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Journal Pre-proof Dietary flavonoids may have a protective and therapeutic effect in Parkinson's disease: A systematic review
The rising prevalence of Parkinson’s disease (PD) globally presents a significant public health challenge for national healthcare systems, particularly in low-to-middle income countries, such as Thailand, which may have insufficient resources to meet these escalating healthcare needs. There are also many undiagnosed cases of early-stage PD, a period when therapeutic interventions would have the most value and least cost. The traditional “passive” approach, whereby clinicians wait for patients with symptomatic PD to seek treatment, is inadequate. Proactive, early identification of PD will allow timely therapeutic interventions, and digital health technologies can be scaled up in the identification and early diagnosis of cases. The Parkinson’s disease risk survey (TCTR20231025005) aims to evaluate a digital population screening platform to identify undiagnosed PD cases in the Thai population. Recognizing the long prodromal phase of PD, the target demographic for screening is people aged ≥ 40 years, approximately 20 years before the usual emergence of motor symptoms. Thailand has a highly rated healthcare system with an established universal healthcare program for citizens, making it ideal for deploying a national screening program using digital technology. Designed by a multidisciplinary group of PD experts, the digital platform comprises a 20-item questionnaire about PD symptoms along with objective tests of eight digital markers: voice vowel, voice sentences, resting and postural tremor, alternate finger tapping, a “pinch-to-size” test, gait and balance, with performance recorded using a mobile application and smartphone’s sensors. Machine learning tools use the collected data to identify subjects at risk of developing, or with early signs of, PD. This article describes the selection and validation of questionnaire items and digital markers, with results showing the chosen parameters and data analysis methods to be robust, reliable, and reproducible. This digital platform could serve as a model for similar screening strategies for other non-communicable diseases in Thailand.
Purpose: Iron is an essential nutrient which can only be absorbed through an individual's diet. Excess iron accumulates in organs throughout the body including the brain. Iron dysregulation in the brain is commonly associated with neurodegenerative diseases like Alzheimer's disease and Parkinson's Disease (PD). Our previous research has shown that a pattern of iron accumulation in motor regions of the brain related to a genetic iron-storage disorder called hemochromatosis is associated with an increased risk of PD. To understand how diet and lifestyle factors relate to this brain endophenotype and risk of PD we analyzed the relationship between these measures, estimates of nutrient intake, and diet and lifestyle preference using data from UK Biobank.
Methods: Using distinct imaging and non-imaging samples (20,477 to 28,388 and 132,023 to 150,603 participants, respectively), we performed linear and logistic regression analyses using estimated dietary nutrient intake and food preferences to predict a) brain iron accumulation score (derived from T2-Weighted Magnetic Resonance Imaging) and b) PD risk. In addition, we performed a factor analysis of diet and lifestyle preferences to investigate if latent lifestyle factors explained significant associations. Finally, we performed an instrumental variable regression of our results related to iron accumulation and PD risk to identify if there were common dietary and lifestyle factors that were jointly associated with differences in brain iron accumulation and PD risk.
Results: We found multiple highly significant associations with measures of brain iron accumulation and preferences for alcohol (factor 7: t=4.02, pFDR=0.0003), exercise (factor 11: t=-4.31, pFDR=0.0001), and high-sugar foods (factor 2: t=-3.73, pFDR=0.0007). Preference for alcohol (factor 7: t=-5.83, pFDR<1x10-8), exercise (factor 11: t=-7.66, pFDR<1x10-13), and high sugar foods (factor 2: t=6.03, pFDR<1x10-8) were also associated with PD risk. Instrumental variable regression of individual preferences revealed a significant relationship in which dietary preferences associated with higher brain iron levels also appeared to be linked to a lower risk for PD (p=0.004). A similar relationship was observed for estimates of nutrient intake (p=0.0006). Voxel-wise analysis of i) high-sugar and ii) alcohol factors confirmed T2-weighted signal differences consistent with iron accumulation patterns in motor regions of the brain including the cerebellum and basal ganglia.
Conclusion: Dietary and lifestyle factors and preferences, especially those related to carbohydrates, alcohol, and exercise, are related to detectable differences in brain iron accumulation and alterations in risk of PD, suggesting a potential avenue for lifestyle interventions that could influence risk.
Background
Depression in Parkinson's disease (PD) is a major health concern worldwide. Recently, an increasing number of non-pharmacological interventions have been used in PD to alleviate depressive symptoms. However, it is uncertain which intervention is the best, and related evidence is limited. This network meta-analysis was performed to compare and rank non-pharmacological interventions for PD and analyze their effects on depression to provide evidence for clinicians to choose appropriate non-pharmacological management options.
Methods
The PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, China National Knowledge Infrastructure (CNKI), and Wanfang databases were searched from inception to April 7, 2022. Two authors screened all studies, extracted the data, and evaluated the methodological quality. STATA software version 16.0 was used to conduct the network meta-analysis.
Results
Our network meta-analysis included 62 studies involving 3,050 participants and 35 non-pharmacological interventions. Although most non-pharmacological interventions showed non-significant effects, the surface under the cumulative ranking curve (SUCRA) values indicated that the best non-pharmacological intervention for depression was dance (82.3%), followed by LSVT-BIG therapy (77.4%), and CBT (73.6%).
Conclusion
Dance can be considered as an effective therapy for improving depression in patients with PD. In the future, more strictly designed trials are needed to verify the conclusions of this network meta-analysis.
Neuroinflammation is the fundamental immune response against multiple factors in the central nervous system and is characterized by the production of inflammatory mediators, activated microglia and astrocytes, and the recruitment of innate and adaptive immune cells to inflammatory sites, that contributes to the pathological process of related brain diseases, such as Alzheimer’s disease, Parkinson’s disease, depression, and stroke. Flavonoids, as a species of important natural compounds, have been widely revealed to alleviate neuroinflammation by inhibiting the production of pro-inflammatory mediators, elevating the secretion of anti-inflammatory factors, and modulating the polarization of microglia and astrocyte, mainly via suppressing the activation of NLRP3 inflammasome, as well as NF-κB, MAPK, and JAK/STAT pathways, promoting Nrf2, AMPK, BDNF/CREB, Wnt/β-Catenin, PI3k/Akt signals and SIRT1-mediated HMGB1 deacetylation. This review will provide the latest and comprehensive knowledge on the therapeutic benefits and mechanisms of natural flavonoids in neuroinflammation, and the natural flavonoids might be developed into food supplements or lead compounds for neuroinflammation-associated brain disorders.
Abstract: The prevalence of cardiovascular disease, oxidative stress-related complications, and chronic age-related illnesses is gradually increasing worldwide. Several causes include the ineffectiveness of medicinal treatment therapies, their toxicity, their inability to provide radical solutions in some diseases, and the necessity of multiple drug therapy in certain chronic diseases. It is therefore necessary for alternative treatment methods to be sought. In this review, polyphenols were identified and classified according to their chemical structure, and the sources of these polyphenol molecules are indicated. The cardioprotective, ROS scavenging, anti-aging, anticancer properties of polyphenolic compounds have been demonstrated by the results of many studies, and these natural antioxidant molecules are potential alternative therapeutic agents.
