can treat cancer and various disease [1].In clinical trials, resveratrol has therapeutic effects on cancer [2][3][4][5][6], obesity [7][8][9], diabetes [10,11], neurological [12][13][14] and cardiovascular diseases [15][16][17], and has significant antibacterial activities against a variety of bacteria, viruses and fungi [18,19]. In recent years, resveratrol has been widely concerned because of its various health benefits. ...
Resveratrol in Polygonum cuspidatum is a β-glycoside, which can be hydrolyzed to resveratrol by β-glucosidase. it is an efficient production process to degrade polydatin from Polygonum cuspidatum extract by immobilized β-glucosidase. It is of great significance to explore suitable immobilization conditions to improve the catalytic efficiency and reusability of β-glucosidase for polydatin degradation and cost reduction. In this paper, the recombinant Escherichia coli bgl2238, which was screened and constructed from corn soil of Heilongjiang Province in the early laboratory, was immobilized by chitosan adsorption and glutaraldehyde crosslinking. The preparation conditions and immobilization process of bgl2238 were determined by single factor method: the optimal crosslinking time was 1 h, the optimal crosslinking temperature was 20 °C, the recovery rate of enzyme activity of bgl2238 was 87 %, and the enzyme activity was 859.65 mU/g. The optimum temperature of the immobilized bgl2238 is 50 °C, which is 6 °C higher than that of the free bgl2238, and the temperature stability and pH stability are improved. After six consecutive hydrolysis of Polygonum cuspidatum, the degradation rate of polydatin is still over 70 %, which proves that the immobilized bgl2238 has good reusability. This will be helpful to evaluate the application prospect of β - glucosidase immobilized in this system and determine the best conditions for its production.
... The therapies for many incremental neurodegenerative disorders, such as Huntington disease, Parkinson's disease, and AD, were neurological problems. Resveratrol has strong metabolic effects and is considered an example of caloric limitation (Pasinetti et al., 2011). Resveratrol has shown neuroprotective effects on pleiotropic functions in recent years. ...
Alzheimer’s disease (AD) is a progressive cortex and hippocampal neurodegenerative disease which ultimately causes cognitively impaired decline in patients. The AD pathogen is a very complex process, including aggregation of Aβ (β-amyloid peptides), phosphorylation of tau-proteins, and chronic inflammation. Exactly, resveratrol, a polyphenol present in red wine, and many plants are indicated to show the neuroprotective effect on mechanisms mostly above. Resveratrol plays an important role in promotion of non-amyloidogenic cleavage of the amyloid precursor protein. It also enhances the clearance of amyloid beta-peptides and reduces the damage of neurons. Most experimental research on AD and resveratrol has been performed in many species, both in vitro and in vivo, during the last few years. Nevertheless, resveratrol’s effects are restricted by its bioavailability in the reservoir. Therefore, scientists have tried to improve its efficiency by using different methods. This review focuses on recent work done on the cell and animal cultures and also focuses on the neuroprotective molecular mechanisms of resveratrol. It also discusses about the therapeutic potential onto the treatment of AD.
... Consistently, a significant reduction in hippocampal neurodegeneration, associated with a decrease in SIRT1 acetylation [236,237], was observed after intracerebroventricular injection of RSV in an animal model. In addition, other studies showed that in mice overexpressing SIRT1 the cognitive defects, specific of the APP transgenic mouse [140,238], were reduced. ...
A new epoch is emerging with intense research on nutraceuticals, i.e., “food or food product that provides medical or health benefits including the prevention and treatment of diseases”, such as Alzheimer’s disease. Nutraceuticals act at different biochemical and metabolic levels and much evidence shows their neuroprotective effects; in particular, they are able to provide protection against mitochondrial damage, oxidative stress, toxicity of β-amyloid and Tau and cell death. They have been shown to influence the composition of the intestinal microbiota significantly contributing to the discovery that differential microorganisms composition is associated with the formation and aggregation of cerebral toxic proteins. Further, the routes of interaction between epigenetic mechanisms and the microbiota–gut–brain axis have been elucidated, thus establishing a modulatory role of diet-induced epigenetic changes of gut microbiota in shaping the brain. This review examines recent scientific literature addressing the beneficial effects of some natural products for which mechanistic evidence to prevent or slowdown AD are available. Even if the road is still long, the results are already exceptional.
... Previous studies have observed that the symptoms of Alzheimer's disease and Parkinson's disease are alleviated after DR [52]. Drugs that simulate DR, such as resveratrol, have been found to be effective in alleviating symptoms of these three neurodegenerative diseases and improve cognitive ability [53]. However, no research has clearly pointed out the mechanism or key factors so far. ...
To explore the underlying mechanism of dietary restriction (DR) induced lifespan extension in fruit flies at protein level, we performed proteome sequencing in Drosophila at day 7 (young) and day 42 (old) under DR and ad libitum (AL) conditions. A total of 18629 unique peptides were identified in Uniprot, corresponding to 3,662 proteins. Among them, 383 and 409 differentially expressed proteins (DEPs) were identified from comparison between DR vs AL at day 7 and 42, respectively. Bioinformatics analysis revealed that membrane-related processes, post-transcriptional processes, spliceosome and reproduction related processes, were highlighted significantly. In addition, expression of proteins involved in pathways such as spliceosomes, oxidative phosphorylation, lysosomes, ubiquitination, and riboflavin metabolism was relatively higher during DR. A relatively large number of DEPs were found to participate in longevity and age-related disease pathways. We identified 20 proteins that were consistently regulated during DR and some of which are known to be involved in ageing, such as mTORC1, antioxidant, DNA damage repair and autophagy. In the integration analysis, we found 15 genes that were stably regulated by DR at both transcriptional as well as translational levels. Our results provided a useful dataset for further investigations on the mechanism of DR and aging.
... Resveratrol possesses a wide range of biological effects, including anti-oxidative [24], anti-inflammatory [25], antiapoptotic [26,27], and anti-carcinogenic properties [28]. Neuroprotective effects of resveratrol have been shown in animal models of various diseases, such as cerebral ischemia [29,30], kainic acid-induced excitotoxicity [31], Huntington's disease [32], Parkinson's disease [33], and AD [34]. Resveratrol and other polyphenols have been shown to be capable of directly interfering with the hallmark of AD, i.e. toxic β-amyloid protein (Aβ) aggregation [17,18]. ...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. No effective therapies for AD are yet available, and potentially preventive lifestyle factors, including diet and physical activity, have become a focus of AD research. One such factor is moderate wine consumption, which has been claimed to be neuroprotective, and some studies have suggested a potential role for grapes and wine in retarding cognitive decline and other effects of aging. Polyphenols contained in grapes have been investigated as a preventive measure or potential therapy for dementia. The best-studied fruit polyphenol, the stilbenoid resveratrol (trans-3,5,4'-trihydroxystilbene), is known for its anti-oxidant and anti-inflammatory properties. The present short review evaluates the evidence regarding the role of red wine and resveratrol in the prevention and treatment of AD. Some research findings have suggested that resveratrol may be useful in the treatment of neurodegenerative diseases, including AD, due to its ability to reduce cognitive decline and to inhibit amyloid β aggregation in animal models of dementia. Studies in rodents have demonstrated neuroprotective effects of resveratrol on central features of AD, including decreased amyloid deposition and tau-hyperphosphorylation, enhanced hippocampal neurogenesis, and improved memory functions. The mechanisms through which resveratrol exerts neuroprotective efficacy in animals remain to be established. The potential of resveratrol to act as a nutraceutical targeting neuropathological changes in AD and exerting neuroprotective efficacy may be related to its anti-oxidant activities and its ability to antagonize amyloid aggregation, suppress neuroinflammation, decrease mitochondrial dysfunction, and modulate signaling pathways. In contrast to the neuroprotective activity of resveratrol in various in-vitro and in-vivo models, evidence of the ability of resveratrol to prevent age-associated neurodegeneration in humans and to improve cognitive deficits in AD is lacking. Thus, whether resveratrol has any beneficial effects in humans remains to be established. Pterostilbene (trans-3,5-dimethoxy-4'-hydroxystilbene), an analog of resveratrol, appears to be more effective than resveratrol in ameliorating brain alterations associated with aging and may be a more promising compound for future research. Moderate red wine intake is unable to provide resveratrol in amounts required for clinically relevant effects in AD. Were resveratrol proven to be effective in combatting AD, supplements or a drug should be substituted for wine as a source. Moreover, the toxic effects of alcohol should be considered, since recent evidence suggests that no level of alcohol consumption has beneficial health effects. In particular, long-term alcohol consumption, even in moderate quantities, is associated with multiple markers of abnormal brain structure, including hippocampal atrophy. Moderate drinking to promote brain health is not justified, and any claims regarding the potential efficacy of red wine in the prevention of AD are unsubstantiated and irresponsible.
... A lot of studies showed efficacy of resveratrol in protection against mutant polyglutamine-mediated cell death in striatal neuronal cultures isolated from the HdhQ111 knock-in mice model of HD (Parker et al., 2005). Moreover, oral administration of resveratrol reversed motor and cognitive impairments induced by 3-nitropropionic acid in mice, another model for neurotoxicity and HD (Pasinetti et al., 2011). ...
Mucopolysaccharidoses (MPS) represent a devastating group of lysosomal storage diseases (LSD) affecting approximately 1 in 25,000 individuals, where degradation of glycosaminoglycans (GAG) by lysosomal enzymes is impaired due to mutations causing defects in one of GAG-degrading enzymes. The most commonly used therapy for MPS is enzyme replacement therapy, consisting of application of an active form of the missing enzyme. However, supply of the missing enzyme is not enough in case of MPS types whose symptoms are expressed in central nervous system (CNS), as enzyme does not cross the blood-brain barrier. Moreover, even though enzyme replacement therapy for non-neuronopathic MPS IVA type is approved, it has a limited impact on bone abnormalities, that are one of main symptoms in the disease. Therefore, research into alternative therapeutic approaches for these types of MPS is highly desirable. One such alternative strategy is accelerated degradation of GAG by induction of autophagy. Autophagy is a process of lysosomal degradation of macromolecules that become abnormal or unnecessary for cells. One of the latest discoveries is that GAGs can also be such molecules. Potential drug should also cross blood-brain barrier and be safe in long-term therapy. It seems that one of the polyphenols, resveratrol, can meet the requirements. The mechanism of its action in autophagy stimulation is pleiotropic. Therefore, in this review, we will briefly discuss potential of resveratrol treatment for mucopolysaccharidosis through autophagy stimulation based on research in diseases with similar outcome.