Parkinson’s disease (PD) represents one of the most common neurodegenerative disorders, characterized by a dopamine (DA) deficiency in striatal synapses and misfolded toxic α-synuclein aggregates with concomitant cytotoxicity. In this regard, the misfolded proteins accumulation in neurodegenerative disorders induces a remarkable perturbations of endoplasmic reticulum (ER) homeostasis leading to persistent ER stress, which in turn, effects protein synthesis, modification, and folding quality control. A large body of evidence suggests that natural products target the ER stress signaling pathway, exerting a potential action in cancers, diabetes, cardiovascular and neurodegenerative diseases. This study aims to assess the neuroprotective effect of cocoa extract and its purified fractions against a cellular model of Parkinson’s disease represented by 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y human neuroblastoma. Our findings demonstrate, for the first time, the ability of cocoa to specifically targets PERK sensor, with significant antioxidant and antiapoptotic activities as both crude and fractioning extracts. In addition, cocoa also showed antiapoptotic properties in 3D cell model and a notable ability to inhibit the accumulation of α-synuclein in 6-OHDA-induced cells. Overall, these results indicate that cocoa exerts neuroprotective effects suggesting a novel possible strategy to prevent or, at least, mitigate neurodegenerative disorders, such as PD.
Quercetin, a naturally non-toxic flavonoid within the safe dose range with antioxidant, anti-apoptotic and anti-inflammatory properties, plays an important role in the treatment of aging-related diseases. Sirtuin 1 (SIRT1), a member of NAD⁺-dependent deacetylase enzyme family, is extensively explored as a potential therapeutic target for attenuating aging-induced disorders. SIRT1 possess beneficial effects against aging-related diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Depression, Osteoporosis, Myocardial ischemia (M/I) and reperfusion (MI/R), Atherosclerosis (AS), and Diabetes. Previous studies have reported that aging increases tissue susceptibility, whereas, SIRT1 regulates cellular senescence and multiple aging-related cellular processes, including SIRT1/Keap1/Nrf2/HO-1 and SIRTI/PI3K/Akt/GSK-3β mediated oxidative stress, SIRT1/NF-κB and SIRT1/NLRP3 regulated inflammatory response, SIRT1/PGC1α/eIF2α/ATF4/CHOP and SIRT1/PKD1/CREB controlled phosphorylation, SIRT1-PINK1-Parkin mediated mitochondrial damage, SIRT1/FoxO mediated autophagy, and SIRT1/FoxG1/CREB/BDNF/Trkβ-catenin mediated neuroprotective effects. In this review, we summarized the role of SIRT1 in the improvement of the attenuation effect of quercetin on aging-related diseases and the relationship between relevant signaling pathways regulated by SIRT1. Moreover, the functional regulation of quercetin in aging-related markers such as oxidative stress, inflammatory response, mitochondrial function, autophagy and apoptosis through SIRT1 was discussed. Finally, the prospects of an extracellular vesicles (EVs) as quercetin loading and delivery, and SIRT1-mediated EVs as signal carriers for treating aging-related diseases, as well as discussed the ferroptosis alleviation effects of quercetin to protect against aging-related disease via activating SIRT1. Generally, SIRT1 may serve as a promising therapeutic target in the treatment of aging-related diseases via inhibiting oxidative stress, reducing inflammatory responses, and restoring mitochondrial dysfunction.
Parkinson’s disease (PD), the main risk factor for which is age, is one of the most common neurodegenerative diseases and imposes a substantial burden on affected individuals and the economy. While the aetiology of PD is still largely unclear, substantial evidence indicates that mitochondrial dysfunction, aggregation of α-synuclein (α-syn), oxidative stress, inflammation, and autophagy play major roles in the pathogenesis of PD. Sirtuins are NAD+-dependent protein deacetylases, includeing seven members, i.e., SIRT1-SIRT7. Among these sirtuins, SIRT3, SIRT4 and SIRT5 are located in mitochondria and are called mitochondrial sirtuins. Mitochondrial sirtuins regulate the activity and biological function of mitochondrial proteins through posttranslational modification of substrate proteins. Increasing evidence shows that mitochondrial sirtuins play an important role in degenerative diseases, including PD. Mitochondrial sirtuins exert a beneficial neuroprotective effect in various models of PD. This paper summarizes a large number of studies and discusses the latest research progress on the role of mitochondrial sirtuins in PD, focusing especially on the regulation of the mitochondrial respiratory chain (MRC), oxidative stress, the inflammatory response and autophagy, to provide new insight into the pathogenesis of PD and new targets for the diagnosis and treatment of the disease.
Parkinson’s disease (PD) is currently the second most common neurodegenerative disease, being characterized by motor and non-motor symptoms. The therapeutic options available for its treatment are limited, do not slow the progression of the disease, and have serious side effects. For this reason, many studies have sought to find compounds with neuroprotective properties that bring additional benefits to current therapy. In this context, resveratrol is a phenolic compound, found in many plant species, capable of crossing the blood–brain barrier and having multiple biological properties. Experimental studies in vitro and in vivo have shown that it can prevent or slow the progression of a variety of diseases, including PD. In this systematic review, we summarize the effects of resveratrol in experimental in vivo and in vitro models of PD and discuss the molecular mechanisms involved in its action. The bibliographic search was performed in the databases of PubMed, Web of Science, SciELO, and Google Scholar, and based on the inclusion criteria, 41 articles were selected and discussed. Most of the included studies have demonstrated neuroprotective effects of resveratrol. In general, resveratrol prevented behavioral and/or neurological disorders, improved antioxidant defenses, reduced neuroinflammatory processes, and inhibited apoptosis. In summary, this systematic review offers important scientific evidence of neuroprotective effects of resveratrol in PD and also provide valuable information about its mechanism of action that can support future clinical studies.
Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss. The exact pathogenesis of PD is complex and not yet completely understood, but research has established the critical role mitochondrial dysfunction plays in the development of PD. As the main producer of cytosolic reactive oxygen species (ROS), mitochondria are particularly susceptible to oxidative stress once an imbalance between ROS generation and the organelle’s antioxidative system occurs. An overabundance of ROS in the mitochondria can lead to mitochondrial dysfunction and further vicious cycles. Once enough damage accumulates, the cell may undergo mitochondria-dependent apoptosis or necrosis, resulting in the neuronal loss of PD. Polyphenols are a group of natural compounds that have been shown to offer protection against various diseases, including PD. Among these, the plant-derived polyphenol, resveratrol, exhibits neuroprotective effects through its antioxidative capabilities and provides mitochondria protection. Resveratrol also modulates crucial genes involved in antioxidative enzymes regulation, mitochondrial dynamics, and cellular survival. Additionally, resveratrol offers neuroprotective effects by upregulating mitophagy through multiple pathways, including SIRT-1 and AMPK/ERK pathways. This compound may provide potential neuroprotective effects, and more clinical research is needed to establish the efficacy of resveratrol in clinical settings.
Abiotic stressors such as extreme temperatures, drought, flood, light, salt, and heavy metals alter biological diversity and crop production worldwide. Therefore, it is important to know the mechanisms by which plants cope with stress conditions. Polyphenols, which are the largest group of plant-specialized metabolites, are generally recognized as molecules involved in stress protection in plants. This diverse group of metabolites contains various structures, from simple forms consisting of one aromatic ring to more complex ones consisting of large number of polymerized molecules. Consequently, all these molecules, depending on their structure, may show different roles in plant growth, development, and stress protection. In the present review, we aimed to summarize data on how different polyphenol structures influence their biological activity and their roles in abiotic stress responses. We focused our review on phenolic acids, flavonoids, stilbenoids, and lignans.