... It also protects neuronal cells from toxicity of β-amyloid through activation of SIRT1/Akt1 pathway , through downregulation of Rho-associated kinase 1 (ROCK1) (Feng et al., 2013) and by promoting the expression auto-poly-ADP-ribosylation of poly(ADPribose) polymerase 1, as well as tyrosyl transfer-RNA synthetase (Deng and Mi, 2016). Peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha), an important substrate of SIRT1 is a principal regulator of energy metabolism, whose function is significantly impaired in HD (Ferretta et al., 2014;Pasinetti et al., 2011). Administration of resveratrol increased PGC-1α mRNA levels, reduced vacuolation in the brown adipose tissue and decreased elevated blood glucose levels in N171-82Q transgenic mice thus protecting peripheral tissues (Ho et al., 2010). ...
... Thus, the interest in natural products, specifically the large family of polyphenols, is based on current investigations that demonstrate therapeutic properties such as antioxidant, anti-amyloidogenic activity, cell signaling modulation, and metal chelation activity ( Fig. 1) [43][44][45]. Polyphenols have also been demonstrated to have neuroprotective activity against AD [1,46], PD [24,[47][48][49][50], HD [51,52], and ALS [53,54]. Metal chelation is a promising avenue for research due to increasing evidence of metal dyshomeostasis in AD; however, massive chelation as an approach may not be favorable because it could disrupt normal metalloproteins activity [45,55]. ...
Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multifactorial disease is primarily characterized by the formation of amyloid-β (Aβ) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-β protein precursor (AβPP) and Aβ42 peptide, affecting Aβ aggregation and increasing its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD.
... Resveratrol is being tested in many clinical trials, as it may exert these effects by targeting several main metabolic sensor/effector proteins, such as AMPK, SIRT1, and Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) [43]. A randomized, double-blind, placebo-controlled clinical trial in 24 patients with diagnoses of metabolic syndrome showed that resveratrol significantly decreases weight, Body Mass Index (BMI), fat mass, waist circumference, area under curve of insulin, and total insulin secretion [44]. ...
Resveratrol, also known as 3,5,4′-trihydroxystilbene, is a natural polyphenol that occurs as a phytoalexin. It is produced by plant sources such as grapes, apples, blueberries, plums, peanuts, and other oilseeds. This compound has a variety of effects on human health and diseases. This review summarizes the mounting evidence that resveratrol is helpful in treating metabolic syndrome and related disorders. Resveratrol can be provided either early as a reprogramming agent or later as part of treatment. A few of the main mechanisms underlying the beneficial effects of resveratrol on metabolic syndrome are outlined. This review also discusses the potential of resveratrol derivatives as a complementary or alternative medicine. In conclusion, resveratrol could be a useful regimen for the prevention and treatment of metabolic syndrome and its related conditions.
... It also protects neuronal cells from toxicity of β-amyloid through activation of SIRT1/Akt1 pathway , through downregulation of Rho-associated kinase 1 (ROCK1) (Feng et al., 2013) and by promoting the expression auto-poly-ADP-ribosylation of poly(ADPribose) polymerase 1, as well as tyrosyl transfer-RNA synthetase (Deng and Mi, 2016). Peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha), an important substrate of SIRT1 is a principal regulator of energy metabolism, whose function is significantly impaired in HD (Ferretta et al., 2014;Pasinetti et al., 2011). Administration of resveratrol increased PGC-1α mRNA levels, reduced vacuolation in the brown adipose tissue and decreased elevated blood glucose levels in N171-82Q transgenic mice thus protecting peripheral tissues (Ho et al., 2010). ...
http://www.appleacademicpress.com/nutraceuticals-and-dietary-supplements-applications-in-health-improvemepnt-and-disease-management-/9781771888738
https://www.taylorfrancis.com/books/e/9780367821517
... Resveratrol is a naturally occurring polyphenol has been been found to be associated with the protective effect on aging, neurotoxic conditions, metabolic disorders, neurotoxic diseases, inflammation, and cancer in animal models (Pasinetti et al., 2011). It has antioxidant properties and is involved in the activation of the SIRT1, a NAD + -dependent histone deacetylase that further enhance the peroxisome proliferator-γ-activated receptor coactivator-1α (PGC-1α) and FOXO activity. ...
Neurodegenerative diseases are one of the most devastating conditions that are typically associated with mutated genes, accumulation of abnormal proteins, enhanced oxidative stress and like. The mechanisms underlying neurodegenerative disorders are multifactorial and complex. Huntington disease is one such inherited condition that causes progressive degeneration of neurons in the brain. Escalating interests are focused on determining the protection against the progression of such devastating conditions through natural compounds. Nutraceuticals have recently gained importance owing to their safe use and multifaceted effects. In the present chapter, an attempt has been made to demonstrate the potential of coenzyme Q10, curcumin, resveratrol, a- lipoic acid and epigallocatechin 3-gallate in restoring the mitochondrial machinery by acting as highly strong anti-oxidant agents and modulating the pro-survival or pro-apoptotic signalling pathways. These food based compounds are believed to target multiple pathways in a slow but more physiological manner without causing any relentless adverse effects such as generation of ATP through participation in mitochondrial respiratory chain, SIRT1 activation, COX-1 inhibition, anti-protein aggregation, antiinflammatory cascade, restoration of mitochondrial membrane, translocation of NF-kB and restoration of Keap1/Nrf pathway leading to mitochondrial biogenesis, etc. All these effects of the nutraceuticals have attracted many research groups to focus on them so that potential therapeutic candidates against neurodegenerative disorders such as Huntington's disease can be developed to combat such alarming ailments.
... Resveratrol is a naturally occurring polyphenol has been been found to be associated with the protective effect on aging, neurotoxic conditions, metabolic disorders, neurotoxic diseases, inflammation, and cancer in animal models (Pasinetti et al., 2011). It has antioxidant properties and is involved in the activation of the SIRT1, a NAD + -dependent histone deacetylase that further enhance the peroxisome proliferator-γ-activated receptor coactivator-1α (PGC-1α) and FOXO activity. ...
Spices are used as flavouring and scrumptious agents that exhibit a wide range of pharmacological activities. The Indian spices add aroma and fragrance to foods. A few spices and contain many important chemical constituents in the form of essential oils, oleoresin, oleogu and resins, which are used for health and medicinal purposes. Central nervous system disorders are of greater importance and it has been evident in traditional books that spices can protect and cure neuronal ailments. Many spices found in India such as turmeric, pepper, ginger, cloves, cinnamon, onion, garlic and nutmeg are used for culinary purpose and have been found to have reported specific activities against brain disorders. This review focuses on the importance of spices in therapeutics of Huntington's disease by targeting mitochondrial and proteasome dysfunction, oxidative stress, inflammation and apoptosis.
In China, Parkinson’s disease (PD) is the second most prevalent central nervous system (CNS) degenerative illness affecting middle-aged and older persons. Movement disorders including resting tremor, bradykinesia, myotonia, postural instability, and gait instability are the predominant clinical symptoms. The two main types of PD are sporadic and familial, with sporadic PD being the more prevalent of the two. The environment, genetics, mitochondrial dysfunction, oxidative stress, inflammation, protein aggregation and misfolding, loss of trophic factors, cell death, and gut microbiota may all have a role in the etiology of PD. PD is inversely connected with other cancers and positively correlated with COVID-19, diabetes mellitus (DM), melanoma, and ischemic heart disease (IHD) risk. Delaying disease progression, managing motor and non-motor symptoms, and avoiding and controlling dysfunction in the middle and later phases of the disease are the key areas of research and development for its therapy. Presently, the development and progression of PD can be slowed down by using conventional pharmacology, natural items, and innovative technology. This article reviews the pathogenesis of PD, its correlations with other non-genetic diseases, and the research progress of drugs and technologies for alleviating PD.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a triad of motor, cognitive, and psychiatric problems. Caused by CAG repeat expansion in the huntingtin gene (HTT), the disease involves a complex network of pathogenic mechanisms, including synaptic dysfunction, impaired autophagy, neuroinflammation, oxidative damage, mitochondrial dysfunction, and extrasynaptic excitotoxicity. Although current therapies targeting the pathogenesis of HD primarily aim to reduce mHTT levels by targeting HTT DNA, RNA, or proteins, these treatments only ameliorate downstream pathogenic effects. While gene therapies, such as antisense oligonucleotides, small interfering RNAs and gene editing, have emerged in the field of HD treatment, their safety and efficacy are still under debate. Therefore, pharmacological therapy remains the most promising breakthrough, especially multi‐target/functional drugs, which have diverse pharmacological effects. This review summarizes the latest progress in HD drug development based on clinicaltrials.gov search results (Search strategy: key word “Huntington's disease” in HD clinical investigational drugs registered as of December 31, 2023), and highlights the key role of multi‐target/functional drugs in HD treatment strategies.
Neurodegenerative disorders (NDs) are among the most common causes of death across the globe. NDs are characterized by progressive damage to CNS neurons, leading to defects in specific brain functions such as memory, cognition, and movement. The most common NDs are Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). Despite extensive research, no therapeutics or medications against NDs have been proven to be effective. The current treatment of NDs involving symptom‐based targeting of the disease pathogenesis has certain limitations, such as drug resistance, adverse side effects, poor blood–brain barrier permeability, and poor bioavailability of drugs. Some studies have shown that plant‐derived natural compounds hold tremendous promise for treating and preventing NDs. Therefore, the primary objective of this review article is to critically analyze the properties and potency of some of the most studied phytomedicines, such as quercetin, curcumin, epigallocatechin gallate (EGCG), apigenin, and cannabinoids, and highlight their advantages and limitations for developing next‐generation alternative treatments against NDs. Further extensive research on pre‐clinical and clinical studies for developing plant‐based drugs against NDs from bench to bedside is warranted.