Parkinson's disease is a neurodegenerative disorder characterized by a combination of severe motor and non-motor symptoms. Over the years, several factors have been discovered to play a role in the pathogenesis of this disease, in particular, neuroinflammation and oxidative stress. To date, the pharmacological treatments used in Parkinson's disease are exclusively symptomatic. For this reason, in recent years, the research has been directed towards the discovery and study of new natural molecules to develop potential neuroprotective therapies against Parkinson's disease. In this context, natural polyphenols have raised much attention for their important anti-inflammatory and antioxidant properties, but also for their ability to modulate protein misfolding. In this review, we propose to summarize the relevant in vivo and in vitro studies concerning the potential therapeutic role of natural polyphenols in Parkinson's disease.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by a loss of dopaminergic neurons, leading to bradykinesia, rigidity, tremor at rest, and postural instability, as well as non-motor symptoms such as olfactory impairment, pain, autonomic dysfunction, impaired sleep, fatigue, and behavioral changes. The pathogenesis of PD is believed to involve oxidative stress, disruption to mitochondria, alterations to the protein α-synuclein, and neuroinflammatory processes. There is currently no cure for the disease. Polyphenols are secondary metabolites of plants, which have shown benefit in several experimental models of PD. Intake of polyphenols through diet is also associated with lower PD risk in humans. In this review, we provide an overview of the pathology of PD and the data supporting the potential neuroprotective capacity of increased polyphenols in the diet. Evidence suggests that the intake of dietary polyphenols may inhibit neurodegeneration and the progression of PD. Polyphenols appear to have a positive effect on the gut microbiome, which may decrease inflammation that contributes to the disease. Therefore, a diet rich in polyphenols may decrease the symptoms and increase quality of life in PD patients.
Oxidative stress reflects an imbalance between the production of reactive oxygen species (ROS) and antioxidant defense systems, and it can be associated with the pathogenesis and progression of neurodegenerative diseases such as multiple sclerosis, stroke, and Parkinson’s disease (PD). The application of antioxidants, which can defend against oxidative stress, is able to detoxify the reactive intermediates and prevent neurodegeneration resulting from excessive ROS production. There are many reports showing that numerous flavonoids, a large group of natural phenolic compounds, can act as antioxidants and the application of flavonoids has beneficial effects in the adult brain. For instance, it is well known that the long-term consumption of the green tea-derived flavonoids catechin and epigallocatechin gallate (EGCG) can attenuate the onset of PD. Also, flavonoids such as ampelopsin and pinocembrin can inhibit mitochondrial dysfunction and neuronal death through the regulation of gene expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Additionally, it is well established that many flavonoids exhibit anti-apoptosis and anti-inflammatory effects through cellular signaling pathways, such as those involving (ERK), glycogen synthase kinase-3β (GSK-3β), and (Akt), resulting in neuroprotection. In this review article, we have described the oxidative stress involved in PD and explained the therapeutic potential of flavonoids to protect the nigrostriatal DA system, which may be useful to prevent PD.
Increasing evidence points to biological sex as an important factor in the development and phenotypical expression of Parkinson's disease (PD). Risk of developing PD is twice as high in men than women, but women have a higher mortality rate and faster progression of the disease. Moreover, motor and nonmotor symptoms, response to treatments and disease risk factors differ between women and men. Altogether, sex-related differences in PD support the idea that disease development might involve distinct pathogenic mechanisms (or the same mechanism but in a different way) in male and female patients. This review summarizes the most recent knowledge concerning differences between women and men in PD clinical features, risk factors, response to treatments and mechanisms underlying the disease pathophysiology. Unraveling how the pathology differently affect the two sexes might allow the development of tailored interventions and the design of innovative programs that meet the distinct needs of men and women, improving patient care.
Instead of the progress in the understanding of etiology of Parkinson’s disease (PD), effective methods to prevent the progression of the disease have not been developed and only symptomatic treatment is currently possible. One of possible pathways to slow the progression of the disease is protection of dopaminergic neurons by maintaining mitochondrial quality control in neuron cells. Recent studies showed that the most promising target for pharmacological effects on mitochondria is the Nrf2/ARE signaling cascade. It participates in the maintenance of mitochondrial homeostasis, which is provided by an optimal ratio in the processes of mitochondrial biogenesis and mitophagy, as well as the optimal ratio of ROS production and ROS scavenging. Nrf2 activators are capable of modulating these processes, maintaining mitochondrial homeostasis in neurons. In addition, Nrf2 can synergistically interact with other transcription factors, for example, PGC-1a in the regulation of mitochondrial biogenesis and YY1 with the increase of antioxidant defense. All this makes Nrf2 an optimal target for drugs that could support the mitochondrial quality control, which, in combination with antioxidant protection, can significantly slow down the pathogenesis of PD. Some of these compounds have undergone laboratory studies and are at the stage of clinical trials now.
Introduction
Studies have suggested that free radicals-induced neurodegeneration is one of the many studies of Parkinson Disease (PD). Quercetin as a natural polyphenol has been regarded as a significant player in altering the progression of neurodegenerative diseases by protecting from damages caused by free radicals. Owing to its poor water solubility, preparation of its oral formulation is urgently needed. Recently, nanocrystal technique as an effective way has been introduced for oral administration of drugs.
Methods
This study investigated the neuroprotective effects of quercetin nanocrystals on 6-hydroxydopamine (6-OHDA)-induced Parkinson-like model in male rats. Quercetin nanocrystals were prepared by the Evaporative Precipitation of Nanosuspension (EPN) method.
Results
Administration of quercetin and its nanocrystals (10 and 25 mg/kg) prevented disruption of memory, increased antioxidant enzyme activities (superoxide dismutase and catalase) and total glutathione and reduced Malondialdehyde (MDA) level in the hippocampal area.
Conclusion
The present study results demonstrated that quercetin nanocrystals with greater bioavailability is effective than quercetin alone in treatment of Parkinson-like model in rat.
Parkinson's disease (PD) is the second most common neurodegenerative disorder. However, therapeutic options treating only its symptoms are very disappointing. Therefore there is an ongoing search for compounds capable of tackling the multi-dimensional features of PD. Recently natural polyphenols have gained great interest as potential therapeutic agents. Herein, we have attempted to summarize results obtained in different animal models demonstrating their neuroprotective effects. The in vivo findings presented below are supported by human subject data and reports regarding the ability of polyphenols to cross the blood-brain barrier. The beneficial effects of polyphenols are demonstrated by the results of behavioral examinations, mainly related to motor and cognitive capabilities, histopathological and immunohistochemical examination concerning the protection of dopaminergic neurons, analyses of dopamine and the concentration of its metabolites, as well as mechanistic studies regarding the modulation of oxidative stress, neuroinflammation, cellular iron management, proteinopathy, and additionally the regulation of signaling pathways. Importantly, data about brain distribution of the metabolic derivatives of the reviewed polyphenols are crucial for the justification of their nutritional intake in neuroprotective intervention, as well as for the identification of potential targets for a novel therapeutic approach to Parkinson's disease.
Turmeric, a spice that has long been recognized for its medicinal properties, has received interest from both the medical/scientific world and from culinary enthusiasts, as it is the major source of the polyphenol curcumin. It aids in the management of oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, and hyperlipidemia. It may also help in the management of exercise-induced inflammation and muscle soreness, thus enhancing recovery and performance in active people. In addition, a relatively low dose of the complex can provide health benefits for people that do not have diagnosed health conditions. Most of these benefits can be attributed to its antioxidant and anti-inflammatory effects. Ingesting curcumin by itself does not lead to the associated health benefits due to its poor bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and rapid elimination. There are several components that can increase bioavailability. For example, piperine is the major active component of black pepper and, when combined in a complex with curcumin, has been shown to increase bioavailability by 2000%. Curcumin combined with enhancing agents provides multiple health benefits. The purpose of this review is to provide a brief overview of the plethora of research regarding the health benefits of curcumin.