Resveratrol is a biologically active natural phenolic plant product. It has several properties which make them useful to treat the disease. In this review, we have highlighted the neuroprotective effects of resveratrol. Several available animal models have been proven to help understand the disease pathway and mechanism of action by resveratrol. In this review, we have highlighted the neuroprotective activity of resveratrol in AD, which effectively counter the neurodegenerative disease by decreasing the formation of plaques.
Resveratrol is a natural plant product that is easily available, cost-effective, and possesses neuroprotective activity, which is useful for treating neurodegenerative diseases. Resveratrol presents a promising avenue for AD treatment due to its diverse neuroprotective mechanisms. Given the ongoing global challenge in treating AD, researchers have increasingly focused on exploring the therapeutic potential of resveratrol.
The formation of the central nervous system is a meticulously planned and intricate process. Any modification to this process has the potential to disrupt the structure and operation of the brain, which could result in deficiencies in neurological growth. When neurotoxic substances are present during the early stages of development, they can be exceptionally dangerous. Prenatally, the immature brain is extremely vulnerable and is therefore at high risk in pregnant women associated with occupational exposures. Lead, fluoride, aluminum, and cadmium are examples of possibly toxic trace elements that have been identified as an environmental concern in the aetiology of a number of neurological and neurodegenerative illnesses. SIRT1, a member of the sirtuin family has received most attention for its potential neuroprotective properties. SIRT1 is an intriguing therapeutic target since it demonstrates important functions to increase neurogenesis and cellular lifespan by modulating multiple pathways. It promotes axonal extension, neurite growth, and dendritic branching during the development of neurons. Additionally, it contributes to neurogenesis, synaptic plasticity, memory development, and neuroprotection. This review summarizes the possible role of SIRT1 signalling pathway in potentially toxic trace elements -induced neurodevelopmental toxicity, highlighting some molecular pathways such as mitochondrial biogenesis, CREB/BDNF and PGC-1α/NRF1/TFAM.
Neurodegenerative disorders are characterized by mitochondrial dysfunction and subsequently oxidative stress, inflammation, and apoptosis that contribute to neuronal cytotoxicity and degeneration. Huntington’s (HD), Alzheimer’s (AD), and Parkinson’s (PD) diseases are three of the major neurodegenerative diseases. To date, researchers have found various natural phytochemicals that could potentially be used to treat neurodegenerative diseases. Particularly, the application of natural phenolic compounds has gained significant traction in recent years, driven by their various biological activities and therapeutic efficacy in human health. Polyphenols, by modulating different cellular functions, play an important role in neuroprotection and can neutralize the effects of oxidative stress, inflammation, and apoptosis in animal models. This review focuses on the current state of knowledge on phenolic compounds, including phenolic acids, flavonoids, stilbenes, and coumarins, as well as their beneficial effects on human health. We further provide an overview of the therapeutic potential and mechanisms of action of natural dietary phenolics in curing neurodegenerative diseases in animal models.
Advances in the treatment of neurodegenerative diseases (NDs) are nominal. Currently available therapies are merely symptomatic treatments that cannot prevent the development of the disease. Several herbs have been found very useful for managing neurological diseases. There are immense possibilities to discover a more successful line of ND treatment. Phytochemicals from medicinal plants may play a vital role in maintaining the chemical balance of the brain by affecting the capacity of receptors for the major inhibitory neurotransmitters. A few plants have already gained popularity for the potential treatment of NDs. This volume highlights the therapeutic role of medicinal plants and their scientific validation for improving neuronal health. It presents 15 chapters that cover the herbal treatment of NDs, including Parkinson's disease and Alzheimer's disease. The contents cover a range of pharmaceutical agents like sirtuins, berberine, rosmarinic acid and resveratrol. The book serves as a reference for pharmacology and herbal medicine scholars as well as healthcare workers interested in information about alternative and complementary therapies for neurological disorders.
Huntington's disease (HD) is an autosomal cognitive impairment neurodegenerative disorder that is characterized by behavioral and psychiatric disorders followed by dementia. HD is caused by repeated expansion of cytosine-adenine-guanine trinucleotide within the Huntingtin gene (Htt), which encodes for polyglutamine repeat in Huntingtin protein (Htt). Although a number of conventional treatment options such as antipsychotic drugs, antidepressants, mood stabilizing agents, anti-anxiety drugs and omega fatty acids are available for HD but all of them are associated with one or more side effects. Herbal products are an alternative remedies used for treatment of diverse pathological conditions are comparatively safe as compared to synthetic molecules. The present review summarizes various clinical and preclinical studies involving phytoconstituents which have been explored for treatment of huntington disease. Literature search was conducted using various electronic database i.e Scopus, Google, Pubmed, Web of Science. Search was conducted using different keywords such as “huntignton disease”, “herbal products”, “phytoconstituents”, “antihuntignton botanicals”, “herbal products for huntington disease”, “natural products for huntington disease” and “phytomedicine for huntington disease”. Further studies were screening by assessing abstracts and cross references and previously published review and research articles. A number of natural products are reported with antihuntington effects in various clinical and preclinical studies and some of them are also available as herbal formulations. Prominent phytoconstituents present in different plants exhibiting antihuntington effects include asiatic acid, celastrol, sesamol psoralen, isopsoralen, quercetin, madecassic acid, catechin, kaempferol, charantin, 6-shogoal, ellagic acid, celastrine, bacoside A, ginkgolide B, withaferin A, curcumin, scopoletin, caffeine, β-sitosterol, vitexin, rutin, apigenin, luteolin, cannabidiol, tetrahydrocannabinol, and resveratrol. The plant extracts containing these phytoconstituents or their isolated components are reported to exhibit antihuntington effect by targeting various enzymes, modulating inflammatory mediators and/or by improving cognitive impairment. Although, various preclinical studies have shown promising effects of phytochemicals in treatment of Huntington disease, but further investigation is required to prove their efficacy and safety in human beings.
Huntington disease (HD) is a distressing, innate neurodegenerative disease that descends from CAG repeat expansion in the huntingtin gene causing behavioral changes, motor dysfunction, and dementia in children and adults. Mutation in huntingtin (HTT) protein has been suggested to cause neuron loss in the cortex and striatum through various mechanisms including abnormal regulation of transcription, proteasomal dysfunction, post-translational modification, and other events, regulating toxicity. Pathogenesis of HD involves cleavage of the huntingtin protein followed by the neuronal accumulation of its aggregated form. Several research groups made possible efforts to reduce huntingtin gene expression, protein accumulation, and protein aggregation using inhibitors and molecular chaperones as developing drugs against HD. Herein, we review the mechanism proposed towards the formation of HTT protein aggregation and the impact of therapeutic strategies for the treatment of HD.
Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS) are neurological disorders, pathologically characterized by chronic degeneration of dopaminergic neurons and motor neurons respectively. There is still no cure or effective treatment against the disease progression and most of the treatments are symptomatic. The present review offers an overview of the different factors involved in the pathogenesis of these diseases. Subsequently, we focused on the recent advanced studies of dietary polyphenols and stem cell therapies, which have made it possible to slow down the progression of neurodegeneration. To date, stem cells and different polyphenols have been used for the directional induction of neural stem cells into dopaminergic neurons and motor neurons. We have also discussed their involvement in the modulation of different signal transduction pathways and growth factor levels in various in vivo and in vitro studies. Likewise stem cells, polyphenols also exhibit the potential of neuroprotection by their anti-apoptotic, anti-inflammatory, anti-oxidant properties regulating the growth factors levels and molecular signaling events. Overall this review provides a detailed insight into recent strategies that promise the use of polyphenol with stem cell therapy for the possible treatment of PD and ALS.
Neurodegenerative diseases are globally one of the leading causes of death and represent an enormous burden in human suffering, social distress, and economic costs. Recent data expanded on the initial antioxidant-based mechanism of polyphenols’ action by showing that they can modulate several cell-signaling pathways and mediators. The proposed benefits of polyphenols, either as protective/prophylactic substances or as therapeutic molecules, may be achieved by consuming a natural polyphenol-enriched diet by using food supplements nutraceuticals. It has also been proved that polyphenols’ health effects depend on the consumed amount and their bioavailability. This chapter addresses the impacts of food polyphenols and focuses on neuroprotection.
AMP-activated protein kinase (AMPK) is a serine/threonine kinase and a driving or deterrent factor in the development of neurodegenerative diseases and dementia. AMPK affects intracellular proteins like the mammalian target of rapamycin (mTOR). Peroxisome proliferator-activated receptor-γ coactivator 1-α (among others) contributes to a wide range of intracellular activities based on its downstream molecules such as energy balancing (ATP synthesis), extracellular inflammation, cell growth, and neuronal cell death (such as apoptosis, necrosis, and necroptosis). Several studies have looked at the dual role of AMPK in neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington disease (HD) but the exact effect of this enzyme on dementia, stroke, and motor neuron dysfunction disorders has not been elucidated yet. In this article, we review current research on the effects of AMPK on the brain to give an overview of the relationship. More specifically, we review the neuroprotective or neurodegenerative effects of AMPK or AMPK activators like metformin, resveratrol, and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside on neurological diseases and dementia, which exert through the intracellular molecules involved in neuronal survival or death.
Declined function of aged mesenchymal stem cells (MSCs) diminishes the benefits of cell therapy for myocardial infarction (MI). Our previous study has demonstrated that SRT1720, a specific SIRT1 activator, could protect aged human MSCs (hMSCs) against apoptosis. The purpose of the present study was to investigate the role of mitochondria in the anti-apoptotic effects of SRT1720. In addition, we established a non-human primate MI model to evaluate cell engraftment of SRT1720-pretreated aged hMSCs (SRT1720-OMSCs). A hydrogen peroxide (H2O2)-induced apoptosis model was established in vitro to mimic MI microenvironment. Compared with vehicle-treated aged hMSCs (Vehicle-OMSCs)，SRT1720-OMSCs showed alleviated apoptosis level, significantly decreased caspase-3 and caspase-9 activation, and reduced release of cytochrome c when subjected to H2O2 treatment. Mitochondrial contents were compared between young and aged hMSCs and our data showed that aged hMSCs had lower mitochondrial DNA (mtDNA) copy numbers and protein expression levels of components of the mitochondrial electron transport chain (ETC) than young hMSCs. And treatment with SRT1720 resulted in enhanced mitotracker staining, increased mtDNA levels and expression of mitochondrial ETC components in aged hMSCs. Furthermore, SRT1720-OMSCs exhibited elevated mitochondrial respiratory capacity and higher mitochondrial membrane potential. In vivo study demonstrated that SRT1720-OMSCs had higher engraftment rates than Vehicle-OMSCs at 3 days after transplantation into the infarcted non-human primate hearts. Taken together, these results suggest that SRT1720 promotes mitochondrial biogenesis and function of aged hMSCs, which is involved in its protective effects against H2O2-induced apoptosis. These findings encourage further exploration of the optimization of aged stem cells function via regulating mitochondrial function.
Mitochondria, colloquially known as "the powerhouse of the cell", play important roles in production, but also in processes critical for cellular fate such as cell death, differentiation, signaling, metabolic homeostasis, and innate immunity. Due to its many functions in the cell, the mitochondria have been linked to a variety of human illnesses such as diabetes, cancer, and neurodegenerative diseases. In order to further our understanding and pharmaceutical targeting of this critical organelle, effective strategies must be employed to breach the complex barriers and microenvironment of mitochondria. Here, we summarize advancements in mitochondria-targeted probes and therapeutics.
Purpose
The prevalence of Alzheimer's Disease is rising, in part due to increase in the medium age of residents in developed countries. The aim of the study has been to determine whether resveratrol (RSV) can be effective in the prevention or treatment of Alzheimer's Disease, providing its antioxidant, anti-inflammatory, and SIRT1-activating properties.
Methods
A systematic review of some experimental and clinical studies has been made. The eligibility criteria have comprised: maximum 10 years passed from the study publication, geographical diversity of the studies performed, and - as much as possible - pertaining of the reviewed study results both to animal models of AD, and to humans.
Results
After the final assessment of the eligibility criteria, 96 research studies have been included in the review. Overall results suggest that RSV can be effectively used in the prevention of AD, especially in reference to its familial forms with an early onset. At the same time, efficacy of RSV in the treatment of AD needs further studies, aimed at: improving its transport through the blood-brain barrier (BBB), performing prospective clinical in vivo trials on large groups of patients, and determining the optimal RSV dosage.
Discussion
Providing RSV mechanisms of action, inhibitory in reference to many pathomechanisms of AD, it seems very likely that RSV could be effective in AD prevention. The main limitations referring to such presumption include: limited permeability of BBB to RSV, and scarcity of clinical studies on RSV pertaining to large groups of humans.
Considerable evidences suggest a link between autophagy dysfunction, protein aggregation and neurodegenerative diseases. Given that autophagy is a conserved intracellular housekeeping process, modulation of autophagy flux in various model organisms have highlighted its importance for maintaining proteostasis. In postmitotic cells such as neurons, compromised autophagy is sufficient to cause accumulation of ubiquitinated aggregates, neuronal dysfunction, degeneration and loss of motor coordination-all hallmarks of neurodegenerative diseases. Reciprocally, enhanced autophagy flux augments cellular and organismal health, in addition to extending life span. These genetic studies not-withstanding, a plethora of small molecule modulators of autophagy flux have been reported that alleviate disease symptoms in models of neurodegenerative diseases. This review summarizes the potential of such molecules to be, perhaps, one of the first autophagy drugs for treating these currently incurable diseases.
Regarding the importance of genetic and epigenetic factors in regulation of aging process, different expression pattern of non-coding RNAs in aging could be investigated. Accordingly, micro RNAs (miRNAs) with a wide range of physiological functions as well as a significant footprint in many diseases have been demonstrated to be down or upregulated during the aging process. Therefore, age‐associated microRNAs and their targets have potentially detected the accelerated aging and predicted the risks for age‐related diseases. Polyphenols as important antioxidants in human dietary observed in fruits and some beverages have beneficial effects on longevity and aging. Considering miRNAs as an interesting mediator in modulating polyphenols′ biological effects, targeting miRNAs which is using polyphenols could be a novel strategy for aging.
Background
Alzheimer’s disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubule-associated protein tau. Increasing evidences demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has been previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown.
Method
The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging; The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay; The uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the mouse brains were evaluated by immunoblotting, immunostaining and ELISA, respectively.
Results
RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reduced the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice.
Conclusion
These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.
Huntington’s disease (HD) is a monogenic neurodegenerative disorder with no known cure. Selisistat is a novel, highly potent Sirt1 inhibitor with supportive pre-clinical data. Facilitation of autophagy and amelioration of transcriptional dysregulation are proposed as mechanisms of action. A first in disease Phase 1B study showed safety and tolerability. The peripheral immune dysfunction in HD could be modulated by Sirtuins which have both pro and anti-inflammatory activities. However selisistat did not alter the cytokine profile in this study. Phase 2 data over a longer duration was also well tolerated however potential hepatotoxicity is a concern. Sub-analysis of clinical assessments did not reveal any significant effect. Confirmation of proposed mechanisms of action is lacking and no Phase III studies are planned. Significant clinical heterogeneity exists in HD phenotypes which must reflect differing neuronal susceptibilities. A novel total motor score based sub-division of HD phenotypes failed to demonstrate any changes in a whole brain voxel-based morphometry (VBM) analysis. Clinical assessment alone lacks sensitivity over shorter time-spans in HD, and thus reliable, tolerable and sensitive biomarkers are required. Optical coherence tomography is a potential novel biomarker. The hypothesis that neuroretinal structures may be surrogate marker of intracranial disease was tested in a pilot biomarker study, the first of its kind in HD. Evidence of a statistically significant (p < 0.01) reduction in macular volume in HD subjects versus age and sex-matched controls is seen. No change in RFNL measures was seen. A correlation with increasing disease severity on ordinal regression was also noted. No correlation of macular volume and RNFL thickness with change in whole brain and caudate volumes. Furthermore, OCT was well tolerated by the majority of participants. Retinal abnormalities in HD have been confirmed in three subsequent independent OCT studies.
A POLYGLUTAMINE expansion (encoded by a CAG repeat) in specific proteins causes neurodegeneration in Huntington's disease (HD) and four other disorders1–6, by an unknown mechanism thought to involve gain of function or toxicity of the mutated protein7,8. The pathological threshold is 37–40 glutamines in three of these diseases, whereas the corresponding normal proteins contain polymorphic repeats of up to about 35 glutamines1–3. The age of onset of clinical manifestations is inversely correlated to the length of the polyglutamine expansion. Here we report the characterization of a monoclonal antibody that selectively recognizes polyglutamine expansion in the proteins implicated in HD and in spinocerebellar ataxia (SCA) 1 and 3. The intensity of signal depends on the length of the polyglutamine expansion, and the antibody also detects specific pathological proteins expected to contain such expansion, in SCA2 and in autosomal dominant cere-bellar ataxia with retinal degeneration, whose genes have not yet been identified9–13.
Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor- coactivator 1 (PGC-1) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a major role in maintaining energy homoeostasis. Within individual cells, AMPK is activated by a rise in the AMP/ATP ratio that occurs following a fall in ATP levels. AMPK is also regulated by the adipokines, adiponectin and leptin, hormones that are secreted from adipocytes. AMPK regulates a wide range of metabolic pathways, including fatty acid oxidation, fatty acid synthesis, glycolysis and gluconeogenesis. In peripheral tissues, activation of AMPK leads to responses that are beneficial in counteracting the deleterious effects that arise in the metabolic syndrome. Recent studies have demonstrated that modulation of AMPK activity in the hypothalamus plays a role in feeding. A decrease in hypothalamic AMPK activity is associated with decreased feeding, whereas activation of AMPK leads to increased food intake. Furthermore, signalling pathways occurring in the hypothalamus lead to changes in AMPK activity in peripheral tissues, such as skeletal muscle, via the sympathetic nervous system. AMPK, therefore, provides a mechanism for monitoring changes in energy metabolism within individual cells and at the level of the whole body. Activation of AMPK requires phosphorylation of threonine 172 (Thr-172) within the catalytic subunit. Recent studies have shown that both LKB1 and Ca(2+)/calmodulin-dependent protein kinase kinase-beta (CaMKKbeta) play important roles in phosphorylating and activating AMPK. In addition, there is evidence that AMPK can be activated by other upstream kinases, although the physiological significance of this is not clear at present. This review focuses on the role of LKB1 and CaMKKbeta in the regulation of AMPK.
The phytochemical resveratrol has undergone extensive preclinical investigation for its putative cancer chemopreventive properties. Low systemic availability of the parent compound due to rapid and extensive metabolism may confound its usefulness as a potential agent to prevent malignancies in organs remote from the site of absorption. Micronization allows increased drug absorption, thus increasing availability. Here we describe a pilot study of SRT501, micronized resveratrol, given as 5.0 g daily for 14 days, to patients with colorectal cancer and hepatic metastases scheduled to undergo hepatectomy. The purpose of the study was to assess the safety, pharmacokinetics, and pharmacodynamics of the formulation. SRT501 was found to be well tolerated. Mean plasma resveratrol levels following a single dose of SRT501 administration were 1,942 ± 1,422 ng/mL, exceeding those published for equivalent doses of nonmicronized resveratrol by 3.6-fold. Resveratrol was detectable in hepatic tissue following SRT501 administration (up to 2,287 ng/g). Cleaved caspase-3, a marker of apoptosis, significantly increased by 39% in malignant hepatic tissue following SRT501 treatment compared with tissue from the placebo-treated patients. SRT501 warrants further clinical exploration to assess its potential clinical utility.
Huntington's disease (HD) is a progressive neurodegenerative disorder associated with selective neuronal cell death. Abnormal aggregation of huntingtin protein with polyQ expansion has been shown to be causally linked to HD. Grape seed polyphenolic extract (GSPE) is a natural compound that has previously been shown to interfere with aggregations of proteins involved in neurological disorders, such as amyloid beta peptides (Aβ) and Tau protein. In this study we found that GSPE treatment significantly inhibits polyQ aggregation in phaeochromocytoma (PC)-12 cell line containing an ecdysone-inducible protein comprising the first 17 amino acid of huntingtin plus 103 glutamines fused with enhanced GFP. In vivo feasibility studies using the Q93httexon1 drosophila model of HD, we extended our in vitro evidence and found that flies fed with GSPE had a significantly improved lifespan compared to the control flies. Using the R6/2 rodent model of HD, we found that oral administration of 100 mg/kg/day GSPE (equivalent to 500mg per day in human) significantly attenuated the motor skill decay as well as extended the lifespan in the R6/2 mice relative to vehicle-control mice. Collectively, our studies strongly suggest that GSPE might be able to modulate the onset and/or progression of HD.