Parkinson’s disease (PD) pathology is characterized by the abnormal accumulation and aggregation of the pre-synaptic protein α-synuclein in the dopaminergic neurons as Lewy bodies (LBs). Curcumin, which plays a neuroprotective role in various animal models of PD, was found to directly modulate the aggregation of α-synuclein in in vitro as well as in in vivo studies. While curcumin has been shown to exhibit strong anti-oxidant and anti-inflammatory properties, there are a number of other possible mechanisms by which curcumin may alter α-synuclein aggregation which still remains obscure. Therefore, the present study was designed to understand such concealed mechanisms behind neuroprotective effects of curcumin. An animal model of PD was established by injecting lipopolysaccharide (LPS, 5 µg/5 µl PBS) into the substantia nigra (SN) of rats which was followed by curcumin administration (40 mg/kg b.wt (i.p.)) daily for a period of 21 days. Modulatory functions of curcumin were evident from the inhibition of astrocytic activation (GFAP) by immunofluorescence and NADPH oxidase complex activation by RT-PCR. Curcumin supplementation prevented the LPS-induced upregulation in the protein activity of transcription factor NFκB, proinflammatory cytokines (TNF-α, IL-1β, and IL-1α), inducible nitric oxide synthase (iNOS) as well as the regulating molecules of the intrinsic apoptotic pathway (Bax, Bcl-2, Caspase 3 and Caspase 9) by ELISA. Curcumin also resulted in significant improvement in the glutathione system (GSH, GSSG and redox ratio) and prevented iron deposition in the dopaminergic neurons as depicted from atomic absorption spectroscopy (AAS) and Prussian blue staining, respectively. Curcumin also prevented α-synuclein aggregates in the dopaminergic neurons as observed from gene as well as protein activity of α-synuclein using RT-PCR and IHC. Collectively, our results suggest that curcumin can be further pursued as a candidate drug in the molecules targeted therapy for PD and other related synucleopathies.
The fibrillation and aggregation of α‐synuclein ( AS ), along with the conformational transition from random coil to β‐sheet, are the critical steps in the development of Parkinson's disease ( PD ). It is acknowledged that iron accumulation in the brain may lead to the fibrillation of AS . However, (‐)‐epigallocatechin gallate ( EGCG ) can penetrate the blood–brain barrier, chelate metal ions, and inhibit the fibrillation of amyloid proteins. Therefore, EGCG is warranted to be investigated for its potential to cure amyloid‐related diseases. In the present work, we sought to study the effects of EGCG on Fe( III )‐induced fibrillation of AS on both molecular and cellular levels. We demonstrate that Fe( III ) interacts with the amino residue of Tyr and Ala of AS , then accelerates the fibrillation of AS , and increases intracellular reactive oxygen species ( ROS ) in the AS transduced‐ PC 12 cells ( AS ‐ PC 12 cells). However, EGCG significantly inhibits this process by chelating Fe( III ) and protects AS ‐ PC 12 cells against the toxicity induced by ROS and β‐sheet‐enriched AS fibrils. These findings yield useful information that EGCG might be a promising drug to prevent and treat the neurodegenerative diseases.
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Parkinson’s disease (PD) affects 1–2 per 1000 of the population at any time. PD prevalence is increasing with age and PD affects 1% of the population above 60 years. The main neuropathological finding is α-synuclein-containing Lewy bodies and loss of dopaminergic neurons in the substantia nigra, manifesting as reduced facilitation of voluntary movements. With progression of PD, Lewy body pathology spreads to neocortical and cortical regions. PD is regarded as a movement disorder with three cardinal signs: tremor, rigidity and bradykinesia. A recent revision of the diagnostic criteria excludes postural instability as a fourth hallmark and defines supportive criteria, absolute exclusion criteria and red flags. Non-motor symptoms in PD have gained increasing attention and both motor and non-motor signs are now included among the supportive criteria. The cause of PD is unknown in most cases. Genetic risk factors have been identified, including monogenetic causes that are rare in unselected populations. Some genetic factor can be identified in 5–10% of the patients. Several environmental factors are associated with increased risk of PD. Autopsy studies show that the clinical diagnosis of PD is not confirmed at autopsy in a significant proportion of patients. Revised diagnostic criteria are expected to improve the clinician´s accuracy in diagnosing PD. Increasing knowledge on genetic and environmental risk factors of PD will probably elucidate the cause of this disease within the near future.
Parkinson's disease (PD), the second most common age-associated neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons and the presence of α-synuclein-containing aggregates in the substantia nigra pars compacta (SNpc). Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Post-mortem analyses of human PD patients and experimental animal studies indicate that activation of glial cells and increases in pro-inflammatory factor levels are common features of the PD brain. Chronic release of pro-inflammatory cytokines by activated astrocytes and microglia leads to the exacerbation of DA neuron degeneration in the SNpc. Besides, peripheral immune system is also implicated in the pathogenesis of PD. Infiltration and accumulation of immune cells from the periphery are detected in and around the affected brain regions of PD patients. Moreover, inflammatory processes have been suggested as promising interventional targets for PD and even other neurodegenerative diseases. A better understanding of the role of inflammation in PD will provide new insights into the pathological processes and help to establish effective therapeutic strategies. In this review, we will summarize recent progresses in the neuroimmune aspects of PD and highlight the potential therapeutic interventions targeting neuroinflammation.
Introduction: Neuroinflammation may play as an important risk factor in progressive degeneration of dopaminergic cells. Antioxidants have protective effects against free radicals induced neural damage in Parkinson’s disease (PD). In the present study, we examined the effects of ellagic acid (EA) on locomotion and neuroinflammatory biomarkers in a rat model of PD induced by 6-hydroxidopamine (6-OHDA).
Methods: 6-OHDA (16 μg/2 μl) was injected into the right medial forebrain bundle (MFB) in MFB-lesioned rat’s brain. Sham group received vehicle instead of 6-OHDA. PD-model was confirmed by rotational test using apomorphine injection. EA (50 mg/kg/2 ml, by gavages) was administered in PD+EA group. One group of MFB-lesioned rats received pramipexole (PPX; 2 mg/kg/2 ml, by gavages) as positive control group (PD+PPX group). Motor activity was assessed by stride length and cylinder tests. The levels of TNF-α and IL-1β were measured in both striatum and hippocampus tissues.
Results: MFB lesion caused significant reduction of stride-length (P<0.001) and also increased the contralateral rotations (P<0.001) and score of the cylinder test (P<0.001). Use of 6-OHDA to induce the PD significantly increased the levels of TNF-α (P<0.001) and IL-1β (P<0.001) in MFB-lesioned rats. EA significantly restored all of the above parameters.
Discussion: EA can improve the motor impairments in the MFB-lesioned rats via reducing the neuroinflammatory biomarkers and protect the brain against free radicals-induced neural damage. The results suggest that EA can be helpful in management of PD treatment.
Healthcare decisions for individual patients and for public health policies should be informed by the best available research evidence. The practice of evidence-based medicine is the integration of individual clinical expertise with the best available external clinical evidence from systematic research and patient's values and expectations. Primary care physicians need evidence for both clinical practice and for public health decision making. The evidence comes from good reviews which is a state-of-the-art synthesis of current evidence on a given research question. Given the explosion of medical literature, and the fact that time is always scarce, review articles play a vital role in decision making in evidence-based medical practice. Given that most clinicians and public health professionals do not have the time to track down all the original articles, critically read them, and obtain the evidence they need for their questions, systematic reviews and clinical practice guidelines may be their best source of evidence. Systematic reviews aim to identify, evaluate, and summarize the findings of all relevant individual studies over a health-related issue, thereby making the available evidence more accessible to decision makers. The objective of this article is to introduce the primary care physicians about the concept of systematic reviews and meta-analysis, outlining why they are important, describing their methods and terminologies used, and thereby helping them with the skills to recognize and understand a reliable review which will be helpful for their day-to-day clinical practice and research activities.