Huntington's disease (HD) is an inherited, progressive and ultimately fatal neurodegenerative disorder that is characterized by psychiatric, cognitive and motor symptoms. Among the pathways implicated in HD are those involving mitogen-activated protein kinase signaling and particularly the Ras-extracellular signal-regulated kinase (ERK) cascade. Studies in both cells and animal models suggest that ERK activation might provide a novel therapeutic target for the treatment of HD but compounds that specifically activate ERK are few. To test the hypothesis that pharmaceutical activation of ERK might be protective for HD, a polyphenol, fisetin, which was previously shown to activate the Ras-ERK cascade, was tested in three different models of HD: PC12 cells expressing mutant Httex1 under the control of an inducible promoter, Drosophila expressing mutant Httex1 and the R6/2 mouse model of HD. The results indicate that fisetin can reduce the impact of mutant huntingtin in each of these disease models. Prompted by this observation, we determined that the related polyphenol, resveratrol, also activates ERK and is protective in HD models. Notably, although more than a dozen small molecule inhibitors of ERK activation are in clinical trials, very few small molecule activators of ERK signaling are reported. Thus, fisetin, resveratrol and related compounds might be useful for the treatment of HD by virtue of their unique ability to activate ERK.
Drosophila models of tauopathies have been developed by transgenically overexpressing the disease-associated forms of tau. In this paper we report for the first time that a recently developed Grape-Seed Polyphenolic Extract (GSPE) improves the eye phenotype of a Drosophila eye model of R406W tau. GSPE-mediated improvements in this distinct in vivo neurodegeneration model for protein misfolding/aggregation suggest that GSPE may have therapeutic value in disorders involving aberrant protein aggregation.
The AMP-activated protein kinase (AMPK) is a key regulator of catabolic versus anabolic processes. Its properties as an energy sensor allow it to couple the energy status of the cell to the metabolic environment. These adaptations not only take place through the acute modulation of key metabolic enzymes via direct phosphorylation, but also through a slower transcriptional adaptative response. The question of how AMPK regulates the expression of a number of gene sets, such as those related to mitochondrial biogenesis, energy production and oxidative protection, is only beginning to be elucidated, and still many questions remain to be answered. In this review we will try to integrate our current knowledge on how AMPK regulates transcription in muscle and liver, which will serve as examples to illustrate the major advances in the field and the key challenges ahead.
A wide variety of agents activate AMPK, but in many cases the mechanisms remain unclear. We generated isogenic cell lines stably expressing AMPK complexes containing AMP-sensitive (wild-type, WT) or AMP-insensitive (R531G) gamma2 variants. Mitochondrial poisons such as oligomycin and dinitrophenol only activated AMPK in WT cells, as did AICAR, 2-deoxyglucose, hydrogen peroxide, metformin, phenformin, galegine, troglitazone, phenobarbital, resveratrol, and berberine. Excluding AICAR, all of these also inhibited cellular energy metabolism, shown by increases in ADP:ATP ratio and/or by decreases in cellular oxygen uptake measured using an extracellular flux analyzer. By contrast, A769662, the Ca(2+) ionophore, A23187, osmotic stress, and quercetin activated both variants to varying extents. A23187 and osmotic stress also increased cytoplasmic Ca(2+), and their effects were inhibited by STO609, a CaMKK inhibitor. Our approaches distinguish at least six different mechanisms for AMPK activation and confirm that the widely used antidiabetic drug metformin activates AMPK by inhibiting mitochondrial respiration.
AMP-activated protein kinase (AMPK) and the histone/protein deacetylase SIRT1 are fuel-sensing molecules that have coexisted in cells throughout evolution. When a cell's energy state is diminished, AMPK activation restores energy balance by stimulating catabolic processes that generate ATP and downregulating anabolic processes that consume ATP but are not acutely needed for survival. SIRT1 in turn is best known historically for producing genetic changes that mediate the increase in longevity caused by calorie restriction. Although the two molecules have been studied intensively for many years, only recently has it become apparent that they have similar effects on diverse processes such as cellular fuel metabolism, inflammation, and mitochondrial function. In this review we will examine the evidence that these similarities occur because AMPK and SIRT1 both regulate each other and share many common target molecules. In addition, we will discuss the clinical relevance of these interactions and in particular the possibility that their dysregulation predisposes to disorders such as type 2 diabetes and atherosclerotic cardiovascular disease and is a target for their therapy.
Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-beta (Abeta) peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers Abeta levels in cell lines; however, the underlying mechanism responsible for this effect is largely unknown. Moreover, the bioavailability of resveratrol in the brain remains uncertain. Here we show that AMPK signaling controls Abeta metabolism and mediates the anti-amyloidogenic effect of resveratrol in non-neuronal and neuronal cells, including in mouse primary neurons. Resveratrol increased cytosolic calcium levels and promoted AMPK activation by the calcium/calmodulin-dependent protein kinase kinase-beta. Direct pharmacological and genetic activation of AMPK lowered extracellular Abeta accumulation, whereas AMPK inhibition reduced the effect of resveratrol on Abeta levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of Abeta. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Abeta levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer disease.
Sirtuins catalyze NAD(+)-dependent protein deacetylation and are critical regulators of transcription, apoptosis, metabolism, and aging. There are seven human sirtuins (SIRT1-7), and SIRT1 has been implicated as a key mediator of the pathways downstream of calorie restriction that have been shown to delay the onset and reduce the incidence of age-related diseases such as type 2 diabetes. Increasing SIRT1 activity, either by transgenic overexpression of the Sirt1 gene in mice or by pharmacological activation by small molecule activators resveratrol and SRT1720, has shown beneficial effects in rodent models of type 2 diabetes, indicating that SIRT1 may represent an attractive therapeutic target. Herein, we have assessed purported SIRT1 activators by employing biochemical assays utilizing native substrates, including a p53-derived peptide substrate lacking a fluorophore as well as the purified native full-length protein substrates p53 and acetyl-CoA synthetase1. SRT1720, its structurally related compounds SRT2183 and SRT1460, and resveratrol do not lead to apparent activation of SIRT1 with native peptide or full-length protein substrates, whereas they do activate SIRT1 with peptide substrate containing a covalently attached fluorophore. Employing NMR, surface plasmon resonance, and isothermal calorimetry techniques, we provide evidence that these compounds directly interact with fluorophore-containing peptide substrates. Furthermore, we demonstrate that SRT1720 neither lowers plasma glucose nor improves mitochondrial capacity in mice fed a high fat diet. SRT1720, SRT2183, SRT1460, and resveratrol exhibit multiple off-target activities against receptors, enzymes, transporters, and ion channels. Taken together, we conclude that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.
Concord grape juice contains polyphenol compounds, which have antioxidant and anti-inflammatory properties and influence neuronal signalling. Concord grape juice supplementation has been shown to reduce inflammation, blood pressure and vascular pathology in individuals with CVD, and consumption of such flavonoid-containing foods is associated with a reduced risk for dementia. In addition, preliminary animal data have indicated improvement in memory and motor function with grape juice supplementation, suggesting potential for cognitive benefit in ageing humans. In this initial investigation of neurocognitive effects, we enrolled twelve older adults with memory decline but not dementia in a randomised, placebo-controlled, double-blind trial with Concord grape juice supplementation for 12 weeks. We observed significant improvement in a measure of verbal learning and non-significant enhancement of verbal and spatial recall. There was no appreciable effect of the intervention on depressive symptoms and no effect on weight or waist circumference. A small increase in fasting insulin was observed for those consuming grape juice. These preliminary findings suggest that supplementation with Concord grape juice may enhance cognitive function for older adults with early memory decline and establish a basis for more comprehensive investigations to evaluate potential benefit and assess mechanisms of action.
Activation of AMPK (AMP-activated protein kinase) by phosphorylation at Thr172 is catalysed by at least two distinct upstream kinases, i.e. the tumour suppressor LKB1, and CaMKKbeta (Ca2+/calmodulin-dependent protein kinase kinase-beta). The sequence around Thr172 is highly conserved between the two catalytic subunit isoforms of AMPK and the 12 AMPK-related kinases, and LKB1 has been shown to act upstream of all of them. In the present paper we report that none of the AMPK-related kinases tested could be phosphorylated or activated in intact cells or cell-free assays by CaMKKbeta, although we did observe a slow phosphorylation and activation of BRSK1 (brain-specific kinase 1) by CaMKKalpha. Despite recent reports, we could not find any evidence that the alpha and/or beta subunits of AMPK formed a stable complex with CaMKKbeta. We also showed that increasing AMP concentrations in HeLa cells (which lack LKB1) had no effect on basal AMPK phosphorylation, but enhanced the ability of agents that increase intracellular Ca2+ to activate AMPK. This is consistent with the effect of AMP on phosphorylation of Thr172 being due to inhibition of dephosphorylation, and confirms that the effect of AMP is independent of the upstream kinase utilized.
Resveratrol, a natural polyphenolic compound that is found in grapes and red wine, increases metabolic rate, insulin sensitivity, mitochondrial biogenesis, and physical endurance and reduces fat accumulation in mice. Although it is thought that resveratrol targets Sirt1, this is controversial because resveratrol also activates 5' AMP-activated protein kinase (AMPK), which also regulates insulin sensitivity and mitochondrial biogenesis. Here, we use mice deficient in AMPKalpha1 or -alpha2 to determine whether the metabolic effects of resveratrol are mediated by AMPK.
Mice deficient in the catalytic subunit of AMPK (alpha1 or alpha2) and wild-type mice were fed a high-fat diet or high-fat diet supplemented with resveratrol for 13 weeks. Body weight was recorded biweekly and metabolic parameters were measured. We also used mouse embryonic fibroblasts deficient in AMPK to study the role of AMPK in resveratrol-mediated effects in vitro.