BACKGROUND: Evidence suggests that diets rich in flavonoids affect human health. Among flavonoids, anthocyanins have been demonstrated to exert beneficial effects toward brain through modulation of neuroinflammation, neurogenesis, neuronal signaling and by modulating gut microbiota. OBJECTIVE: This study aimed to investigate the association between consumption of anthocyanin-rich fruits (strawberries, berries, cherries, prickly pears, grapes, blood oranges) and mental health in an Italian cohort study. METHODS: Dietary information was collected using a validated food frequency questionnaire. Mental health outcomes were assessed using the Pittsburgh Sleep Quality Index (PSQI), the Perceived Stress Scale (PSS), the 10-item Center for the Epidemiological Studies of Depression Short Form (CES-D-10) as a screening tool for sleep quality, perceived stress and depressive symptoms, respectively. RESULTS: A significant inverse association between higher anthocyanin-rich fruits intake and occurrence of poor sleep quality, high perceived stress, and depressive symptoms was found. In the most adjusted model, individuals in the highest tertile of anthocyanin-rich fruits were less likely to have poor sleep quality (OR = 0.63, 95% CI: 0.47–0.86), high perceived stress (OR = 0.68, 95% CI: 0.51–0.92), and depressive symptoms (OR = 0.67, 95% CI: 0.49–0.90). CONCLUSIONS: Diets including fruits rich in anthocyanins may result in positive mental health outcomes.
Background and objective
Preclinical studies suggest that curcumin might be a potential neuroprotective agent in Parkinson's disease (PD). This clinical trial aimed to evaluate the efficacy of adding nanomicelle curcumin on improving the motor and non-motor symptoms of PD patients and their quality of life.
Material and methods
Idiopathic PD patients aged ≥30 whose symptoms were under control were included in this pilot, randomized, triple-blind, placebo-controlled, add-on trial. Eligible patients were randomly assigned to either the curcumin (n= 30, 80 mg/day) or placebo (n= 30) groups and were followed for nine months. Primary outcomes were the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Parkinson's Disease Questionnaire (PDQ-39). These variables, along with demographic data, drug history, and possible side effects of curcumin, were gathered at the beginning of the study and every three months. A mixed effects model was used to compare the group-by-time interaction, followed by post hoc analysis.
Results
Although the mean MDS-UPDRS and PDQ-39 scores were not significantly different between the curcumin and placebo groups at any time points, MDS-UPDRS part III (P=0.04) showed a significant difference in its overall trend between the study groups. However, post hoc analysis failed to spot this difference at study time points. The most common side effects of curcumin were nausea and vomiting (P=0.25) and gastroesophageal reflux (P=0.42).
Conclusion
While curcumin is a well-tolerated natural compound, this trial was unsuccessful in showing its efficacy in quality of life and clinical symptoms of PD patients.
Ethnopharmacological relevance
Liquiritin is a flavonoid derived from Radix et Rhizoma Glycyrrhizae, which is a widely used traditional Chinese medicine with the effects of invigorating spleen qi, clearing heat, resolving toxins, and dispelling phlegm to stop coughs.
Aim of the study
In this review,the pharmacokinetics and pharmacological activities of liquiritin have been summarized.
Materials and methods
The information on liquiritin up to 2021 was collected from PubMed, Web of Science, Springer Link, and China National Knowledge Infrastructure databases. The key words were “liquiritin”, “nerve”, “tumor”, “cardiac”, etc.
Results
The absorption mechanism of liquiritin conforms to the passive diffusion and first-order kinetics while with low bioavailability. Liquiritin can penetrate the blood-brain-barrier. Besides, liquiritin displays numerous pharmacological effects including anti-Alzheimer's disease, antidepressant, antitumor, anti-inflammatory, cardiovascular protection, antitussive, hepatoprotection, and skin protective effects. In addition, the novel preparations, new pharmacological effects,and cdusafty of liquiritin are also discussed in this review.
Conclusion
This review provides a comprehensive state of knowledge on the pharmacokinetics and pharmacological activities of liquiritin, and makes a forecast for its research directions and applications in clinic.
Flavonoids, plant compounds found in certain foods, may have the ability to improve fatigue and fatigability. However, to date, no well-designed intervention studies assessing the role of flavonoid consumption for fatigue management in people with Parkinson’s (pwP) have been performed.
Objectives
To determine the feasibility and estimate potential effect of flavonoid-rich cocoa on fatigue and fatigability in pwP.
Methods
This was a randomised (1:1) double-blind placebo controlled feasibility study in which 30 pwP were recruited from the European Parkinson Therapy Centre, Italy (trial registration: NCT03288155). During a six day intervention participants consumed a high (10.79mg/g) or low flavonoid cocoa (1.02mg/g) beverage (18 grams Cocoa with 200ml Rice milk) once daily. Potential effect on fatigue and fatigability was measured (baseline to day 6). Feasibility and fidelity were assessed through recruitment and retention, adherence and a process evaluation.
Results
From July 2017 to May 2018, 30 pwP were recruited and randomised and allocated to high (n=15) or low (n=15) flavonoid groups and included in analysis. Missing data was less than 5% and adherence to intervention of all allocated individuals was 97%. There was a small effect on fatigability (six minute walk test: ES 0.11 (95%CI=-0.11-0.26); Z=0.81).There were 2 adverse events (one in the control and one in the intervention group).
Conclusion
The consumption of cocoa is feasible and well received in pwP, and further investigation on the effect on fatigability is warranted.
Background and Objectives
Although flavonoids have the potential to exert neuroprotective benefits, evidence of their role in improving survival rates among individuals with Parkinson disease (PD) remains lacking. We aimed to prospectively study the association between pre- and post-diagnosis flavonoid intakes and risk of mortality among individuals with PD identified from two large ongoing cohorts of US men and women.
Methods
Included in the current analysis were 599 women from the Nurses’ Health Study and 652 men from the Health Professionals Follow-up Study who were newly diagnosed with PD during follow-up. Dietary intakes of total flavonoid and its subclasses together with major flavonoid-rich foods (tea, apples, berries, orange and orange juice, and red wine) were repeatedly assessed based on a validated food frequency questionnaire every 4 years. Mortality was ascertained via the National Death Index and state vital statistics records.
Results
We documented 944 deaths during 32–34 years of follow-up. A higher total flavonoid intake before PD diagnosis was associated with a lower future risk for all-cause mortality in men (hazard ratio [HR] comparing two extreme quartiles=0.53, 95% CI: 0.39, 0.71; p-trend<0.001) but not in women (HR=0.93, 95% CI: 0.68, 1.28; p-trend=0.69), after adjusting for age, smoking status, total energy intake, and other covariates. The pooled HR comparing the extreme quartiles was 0.70 (95% CI: 0.40, 1.22; p-trend=0.25) with significant heterogeneity (p=0.01). For flavonoid subclasses, the highest quartile of anthocyanins, flavones, and flavan-3-ols intakes before diagnosis had a lower mortality risk compared to the lowest quartile (pooled HR=0.66, 0.78, and 0.69, respectively, p<0.05 for all); for berries and red wine, participants consuming >=3 servings/week had a lower risk (pooled HR=0.77 (95%CI: 0.58, 1.02) and 0.68 (95%CI: 0.51, 0.91), respectively), compared to <1 serving/month. After PD diagnosis, greater consumptions of total flavonoid, subclasses including flavonols, anthocyanins, flavan-3-ols, and polymers, and berries and red wine, were associated with lower mortality risk (p<0.05 for all).
Discussion
Among individuals with PD, higher consumption of flavonoids, especially anthocyanins and flavan-3-ols, and flavonoid-rich food such as berries and red wine, was likely to be associated with a lower risk of mortality.
The D1- and D2-dopamine receptors (D1R and D2R), which signal through Gs and Gi, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson’s disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-Gs and D2R-Gi signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson’s disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.