Resveratrol increased the metabolic rate and reduced fat mass in wild-type mice but not in AMPKalpha1(-/-) mice. In the absence of either AMPKalpha1 or -alpha2, resveratrol failed to increase insulin sensitivity, glucose tolerance, mitochondrial biogenesis, and physical endurance. Consistent with this, the expression of genes important for mitochondrial biogenesis was not induced by resveratrol in AMPK-deficient mice. In addition, resveratrol increased the NAD-to-NADH ratio in an AMPK-dependent manner, which may explain how resveratrol may activate Sirt1 indirectly.
We conclude that AMPK, which was thought to be an off-target hit of resveratrol, is the central target for the metabolic effects of resveratrol.
The sirtuins are a highly conserved family of NAD(+)-dependent enzymes that regulate lifespan in lower organisms. Recently, the mammalian sirtuins have been connected to an ever widening circle of activities that encompass cellular stress resistance, genomic stability, tumorigenesis and energy metabolism. Here we review the recent progress in sirtuin biology, the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of enzymes somehow regulates how long we live.
AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1alpha and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.
We recently found that moderate consumption of two unrelated red wines generate from different grape species, a Cabernet Sauvignon and a muscadine wine that are characterized by distinct component composition of polyphenolic compounds, significantly attenuated the development of Alzheimer's disease (AD)-type brain pathology and memory deterioration in a transgenic AD mouse model. Interestingly, our evidence suggests that the two red wines attenuated AD phenotypes through independent mechanisms. In particular, we previously found that treatment with Cabernet Sauvignon reduced the generation of AD-type amyloid-β (Aβ) peptides. In contrast, evidence from our present study suggests that muscadine treatment attenuates Aβ neuropathology and Aβ-related cognitive deterioration in Tg2576 mice by interfering with the oligomerization of Aβ molecules to soluble high-molecular-weight Aβ oligomer species that are responsible for initiating a cascade of cellular events resulting in cognitive decline. Collectively, our observations suggest that distinct polyphenolic compounds from red wines may be bioavailable at the organism level and beneficially modulate AD phenotypes through multiple Aβ-related mechanisms. Results from these studies suggest the possibility of developing a “combination” of dietary polyphenolic compounds for AD prevention and/or therapy by modulating multiple Aβ-related mechanisms.
Several epidemiological studies indicate that moderate consumption of red wine is associated with a lower incidence of dementia and Alzheimer's disease. Red wine is enriched in antioxidant polyphenols with potential neuroprotective activities. Despite scepticism concerning the bioavailability of these polyphenols, in vivo data have clearly demonstrated the neuroprotective properties of the naturally occurring polyphenol resveratrol in rodent models for stress and diseases. Furthermore, recent work in cell cultures and animal models has shed light on the molecular mechanisms potentially involved in the beneficial effects of resveratrol intake against the neurodegenerative process in Alzheimer's disease.
Huntington's disease (HD) is one of an increasing number of human neurodegenerative disorders caused by a CAG/polyglutamine-repeat expansion. The mutation occurs in a gene of unknown function that is expressed in a wide range of tissues. The molecular mechanism responsible for the delayed onset, selective pattern of neuropathology, and cell death observed in HD has not been described. We have observed that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to (CAG)156 repeat expansions develop pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, prior to developing a neurological phenotype. The appearance in transgenic mice of these inclusions, followed by characteristic morphological change within neuronal nuclei, is strikingly similar to nuclear abnormalities observed in biopsy material from HD patients.
Neurodegenerative disorders like Huntington's disease (HD) are characterized by progressive and putative irreversible clinical and neuropathological symptoms, including neuronal protein aggregates. Conditional transgenic models of neurodegenerative diseases therefore could be a powerful means to explore the relationship between mutant protein expression and progression of the disease. We have created a conditional model of HD by using the tet-regulatable system. Mice expressing a mutated huntingtin fragment demonstrate neuronal inclusions, characteristic neuropathology, and progressive motor dysfunction. Blockade of expression in symptomatic mice leads to a disappearance of inclusions and an amelioration of the behavioral phenotype. We thus demonstrate that a continuous influx of the mutant protein is required to maintain inclusions and symptoms, raising the possibility that HD may be reversible.
In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.
This study was designed to explore the possibility that caloric restriction (CR) may benefit Alzheimer's disease (AD) by preventing beta-amyloid (Abeta) neuropathology pivotal to the initiation and progression of the disease. We report that a CR dietary regimen prevents Abeta peptides generation and neuritic plaque deposition in the brain of a mouse model of AD neuropathology through mechanisms associated with promotion of anti-amyloidogenic alpha-secretase activity. Study findings support existing epidemiological evidence indicating that caloric intake may influence risk for AD and raises the possibility that CR may be used in preventative measures aimed at delaying the onset of AD amyloid neuropathology.
The NAD+-dependent protein deacetylase family, Sir2 (or sirtuins), is important for many cellular processes including gene silencing, regulation of p53, fatty acid metabolism, cell cycle regulation, and life span extension. Resveratrol, a polyphenol found in wines and thought to harbor major health benefits, was reported to be an activator of Sir2 enzymes in vivo and in vitro. In addition, resveratrol was shown to increase life span in three model organisms through a Sir2-dependent pathway. Here, we investigated the molecular basis for Sir2 activation by resveratrol. Among the three enzymes tested (yeast Sir2, human SIRT1, and human SIRT2), only SIRT1 exhibited significant enzyme activation ( approximately 8-fold) using the commercially available Fluor de Lys kit (BioMol). To examine the requirements for resveratrol activation of SIRT1, we synthesized three p53 acetylpeptide substrates either lacking a fluorophore or containing a 7-amino-4-methylcoumarin (p53-AMC) or rhodamine 110 (p53-R110). Although SIRT1 activation was independent of the acetylpeptide sequence, resveratrol activation was completely dependent on the presence of a covalently attached fluorophore. Substrate competition studies indicated that the fluorophore decreased the binding affinity of the peptide, and, in the presence of resveratrol, fluorophore-containing substrates bound more tightly to SIRT1. Using available crystal structures, a model of SIRT1 bound to p53-AMC peptide was constructed. Without resveratrol, the coumarin of p53-AMC peptide is solvent-exposed and makes no significant contacts with SIRT1. We propose that binding of resveratrol to SIRT1 promotes a conformational change that better accommodates the attached coumarin group.
Previous studies of verbal episodic memory in pre-diagnostic Huntington's disease (HD) have yielded mixed results; some evidence suggests that memory decline is evident prior to the onset of pronounced neurological signs of HD, whereas other data indicate that memory function remains normal throughout the pre-diagnostic period. This study examines verbal episodic memory in a sample of CAG expanded individuals who have not yet been clinically diagnosed, and who represent a wide range of points along the continuum from health to disease. The Hopkins Verbal Learning Test—Revised (HVLT-R) was administered to 479 participants (428 with the HD CAG expansion and 51 without), and performance was compared to neurobiological indices of disease progression, including a DNA-based estimate of proximity to clinical diagnosis, magnetic resonance imaging (MRI) measures of striatal volume, and neurologist ratings of motor signs. Lower HVLT-R scores were associated with closer proximity to clinical diagnosis and smaller striatal volumes; these relationships were found even in groups with no neurological signs of HD. The CAG expanded groups, including those with only minimal neurological signs, had significantly lower HVLT-R scores than the control group, and performance was worse in sub-groups that had more neurological signs consistent with HD. These findings indicate that verbal episodic memory is affected in early pre-diagnostic HD and may decline as striatal volumes decrease and individuals approach the motor diagnostic threshold. (J.C. Stout).
Huntington's disease may present at any age, but most typically manifests between the ages of 35 and 45 years as a slowly progressive neurodegenerative movement disorder with cognitive and behavioral impairment. It is an autosomal-dominant disorder that has a substantial impact on family structure and dynamics in terms of providing care for affected family members and, for the offspring of an affected parent, dealing with at-risk status. Therapy that slows the progressive neuronal dysfunction or degeneration is unavailable, so pharmacotherapy is currently aimed primarily at managing behavioral and psychiatric symptoms, and, in selected cases, controlling severe chorea. Effective intervention by clinicians is possible, however, in terms of providing patients and families with accurate information about the disease, counseling them about availability of genetic testing at specialized centers, and in giving them sound advice regarding work, driving, relationships, finances, research participation, and support groups.
This paper reviews our current understanding of the absorption, bioavailability, and metabolism of resveratrol, with an emphasis on humans. The oral absorption of resveratrol in humans is about 75% and is thought to occur mainly by transepithelial diffusion. Extensive metabolism in the intestine and liver results in an oral bioavailability considerably less than 1%. Dose escalation and repeated dose administration of resveratrol does not appear to alter this significantly. Metabolic studies, both in plasma and in urine, have revealed major metabolites to be glucuronides and sulfates of resveratrol. However, reduced dihydroresveratrol conjugates, in addition to highly polar unknown products, may account for as much as 50% of an oral resveratrol dose. Although major sites of metabolism include the intestine and liver (as expected), colonic bacterial metabolism may be more important than previously thought. Deconjugation enzymes such as β-glucuronidase and sulfatase, as well as specific tissue accumulation of resveratrol, may enhance resveratrol efficacy at target sites. Resveratrol analogs, such as methylated derivatives with improved bioavailability, may be important in future research.
A hallmark of Alzheimer's disease (AD) is the accumulation of plaques of Abeta 1-40 and 1-42 peptides, which result from the sequential cleavage of APP by the beta and gamma-secretases. The production of Abeta peptides is avoided by alternate cleavage of APP by the alpha and gamma-secretases. Here we show that production of beta-amyloid and plaques in a mouse model of AD are reduced by overexpressing the NAD-dependent deacetylase SIRT1 in brain, and are increased by knocking out SIRT1 in brain. SIRT1 directly activates the transcription of the gene encoding the alpha-secretase, ADAM10. SIRT1 deacetylates and coactivates the retinoic acid receptor beta, a known regulator of ADAM10 transcription. ADAM10 activation by SIRT1 also induces the Notch pathway, which is known to repair neuronal damage in the brain. Our findings indicate SIRT1 activation is a viable strategy to combat AD and perhaps other neurodegenerative diseases.
A diverse group of neurodegenerative diseases are characterized by progressive, age-dependent intracellular formation of misfolded protein aggregates. These include Alzheimer's disease, Huntington's disease, Parkinson's disease and a number of tau-mediated disorders. There is no effective treatment for any of these disorders; currently approved interventions are designed to treat disease symptoms and generally lead to modest modulation of clinical symptoms. None are known to mitigate underlying neuropathologic mechanisms and, thus, it is not unexpected that existing treatments appear ineffective in modulating disease progression. We note that these neurodegenerative disorders all share a common mechanistic theme in that depositions of misfolded protein in the brain is a key molecular feature underlying disease onset and/or progression. While previous studies have identified a number of drugs and nutraceuticals capable of interfering with the formation and/or stability of misfolded protein aggregates, none have been demonstrated to be effective in vivo for treating any of the neurodegenerative disorders. We hereby review accumulating evidence that a select nutraceutical grape-seed polyphenolic extract (GSPE) is effective in vitro and in vivo in mitigating certain misfolded protein-mediated neuropathologic and clinical phenotypes. We will also review evidence implicating bioavailability of GSPE components in the brain and the tolerability as well as safety of GSPE in animal models and in humans. Collectively, available information supports continued development of the GSPE for treating a variety of neurodegenerative disorders involving misfolded protein-mediated neuropathologic mechanisms.
Sirtuins are NAD-dependent deacetylases that regulate important biologic processes including transcription, cell survival and metabolism. Activation of SIRT1, a mammalian sirtuin, extends longevity and increases neuronal survival. An important substrate of SIRT1 is peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha), a principal regulator of energy metabolism, whose function is significantly impaired in Huntington's disease (HD). We studied the effects of a pharmacological preparation of the SIRT1 activator resveratrol (SRT501-M), in the N171-82Q transgenic mouse model of HD. We analyzed motor performance, survival, central and peripheral pathology and levels of PGC-1alpha expression. Administration of SRT501-M increased expression of PGC-1alpha, as well as its downstream targets, nuclear respiratory factor-1 (NRF-1) and uncoupling protein-1 (UCP-1) in brown adipose tissue (BAT), but there was no effect on PGC-1alpha, NRF-1 or the mitochondrial transcription factor (Tfam) in the striatum. SRT501-M administration also reduced BAT vacuolation and decreased elevated blood glucose levels. However, there was no significant improvement in weight loss, motor performance, survival and striatal atrophy. Activation of the PGC-1alpha signaling pathway via resveratrol-induced activation of SIRT1, therefore, is an effective therapy in BAT, but not in the central nervous system of HD transgenic mice.
We investigated the ability of AMP-activated protein kinase (AMPK) to activate PPARgamma coactivator-1alpha (PGC-1alpha) in the brain, liver and brown adipose tissue (BAT) of the NLS-N171-82Q transgenic mouse model of Huntington's disease (HD). In the striatum of the HD mice, the baseline levels of PGC-1alpha, NRF1, NRF2, Tfam, COX-II, PPARdelta, CREB and ERRalpha mRNA and mitochondrial DNA (mtDNA), were significantly reduced. Administration of the creatine analog beta guanidinopropionic acid (GPA) reduced ATP and PCr levels and increased AMPK mRNA in both the cerebral cortex and striatum. Treatment with GPA significantly increased expression of PGC-1alpha, NRF1, Tfam and downstream genes in the striatum and cerebral cortex of wild-type (WT) mice, but there was no effect on these genes in the HD mice. The striatum of the untreated HD mice showed microvacuolation in the neuropil, as well as gliosis and huntingtin aggregates, which were exacerbated by treatment with GPA. GPA treatment produced a significant increase in mtDNA in the cerebral cortex and striatum of WT mice, but not in HD mice. The HD mice treated with GPA had impaired activation of liver PGC-1alpha and developed hepatic steatosis with accumulation of lipids, degeneration of hepatocytes and impaired activation of gluconeogenesis. The BAT in the HD mice showed vacuolation due to accumulation of neutral lipids, and age-dependent impairment of UCP-1 activation and temperature regulation. Impaired activation of PGC-1alpha, therefore, plays an important role in the behavioral phenotype, metabolic disturbances and pathology of HD, which suggests the possibility that agents that enhance PGC-1alpha function will exert therapeutic benefits in HD patients.
Alzheimer's disease is the largest unmet medical need in neurology. Current drugs improve symptoms, but do not have profound disease-modifying effects. However, in recent years, several approaches aimed at inhibiting disease progression have advanced to clinical trials. Among these, strategies targeting the production and clearance of the amyloid-beta peptide - a cardinal feature of Alzheimer's disease that is thought to be important in disease pathogenesis - are the most advanced. Approaches aimed at modulating the abnormal aggregation of tau filaments (another key feature of the disease), and those targeting metabolic dysfunction, are also being evaluated in the clinic. This article discusses recent progress with each of these strategies, with a focus on anti-amyloid strategies, highlighting the lessons learned and the challenges that remain.
Sirt1, a mammalian member of the sirtuin gene family, holds great potential for promoting longevity, preventing against disease and increasing cell survival. For example, studies suggest that the beneficial impact of caloric restriction in promoting longevity and cellular function may be mediated, in part, by Sirt1 through mechanisms involving PGC-1alpha, which plays important role in the regulation of cellular metabolism and inflammatory and antioxidant responses. Sirt1 may also interfere with mechanisms implicated in pathological disorders. We will present recent evidence indicating that Sirt1 may protect against Alzheimer's disease by interfering with the generation of beta-amyloid peptides. We will discuss Sirt1 as a potential novel target, in addition to the development of Sirt1 activators for the prevention and treatment of Alzheimer's disease.
Resveratrol is a plant polyphenol capable of exerting beneficial metabolic effects which are thought to be mediated in large by the activation of the NAD(+)-dependent protein deacetylase SIRT1. Although resveratrol has been claimed to be a bona fide SIRT1 activator using a peptide substrate (Fluor de Lys-SIRT1 peptide substrate), recent reports indicate that this finding might be an experimental artifact and need to be clarified. Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzyme, (ii) resveratrol does not activate SIRT1 in vitro in the presence of either a p53-derived peptide substrate or acetylated PGC-1alpha isolated from cells, and (iii) although SIRT1 deacetylates PGC-1alpha in both in vitro and cell-based assays, resveratrol did not activate SIRT1 under these conditions. Based on these observations, we conclude that the pharmacological effects of resveratrol in various models are unlikely to be mediated by a direct enhancement of the catalytic activity of the SIRT1 enzyme. In consequence, our data challenge the overall utility of resveratrol as a pharmacological tool to directly activate SIRT1.
Analysis of 78 Huntington's disease (HD) chromosomes with multi-allele markers revealed 26 different haplotypes, suggesting a variety of independent HD mutations. The most frequent haplotype, accounting for about one third of disease chromosomes, suggests that the disease gene is between D4S182 and D4S180. However, the paucity of an expected class of chromosomes that can be related to this major haplotype by assuming single crossovers may reflect the operation of other mechanisms in creating haplotype diversity. Some of these mechanisms sustain alternative scenarios that do not require a multiple mutational origin for HD and/or its positioning between D4S182 and D4S180.
Persons symptomatic and at risk for Huntington's disease (HD) from a large extended family in the state of Zulia, Venezuela, have been followed prospectively for 7 years. Between 1981 and 1988, 593 people were examined, of whom 128 had symptomatic HD and 171 persons at risk had examination abnormalities that were insufficient to meet criteria for diagnosis. The remaining 294 had normal examinations. Abnormalities of saccadic eye movement and slowness of rapid alternating movements were the most common abnormalities found in at-risk individuals. Thirty persons who did not meet criteria for diagnosis at their first examination have subsequently been diagnosed with symptomatic HD. Their average age at diagnosis was 33.5 ± 8.3 (SD) years. The likelihood of developing symptomatic HD within 3 years was 3% for those persons with normal first examinations, 23% for those with mildly abnormal first examinations, and 60% for those with highly abnormal first examinations. The rate of disease progression in early symptomatic cases were 1.4 ± 0.1 (SEM) points per year on the Shoulson-Fahn functional capacity scale. Paternal or maternal inheritance did not appear to affect the rate of progression in this group of individuals. The data suggest that there is not a discrete age of onset but rather a prolonged period of time during which symptoms unfold. Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/50397/1/870050202_ftp.pdf
We investigated the role of PPAR gamma coactivator 1alpha (PGC-1alpha) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1alpha and target genes expression in muscle of HD transgenic mice. We produced chronic energy deprivation in HD mice by administering the catabolic stressor beta-guanidinopropionic acid (GPA), a creatine analogue that reduces ATP levels, activates AMP-activated protein kinase (AMPK), which in turn activates PGC-1alpha. Treatment with GPA resulted in increased expression of AMPK, PGC-1alpha target genes, genes for oxidative phosphorylation, electron transport chain and mitochondrial biogenesis, increased oxidative muscle fibers, numbers of mitochondria and motor performance in wild-type, but not in HD mice. In muscle biopsies from HD patients, there was decreased PGC-1alpha, PGC-1beta and oxidative fibers. Oxygen consumption, PGC-1alpha, NRF1 and response to GPA were significantly reduced in myoblasts from HD patients. Knockdown of mutant huntingtin resulted in increased PGC-1alpha expression in HD myoblast. Lastly, adenoviral-mediated delivery of PGC-1alpha resulted increased expression of PGC-1alpha and markers for oxidative muscle fibers and reversal of blunted response for GPA in HD mice. These findings show that impaired function of PGC-1alpha plays a critical role in muscle dysfunction in HD, and that treatment with agents to enhance PGC-1alpha function could exert therapeutic benefits. Furthermore, muscle may provide a readily accessible tissue in which to monitor therapeutic interventions.
Peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1alpha) has been extensively described as a master regulator of mitochondrial biogenesis. However, PGC-1alpha activity is not constant and can be finely tuned in response to different metabolic situations. From this point of view, PGC-1alpha could be described as a mediator of the transcriptional outputs triggered by metabolic sensors, providing the idea that these sensors, together with PGC-1alpha, might be weaving a network controlling cellular energy expenditure. In this review, we will focus on how disorders such as type 2 diabetes and the metabolic syndrome might be related to an abnormal and improper function of this network.