Objective
To determine whether high baseline dietary antioxidants and total non-enzymatic antioxidant capacity (NEAC) is associated with a lower risk of Parkinson disease in men and women, we prospectively studied 43,865 men and women from a large Swedish cohort.
Methods
In the Swedish National March Cohort 43,865 men and women aged 18–94 years were followed through record linkages to National Health Registries from 1997 until 2016. Baseline dietary vitamin E, C and beta-carotene intake, as well as NEAC, were assessed by a validated food frequency questionnaire collected at baseline. All exposure variables were adjusted for energy intake and categorized into tertiles. Multivariable Cox proportional hazard regression models were fitted to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for Parkinson disease.
Results
After a mean follow-up time of 17.6 years we detected 465 incidence cases of Parkinson disease. In the multivariable adjusted model, dietary vitamin E (HR: 0.68: 95% CI: 0.52–0.90; p for trend: 0.005) and C (HR: 0.68; 95% CI: 0.52–0.89; p for trend: 0.004) were inversely associated with the risk of Parkinson disease, when comparing subjects in the highest to the lowest tertiles of the exposure. No association was found with estimated intake of dietary beta-carotene or NEAC.
Conclusion
Our findings suggest that dietary vitamin E and C intake might be inversely associated with the risk of Parkinson disease. No association was found with dietary beta-carotene or NEAC.
Classification of evidence
This study provides Class III evidence that dietary vitamin E and C intake are inversely associated with the risk of Parkinson disease.
Neurodegenerative disorders are characterized by progressive loss of neurons. To date, no efficacious therapies exist for these disorders, and current therapies provide only symptomatic relief. The neuroprotective effects of natural compounds have been reported in several neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) amyotrophic lateral sclerosis (ALS), cerebral ischemia and brain tumors. Flavonoids are the most widely studied natural products for the prevention and treatment of neurodegenerative disorders. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) represents a complex gene regulated cytoprotective pathway. Several natural compounds have been identified as Nrf2 regulators in various chronic disorders, including carcinogenic, liver ailments, inflammatory conditions, neurodegeneration, diabetes and cardiotoxicities. The current review focuses on Nrf2 targeting by flavonoids in the prevention and treatment of neurodegenerative disorders, addressing the most contemporary information available on this timely subject.
Curcumin, a dietary polyphenol and major constituent of Curcuma longa (Zingiberaceae), is extensively used as a spice in Asian countries. For ages, turmeric has been used in traditional medicine systems to treat various diseases, which was possible because of its anti‐inflammatory, antioxidant, anticancerous, antiepileptic, antidepressant, immunomodulatory, neuroprotective, antiapoptotic, and antiproliferative effects. Curcumin has potent antioxidant, anti‐inflammatory, antiapoptotic, neurotrophic activities, which support its plausible neuroprotective effects in neurodegenerative disease. However, there is limited information available regarding the clinical efficacy of curcumin in neurodegenerative cases. The low oral bioavailability of curcumin may be speculated as a plausible factor that limits its effects in humans. Therefore, utilization of several approaches for the enhancement of bioavailability may improve clinical outcomes. Furthermore, the use of nanotechnology and a targeted drug delivery system may improve the bioavailability of curcumin. The present review is designed to summarize the molecular mechanisms pertaining to the neuroprotective effects of curcumin and its nanoformulations. Improved Neurotherapeutics with Curcumin Nanoformulations.
Since ancient times, licorice, the root of Glycyrrhiza glabra, has been known to have a wide spectrum of therapeutic effects. Glycyrrhizin is cleaved to glycyrrhizic acid, which is subsequently converted to glycyrrhetic acid by human intestinal microflora. Glycyrrhetic acid is a potent inhibitor of 11β-hydroxysteroid dehydrogenase (11β-HSD) and performs a range of corticosteroid-like activities. The pharmacologic effects of licorice contribute to its anti-inflammatory, antioxidative, anti-allergenic, and antimicrobial properties. Licorice has been used to treat liver disease, gastrointestinal disorders, oral disease, and various skin disorders and has been used in gum, candy, herbs, alcoholic beverages, and food supplements. Licorice and its extracts, especially glycyrrhizin, can be taken orally, through the skin (in the form of gels and oils), and intravenously. Licorice demonstrates mineralocorticoid-like activity not only by inhibiting 11β-HSD2, but also by binding to a mineralocorticoid receptor, leading to potentially adverse risks of mineralocorticoid-like overactivity. Chronic use of licorice can lead to hypokalemia and hypertension, and some people are more sensitive to licorice exposure. Based on clinical trials, this review summarizes the positive effects of licorice and other reported side effects.
Parkinson disease (PD) is the most common neurodegenerative movement disorder [1]. Its cardinal motor symptoms are tremor, rigidity, bradykinesia/akinesia and postural instability, but the clinical picture includes other motor and non‐motor symptoms (NMS). The diagnosis is principally clinical, although specific investigations can help the differential diagnosis from other forms of Parkinsonism. The pathological hallmarks of PD are loss of dopaminergic neurons in the substantia nigra (SN) pars compacta (SNpc) and accumulation of misfolded alpha‐synuclein, which is found in intra‐cytoplasmic inclusions called Lewy bodies (LBs). When patients are first diagnosed, a substantial proportion of dopaminergic neurons in the SNpc has already been lost, and neurodegeneration has spread to other central nervous system (CNS) regions. The aetiology of the disease in most patients is unknown, but different genetic causes have been identified in approximately 5‐10% of cases. Current treatment of PD is based on the replacement of dopamine, although alternative approaches such as deep brain stimulation (DBS) are suitable for later stage disease. Currently available treatments offer good control of motor symptoms, but do not halt the progression of neurodegeneration, the evolution of the disease and the increasing disability. This article is intended to provide a comprehensive, general and practical review of PD for the general neurologist.
Ethnopharmacological relevance:
Licorice preparations are used as neuroprotective remedies in Persian ethnomedicine, in order to prevent from disabilities in neurodegenerative conditions like Parkinson's disease (PD).
Aim of the study:
This study was designed to determine the licorice (root of Glycyrrhiza glabra L.) effectiveness as an adjunct treatment in the PD management.
Material and methods:
In this double-blinded trial, 128 patients were assessed for eligibility criteria. Seventy-eight patients were ineligible and 11 of them refused from participating. Thirty-nine PD patients (YAHR staging ≤ 3) were divided into two groups by random. The patients received oral licorice or placebo syrups with a dose of 5 cc, twice a day for 6 months. High-performance liquid chromatography and spectrophotometric instruments determined licorice syrup constituents. The patients' situation for Unified Parkinson's rating scale (UPDRS) was assessed every 6 weeks for the duration of six months. In addition, patients' blood pressure, blood glucose, sodium and potassium levels, quality of life and dizziness were determined.
Results:
Six weeks after intervention, total UPDRS, daily activities and tremor were significantly improved with a considerable effect size. A significant better motor test and rigidity scores were observed 4 months after licorice intake (p > 0.05). No electrolyte abnormality, significant changes in blood pressure or blood glucose levels were observed during the study. Each 5cc of syrup contained 136 mg of licorice extract with 12.14 mg glycyrrhizic acid, and also 136 μg of polyphenols.
Conclusion:
The licorice intake could improve the symptoms in PD patients without serious adverse events.
Inflammation of the nervous system (neuroinflammation) is now recognized as a hallmark of virtually all neurological disorders. In neuroinflammatory conditions such as multiple sclerosis, there is prominent infiltration and a long-lasting representation of various leukocyte subsets in the central nervous system (CNS) parenchyma. Even in classic neurodegenerative disorders, where such immense inflammatory infiltrates are absent, there is still evidence of activated CNS-intrinsic microglia. The consequences of excessive and uncontrolled neuroinflammation are injury and death to neural elements, which manifest as a heterogeneous set of neurological symptoms. However, it is now readily acknowledged, due to instructive studies from the peripheral nervous system and a large body of CNS literature, that aspects of the neuroinflammatory response can be beneficial for CNS outcomes. The recognized benefits of inflammation to the CNS include the preservation of CNS constituents (neuroprotection), the proliferation and maturation of various neural precursor populations, axonal regeneration, and the reformation of myelin on denuded axons. Herein, we highlight the benefits of neuroinflammation in fostering CNS recovery after neural injury using examples from multiple sclerosis, traumatic spinal cord injury, stroke, and Alzheimer’s disease. We focus on CNS regenerative responses, such as neurogenesis, axonal regeneration, and remyelination, and discuss the mechanisms by which neuroinflammation is pro-regenerative for the CNS. Finally, we highlight treatment strategies that harness the benefits of neuroinflammation for CNS regenerative responses.
Background:
Parkinson's disease is the most common neurodegenerative disorder, characterized by loss of dopaminergic neurons in substantia nigra and depletion of dopamine in striatum due to excitotoxicity, oxidative stress and many other factors may contribute to MPTP- and PD-related neurodegeneration. The present study deals with the neuroprotective effect of Naringenin (NGN), a bioflavonoid against MPTP induced Parkinson's disease in the mouse model.
Methods:
Healthy male C57BL/6J mice (18-22 g b wt) were pretreated with NGN [25, 50,100 mg/kg/b.wt, p.o] once daily for 5 days. Thereafter, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) (80 mg/kg b.wt, i.p) was given in two divided doses (2 x 40 mg/kg at 16h interval). The animals were observed for motor functions 48 hours after the first MPTP injection. After completion of behaviour tasks, all animals were euthanized to dissect out the brain and used for biochemical, molecular and histopathological investigations.
Results:
Pretreatment of NGN significantly reversed the toxic effects of MPTP by reducing LPO levels and increasing the activities of glutathione reductase and catalase along with improved behavioral performance. Interestingly, pre-treatment with NGN down-regulated iNOS expression level in MPTP intoxicated mice brain. In addition, the histopathological evaluation revealed that NGN decreased the nuclear pigmentation and cytoplasmic vacuolation in the substantia nigra and striatal regions when compared to MPTP intoxicated mice brain.
Discussion:
The present study showed that NGN exerts neuroprotection by suppressing oxidative stress via antioxidant mechanisms. The above finding suggests that NGN may act as a potential target in the management of PD.
1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) is a neurotoxin that causes Parkinson's disease in animals via mechanisms linked with oxidative stress and inflammation. Resveratrol is a natural polyphenol and a phytoalexin with antioxidative and antiinflammatory properties. Here, we investigated the rescue role of resveratrol on MPTP-triggered toxicity in Drosophila melanogaster for the first time. D. melanogaster (Harwich strain, 1-to 3- days old) were first orally exposed to resveratrol (0, 7.5, 15, 30, 60 and 120 mg/kg diet) and MPTP (0, 250, 500, 1000, 2000, and 3000 μM) for longevity and 7 days survival assays respectively. Consequently, we selected resveratrol (30 and 60 mg/kg diet) to evaluate its rescue role on MPTP (250 and 500 μM)-induced toxicity in D. melanogaster after 3 days of oral treatment. Specifically, we evaluated markers of neurotoxicity (acetylcholinesterase and negative geotaxis), inflammation (nitric oxide), oxidative stress-antioxidant status (hydrogen peroxide, total thiol, catalase and glutathione-S-transferase), cell viability and fecundity. The data showed that resveratrol increased lifespan of D. melanogaster in a dose-dependent manner up to 60 mg/kg diet. Further, resveratrol restored MPTP-induced inhibition of catalase, glutathione-S-transferase and acetylcholinesterase activities in D. melanogaster. Moreover, resveratrol ameliorated MPTP-triggered cell death, histological alterations, behavioural deficits and accumulation of nitric oxide and hydrogen peroxide levels in flies (p < 0.05). Conclusively, the lifespan extension effects of resveratrol and its rescue role on MPTP- mediated toxicity in the flies may be due to its antioxidant and anti-inflammatory properties.
Objective:
To compare access to caregiving between men and women with Parkinson disease (PD).
Methods:
This was a cross-sectional and longitudinal study among participants with PD enrolled in the National Parkinson Foundation Parkinson's Outcomes Project from 2009 to 2014 at 21 international sites. The primary outcome measures were presence of a caregiver at the baseline visit, caregiver burden as measured by the Multidimensional Caregiver Strain Index (MCSI) at baseline, and time to first paid caregiver.
Results:
A total of 7,209 participants (63% men, 37% women) with PD were evaluated. Men had a mean age of 66.0 (SD 9.8) years, and women had a mean age of 66.9 (SD 9.7) years. More men than women had a caregiver (88.4% vs 79.4%, p < 0.0001). Caregivers of men reported greater strain than those of women (MCSI score 19.9 vs 16.4, p < 0.0001). These differences persisted after controlling for age, disease stage, number of comorbidities, cognitive and mobility measures, and health-related quality of life. In addition, the odds of caregiver accompaniment at baseline visit were lower for women compared to men (odds ratio 0.76, 95% confidence interval [CI] 0.67-0.86), and women had a faster rate to using a paid caregiver than men (hazard ratio 1.76, 95% CI 1.35-2.28) after controlling for potential confounders.
Conclusions:
Informal caregiving resources are lower for women than men with PD, despite the finding that their caregivers report less strain than those of men. In addition, women are more likely to use formal, paid caregivers. Strategies to improve access to caregiving, particularly for women, are needed.
Parkinson's disease (PD) is a complex, chronic and progressive neurodegenerative disease. While the etiology of PD is likely multifactorial, the protein α-synuclein is a central component to the pathogenesis of the disease. However, the mechanism by which α-synuclein causes toxicity and contributes to neuronal death remains unclear. Mitochondrial dysfunction is also widely considered to play a major role in the underlying mechanisms contributing to neurodegeneration in PD. This review discusses evidence for the neuropathological role for α-synuclein in the dysfunction of dopamine neurons in PD. We also discuss insights into the structure, localization, and cellular roles for α-synuclein that may influence its aggregation properties, ultimately impacting its pathogenicity, role in lysosomal dysfunction and activation of the neuroimmune response. We further highlight recent evidence linking α-synuclein and mitochondrial dysfunction in neurodegeneration. Identifying the underlying mechanisms responsible for this bi-directional relationship between α-synuclein and mitochondrial dysfunction may provide new insights into the pathophysiology of PD.
This study assessed the modulating effects of liquiritin against cognitive deficits, oxidative damage, and neuronal apoptosis induced by subsequent bilateral intrahippocampal injections of aggregated amyloid-β1-42 (Aβ1-42). This study also explored the molecular mechanisms underlying the above phenomena. Liquiritin was orally administered to rats with Aβ1-42-induced cognitive deficits for 2 weeks. The protective effects of liquiritin on the learning and memory impairment induced by Aβ1-42 were examined in vivo by using Morris water maze. The rats were then euthanized for further studies. The antioxidant activities of liquiritin in the hippocampus of the rats were investigated by biochemical and immunohistochemical methods. The apoptosis of the neurons was assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assay. Liquiritin at doses of 50-100 mg/kg significantly improved the cognitive ability, restored the abnormal activities of glutathione peroxidase and superoxide dismutase, and decreased the levels of malondialdehyde，8-hydroxy-2'-deoxyguanosine and protein carbonyl in the hippocampus of rats with Alzheimer's disease. Moreover, neural apoptosis in the hippocampus of Aβ1-42-treated rats was reversed by liquiritin. Liquiritin can significantly ameliorate Aβ1-42-induced spatial learning and memory impairment by inhibiting oxidative stress and neural apoptosis.