Two metabolic sensors, AMP-activated protein kinase (AMPK) and SIRT1 have been described to directly affect PGC-1alpha activity through phosphorylation and deacetylation, respectively. Although the physiological relevance of these modifications and their molecular consequences are still largely unknown, recent insight from different in-vivo transgenic models clearly suggests that AMPK, SIRT1 and PGC-1alpha might act as an orchestrated network to improve metabolic fitness.
Metabolic sensors such as AMPK and SIRT1, gatekeepers of the activity of the master regulator of mitochondria, PGC-1alpha, are vital links in a regulatory network for metabolic homeostasis. Together, these players explain many of the beneficial effects of physical activity and dietary interventions in our battle against type 2 diabetes and related metabolic disorders. Hence, understanding the mechanisms by which they act could guide us to identify and improve preventive and therapeutic strategies for metabolic diseases.
Type 2 diabetes is one of the fastest growing public health problems worldwide, resulting from both genetic factors and inadequate adaptation to environmental changes. It is characterized by abnormal glucose and lipid metabolism due in part to resistance to the actions of insulin in skeletal muscle, liver and fat. AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, acts as an integrator of regulatory signals monitoring systemic and cellular energy status. The growing realization that AMPK regulates the coordination of anabolic and catabolic metabolic processes represents an attractive concept for type 2 diabetes therapy. Recent findings showing that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profile and blood pressure in insulin-resistant rodents suggest that this kinase could be a novel therapeutic target in the treatment of type 2 diabetes. Consistent with these results, physical exercise and major classes of antidiabetic drugs have recently been reported to activate AMPK. In the present review, we update these topics and discuss the concept of targeting the AMPK pathway for the treatment of type 2 diabetes.
Dietary restriction (DR) has the remarkable ability to extend lifespan and healthspan. A variety of DR regimens have been described in species ranging from yeast to mammals. However, whether different DR regimens extend lifespan via universal, distinct, or overlapping pathways is still an open question. Here we examine the genetic pathways that mediate longevity by different DR regimens in Caenorhabditis elegans. We have previously shown that the low-energy sensing AMP-activated protein kinase AMPK/aak-2 and the Forkhead transcription factor FoxO/daf-16 are necessary for longevity induced by a DR regimen that we developed (sDR). Here we find that AMPK and FoxO are necessary for longevity induced by another DR regimen, but are dispensable for the lifespan extension induced by two different DR methods. Intriguingly, AMPK is also necessary for the lifespan extension elicited by resveratrol, a natural polyphenol that mimics some aspects of DR. Conversely, we test if genes previously reported to mediate longevity by a variety of DR methods are necessary for sDR-induced longevity. Although clk-1, a gene involved in ubiquinone biosynthesis, is also required for sDR-induced lifespan extension, we find that four other genes (sir-2.1, FoxA/pha-4, skn-1, and hsf-1) are all dispensable for longevity induced by sDR. Consistent with the observation that different DR methods extend lifespan by mostly independent genetic mechanisms, we find that the effects on lifespan of two different DR regimens are additive. Understanding the genetic network by which different DR regimens extend lifespan has important implications for harnessing the full benefits of DR on lifespan and healthspan.
Resveratrol, a polyphenol found in red wine, peanuts, soy beans, and pomegranates, possesses a wide range of biological effects. Since resveratrol's properties seem ideal for treating neurodegenerative diseases, its ability to diminish amyloid plaques was tested. Mice were fed clinically feasible dosages of resveratrol for forty-five days. Neither resveratrol nor its conjugated metabolites were detectable in brain. Nevertheless, resveratrol diminished plaque formation in a region specific manner. The largest reductions in the percent area occupied by plaques were observed in medial cortex (-48%), striatum (-89%) and hypothalamus (-90%). The changes occurred without detectable activation of SIRT-1 or alterations in APP processing. However, brain glutathione declined 21% and brain cysteine increased 54%. The increased cysteine and decreased glutathione may be linked to the diminished plaque formation. This study supports the concept that onset of neurodegenerative disease may be delayed or mitigated with use of dietary chemo-preventive agents that protect against beta-amyloid plaque formation and oxidative stress.
Resveratrol is a phytoalexin structurally related to stilbenes, which is synthesized in considerable amounts in the skin of grapes, raspberries, mulberries, pistachios and peanuts, and by at least 72 medicinal and edible plant species in response to stress conditions. It was isolated in 1940 and did not maintain much interest for around five decades until its role in treatment of cardiovascular diseases was suggested. To date, resveratrol has been identified as an agent that may be useful to treat cancer, pain, inflammation, tissue injury, and other diseases. However, currently the attention is being focused in analyzing its properties against neurodegenerative diseases and as antiaging compound. It has been reported that resveratrol shows effects in in vitro models of epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and nerve injury. However, evidences in vivo as well as in human beings are still lacking. Thus, further investigations on the pharmacological effects of resveratrol in vivo are necessary before any conclusions on its effects on neurodegenerative diseases can be obtained.
In postmortem brain specimens from 163 clinically diagnosed cases of Huntington's disease (HD) the striatum exhibited marked variation in the severity of neuropathological involvement. A system for grading this severity was established by macroscopic and microscopic criteria, resulting in five grades (0-4) designated in ascending order of severity. The grade correlates closely with the extent of clinical disability as assessed by a rating scale. In five cases of clinically diagnosed HD there were no discernible neuropathological abnormalities (grade 0), suggesting that the anatomical changes lag behind the development of clinical abnormalities. In eight cases, neuropathological changes could only be recognized microscopically (grade 1). The earliest changes were seen in the medial paraventricular portions of the caudate nucleus (CN), in the tail of the CN, and in the dorsal part of the putamen. Counts of neurons in the CN reveal that 50% are lost in grade 1 and that 95% are lost in grade 4; astrocytes are greatly increased in grades 2-4. These studies indicate that analyses of the CN in grade 4 would reflect mainly its astrocytic composition with a component of remote neurons projecting to the striatum. Because of the relative preservation of the lateral half of the head of the CN in grades 1-2, these regions would reflect early cellular and biochemical changes in HD.
Alcoholism is a possible cause of dementia, mainly through associated nutritional deficiencies and, rarely, through acute direct toxicity. However alcohol consumption was not found to be a risk factor in previous epidemiologic studies. We prospectively studied 3,777 community residents aged 65 and over, in the districts of Gironde and Dordogne. Average daily alcoholic consumption was recorded at baseline. Incident cases of dementia and Alzheimer's disease were screened at follow-up with explicit criteria. At 3 years, 2,273 subjects not demented at baseline were still available for follow-up. Wine was the only alcoholic beverage reported by more than 95 p. 100 of regular drinkers. In the 318 subjects drinking 3 to 4 standard glasses per day (> 250 and up to 500 ml), categorized as moderate drinkers, the crude odds ratio (OR) was 0.18 for incident dementia (p < 0.01) and 0.25 for Alzheimer's disease (p < 0.03), as compared to the 971 non-drinkers. After adjusting for age, sex, education, occupation, baseline MMSE and other possible confounders, the ORs were respectively 0.19 (p < 0.01) and 0.28 (p < 0.05). In the 922 mild drinkers (< 1 to 2 glasses per day) there was a negative association only with AD, after adjustment (OR = 0.55; p < 0.05). The inverse relationship between moderate wine drinking and incident dementia was explained neither by known predictors of dementia nor by medical, psychological or socio-familial factors. Considering also the well documented negative associations between moderate wine consumption and cardiovascular morbidity and mortality in this age group, it seems that there is no medical rationale to advise people over 65 to quit drinking wine moderately, as this habit carries no specific risk and may even be of some benefit for their health. Advising all elderly people to drink wine regularly for prevention of dementia would be however premature at this stage.
The cause of neurodegeneration in Huntington's disease (HD) is unknown. Patients with HD have an expanded NH2-terminal polyglutamine region in huntingtin. An NH2-terminal fragment of mutant huntingtin was localized to neuronal intranuclear inclusions (NIIs) and dystrophic neurites (DNs)
in the HD cortex and striatum, which are affected in HD, and polyglutamine length influenced the extent of huntingtin accumulation
in these structures. Ubiquitin was also found in NIIs and DNs, which suggests that abnormal huntingtin is targeted for proteolysis
but is resistant to removal. The aggregation of mutant huntingtin may be part of the pathogenic mechanism in HD.
Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid beta-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought gamma-secretase, coupled with the recent identification of beta-secretase, has provided discrete biochemical targets for drug screening and development. Alternate and novel strategies for inhibiting the early mechanism of the disease are also emerging. The progress reviewed here, coupled with better ability to diagnose the disease early, bode well for the successful development of therapeutic and preventative drugs for this major public health problem.
The purpose of this study was to investigate the implications of selected chemopreventive parameters and metabolic conversion of resveratrol in vivo. In two 8-week long feeding experiments with rats, a low-resveratrol diet containing 50 mg resveratrol per kg body weight (bw) and day and a high-resveratrol diet with 300 mg per kg bw and day were administered. For chemopreventive evaluation selected phase I and phase II enzymes of the biotransformation system, the total antioxidant activity, and the vitamin E status of the animals were determined. The level of resveratrol and its metabolites in the feces, urine, plasma, liver, and kidneys was identified and quantitated by high-performance liquid chromatography-diode array detection (HPLC-DAD) using synthesized resveratrol conjugate standards. Feeding of different dosages of resveratrol revealed no effect on the different chemopreventive parameters, except for the total antioxidant activity, which was elevated in plasma by 19% after feeding 50 mg resveratrol per kg bw and day. The formation of trans-resveratrol-3-sulfate, trans-resveratrol-4'-sulfate, trans-resveratrol-3,5-disulfate, trans-resveratrol-3,4'-disulfate, trans-resveratrol-3,4',5-trisulfate, trans-resveratrol-3-O-beta-D-glucuronide, and resveratrol aglycone was detected by HPLC analysis, depending on the biological material. Total resveratrol recovery in urine and feces of rats fed on 50 mg resveratrol per kg bw and day was 15% and 13%, respectively. For rats fed the higher dosage of 300 mg resveratrol per kg bw and day recovery was 54% and 17%, respectively. This is the first study performed with synthesized standards of relevant resveratrol conjugates. The lack of effect on the chemopreventive parameters is probably due to the formation of various resveratrol conjugates reducing its bioavailability in the rat.