Unlabelled:
Parkinson's disease (PD) is an age-related complex neurodegenerative disease that affects ≤ 80% of dopaminergic neurons in the substantia nigra pars compacta (SNpc). It has previously been suggested that mitochondrial dysfunction, oxidative stress and oxidative damage underlie the pathogenesis of PD. Curcumin, which is a major active polyphenol component extracted from the rhizomes of Curcuma longa (Zingiberaceae), has been reported to exert neuroprotective effects on an experimental model of PD. The present study conducted a series of in vivo experiments, in order to investigate the effects of curcumin on behavioral deficits, oxidative damage and related mechanisms. The results demonstrated that curcumin was able to significantly alleviate motor dysfunction and increase suppressed tyrosine hydroxylase (TH) activity in the SNpc of rotenone (ROT)-injured rats. Biochemical measurements indicated that rats pretreated with curcumin exhibited increased glutathione (GSH) levels, and reduced reactive oxygen species activity and malondialdehyde content. Mechanistic studies demonstrated that curcumin significantly restored the expression levels of heme oxygenase-1 and
Nad(p)h:
quinone oxidoreductase 1, thus ameliorating ROT-induced damage in vivo, via the phosphorylation of Akt and nuclear factor erythroid 2-related factor 2 (Nrf2). Further studies indicated that the Akt/Nrf2 signaling pathway was associated with the protective role of curcumin in ROT-treated rats. Inhibiting the Akt/Nrf2 pathway using a lentiviral vector containing Nrf2-specific short hairpin RNA, or the phosphoinositide 3-kinase inhibitor LY294002, markedly reduced the expression levels of TH and GSH, ultimately attenuating the neuroprotective effects of curcumin against oxidative damage. These results indicated that curcumin was able to significantly ameliorate ROT-induced dopaminergic neuronal oxidative damage in the SNpc of rats via activation of the Akt/Nrf2 signaling pathway.
The pathophysiologies of neurodegenerative diseases,
including amyotrophic lateral sclerosis (ALS),
Parkinson’s disease (PD), and Alzheimer’s disease (AD), are
far from being fully explained. Oxidative stress (OS) has been
proposed as one factor that plays a potential role in the pathogenesis
of neurodegenerative disorders. Clinical and preclinical
studies indicate that neurodegenerative diseases are characterized
by higher levels of OS biomarkers and by lower
levels of antioxidant defense biomarkers in the brain and peripheral
tissues. In this article, we review the current knowledge
regarding the involvement of OS in neurodegenerative
diseases, based on clinical trials and animal studies. In addition,
we analyze the effects of the drug-induced modulation of
oxidative balance, and we explore pharmacotherapeutic strategies
for OS reduction.
Parkinson's disease is a neurological disorder with evolving layers of complexity. It has long been characterised by the classical motor features of parkinsonism associated with Lewy bodies and loss of dopaminergic neurons in the substantia nigra. However, the symptomatology of Parkinson's disease is now recognised as heterogeneous, with clinically significant non-motor features. Similarly, its pathology involves extensive regions of the nervous system, various neurotransmitters, and protein aggregates other than just Lewy bodies. The cause of Parkinson's disease remains unknown, but risk of developing Parkinson's disease is no longer viewed as primarily due to environmental factors. Instead, Parkinson's disease seems to result from a complicated interplay of genetic and environmental factors affecting numerous fundamental cellular processes. The complexity of Parkinson's disease is accompanied by clinical challenges, including an inability to make a definitive diagnosis at the earliest stages of the disease and difficulties in the management of symptoms at later stages. Furthermore, there are no treatments that slow the neurodegenerative process. In this Seminar, we review these complexities and challenges of Parkinson's disease.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Objective: To determine the incidence of parkinsonism and PD in the Italian elderly, and to explore the relation with age and gender.
Methods: In eight Italian municipalities, a population-based, parkinsonism-free cohort was followed for an average of 3 years. At the end of the follow-up, the cohort survivors were directly contacted (screening and clinical examination). Cohort members who had died were studied using death certificates, clinical records, and information gathered from relatives and general practitioners. Parkinsonism diagnosis and subtyping were made according to specified diagnostic criteria.
Results: The cohort consisted of 4,341 individuals (65 to 84 years of age): 596 died before the examination, 2,863 (76.4% of the survivors) completed the screening procedure, and 882 refused to participate. The authors found 68 incident cases of parkinsonism: 42 PD (62%), 7 drug-induced parkinsonism (10%), 8 parkinsonism in dementia (12%), 8 vascular parkinsonism (12%), and 3 parkinsonism, unspecified (5.8%). Average annual incidence rate (per 100,000 person-years) in the population aged 65 to 84 years, adjusted to the 1992 Italian population, was 529.7 (95% CI, 400.5 to 658.9) for parkinsonism, and 326.3 (95% CI, 224.1 to 427.5) for PD. Incidence rates for both parkinsonism and PD increased with age in both men and women; men had higher rates in every age group. Age-adjusted relative risk in men compared with women was 1.66 (95% CI, 1.02 to 2.70) for parkinsonism and 2.13 (95% CI, 1.11 to 4.11) for PD.
Conclusions: Incidence of parkinsonism and PD increased with age, PD was the most common type of parkinsonism, and men had a risk of developing PD twice that of women.
Inflammation and oxidative stress are two major causes of various life-threatening diseases. Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from citrus species that have numerous biological properties, particularly antioxidant and anti-inflammatory. New findings showed that the antioxidant activity of Hsd/Hst was not only limited to its radical scavenging activity, but it augmented the antioxidant cellular defenses via the ERK/Nrf2 signaling pathway as well. Various in vitro and in vivo studies have been conducted to evaluate Hsd, its metabolites, or its synthetic derivatives at reducing inflammatory targets including NF-κB, iNOS, and COX-2, and the markers of chronic inflammation. In this review, new findings regarding the molecular targets of Hsd and Hst in the reduction of oxidative stress are discussed. Also, in the anti-inflammatory section, we provide a summary of significant investigations concerning the mechanisms of action based on the studied inflammation models. Copyright © 2014 John Wiley & Sons, Ltd.
Objective
Parkinson's disease (PD) may be due to the interaction of a number of factors, including genetic influence, toxins, oxidative stress, mitochondrial abnormalities and aging. Studies have shown that consumption of a diet rich in antioxidants may reduce the incidence of neurodegenerative diseases. In this study, we evaluated the role of the flavonoid hesperidin in an animal model of PD induced by 6-hidroxidopamine (6-OHDA).
Methods
Aged mice were treated with hesperidin (50 mg/kg) during 28 days after an intracerebroventricular injection of 6-OHDA. The enzymatic activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), and glutathione S-transferase (GST), the levels of glutathione (GSH), reactive species (RS), total reactive antioxidant potential (TRAP), dopamine (DA) and its levels of metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), was analyzed in the striatum. The behavioral parameters (depressive-like, memory and locomotor) were measured.
Results
This study demonstrated that hesperidin (50 mg/kg) treatment was effective in preventing memory impairment in the Morris water maze test, as well as, depressive-like behavior in the tail suspension test (TST). Hesperidin attenuated the 6-OHDA-induced reduction in GPx and CAT activity, TRAP and the DA and its metabolite levels in the striatum of aged mice. 6-OHDA increased RS levels and GR activity in the striatum, and these alterations were mitigated by chronic administration of hesperidin.
Conclusion
This study demonstrated a protective effect of hesperidin on the neurotoxicity induced by 6-OHDA in aged mice, indicating that it could be useful as a therapy for the treatment of PD.