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Neuroprotective Mechanisms of Natural Polyphenolic Compounds

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Abstract

Natural polyphenols have been reported to exert beneficial effects in preventing cardiovas-cular diseases but their neuroprotective mechanisms were studied much less. The review is focused on biochemical pathways and molecular neuroprotective mechanisms of natural polyphenols in the brain particularly; of course in close relation to neurophysiological and pathophysiological consequences. This review provides the evidence that antioxidant activity, mainly inhibition of the NADPH oxidase and subsequent reactive oxygen species generation; a balance in NO production from different NO synthase isoforms; reduction of neuroinflammation via attenuation of the release of cytokines and downregulation of the pro-inflammatory transcription factors; and the potential to modulate signalling pathways such as mitogen-activated protein kinase cascade and cAMP response element-binding protein are responsible for the neuroprotective actions of different natural polyphenols. These beneficial effects are mainly in demand in prevention of brain damage including ischemic stroke and neurodegenerative diseases, in the reduction of neuronal death, in memory improvement, as also for learning and general cognitive ability.

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... Provinol was found to increase NO synthase activity after 4 weeks of treatment in the cerebral cortex, cerebellum and brainstem (Jendekova et al., 2006). Also, provinols were reported to increase NO synthase activity in the heart and aorta of NG-nitro-L-arginine methyl ester (L-NAME)-treated rats (Kovacsova et al., 2010). These results suggest that provinols can potently activate NO synthase functions in both the cardiovascular and nervous systems. ...
... These results suggest that provinols can potently activate NO synthase functions in both the cardiovascular and nervous systems. However, it was also found that prolonged provinols treatment for 7 weeks had no effect on NO synthase activity that was decreased by L-NAME treatment (Kovacsova et al., 2010). It was suggested that by the activation of common ''receptor''-binding sites that are particularly present at the level of the cellular plasma membrane in the rat brain, the neuroprotective function of various polyphenols and resveratrol analogs can potentially be activated (Han et al., 2006). ...
... It was suggested that by the activation of common ''receptor''-binding sites that are particularly present at the level of the cellular plasma membrane in the rat brain, the neuroprotective function of various polyphenols and resveratrol analogs can potentially be activated (Han et al., 2006). Researchers have hypothesized that binding polyphenols to this receptor may be associated with increased NO synthase activity in the brain (Kovacsova et al., 2010). ...
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Polyphenols are naturally occurring, synthetic or semisynthetic organic compounds that offer a vast array of advanced biomedical applications. The mostly researched polyphenolic compounds are resveratrol and flavanols, notably (-)-epicatechin. The ongoing research on clinically important resveratrol and flavanols has revealed their potentials as extremely efficient drug agents that can be leveraged for new therapeutic designs for combating stroke related injuries, cancer and renal failures. Here, we have highlighted recent developments in this area with an emphasis on the biomedical applications of polyphenols. Also, a perspective on the future research directions has been discussed. We believe that this review would facilitate further research and development of polyphenols as a therapeutic avenue in medical science.
... Schizophrenia continues to be a mysterious disease, fascinating the minds of psychiatrists, pharmacologists and neuroscientists all over the world for more than a century. Schizophrenia is a disabling condition having onset earlier in men (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) y.) than in women (25-35yrs), with a lifetime global prevalence of 1%. A typical patient of schizophrenia experiences four types of clinical symptoms a) Apathetic attitude such as lack of emotions, flat affect, expressionless gaze b) Bizarre behaviour such as disorganized conduct, hostility, unnecessary laughter or crying episodes, odd or irrational statements, strange way of speaking, deterioration of personal hygiene, delusions, hallucinations, suspicious nature, c) Cognitive dysfunctions such as aphasia, irrelevant talk, dementia, loss of concentration, lack of judgement, d) Depressive symptoms such as lack of motivation, social withdrawal, anhedonia, insomnia, lack of interest in life, self-harm etc [4]. ...
... This activated endothelial nitric oxide synthase produces nitric oxide, which further inhibits NADPH oxidase. This protective effect of natural polyphenols may be important in the prevention of brain damage due to ischemic stroke, neuronal apoptosis and neurodegenerative diseases [20]. ...
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Objective: The present study aim to investigate the anti-psychotic potential of pyrus communis in the rodents.Methods: The fresh juice of pyrus communis (Pear) was administered orally to rodents for 21 d and the anti-psychotic activity was assessed by in vitro methods viz ketamine induced stereotypic behaviour, pole climbing avoidance in rats and swim induced grooming behaviour experimental models. The biochemical estimation was done on 21 d.Results: The different concentrations of fresh pyrus communis juice was assayed. When pyrus communis juice (PCJ) was administered chronically for 21 d remarkably decreased ketamine induced falling, head-bobbing, weaving and turning counts. Administration of Pear juice significantly delayed the latency time taken by the animals to climb the pole in Cook’s pole climb apparatus. In swim induced grooming behaviour model, Pear juice significantly reduced swim induced grooming behaviour. Moreover, Pear juice significantly decreased the brain dopamine levels and inhibited acetyl cholinesterase activity. In the present study, Pear juice significantly enhanced reduced glutathione levels in the brains of mice, thereby reflecting enhanced scavenging of free radicals and in turn preventing occurrence of psychotic attack.Conclusion: The present study revealed that pyrus communis juice possessed significant anti-psychotic activity.
... They are characterized by the deterioration of nerve cells from brain and spinal cord, that leads to functional loss (ataxia) or sensory function (dementia) [100]. It was already noticed that polyphenolic compounds, including epicatechin, can cross blood-brain barrier and here directly scavenge pathological concentration of reactive species and chelate transition metal ions, activating key antioxidant enzymes in the brain and thus breaking the vicious cycle of oxidative stress and tissue damage [101]. Phenolic compounds of red wine, which comprise epicatechin and derivatives, demonstrated anti-neurodegenerative actions, such as the increase of eNOS, downregulation of iNOS activity and inhibition of the synthesis of endothelin-1, well-known as a vasoactive peptide [102,103]. ...
... Phenolic compounds of red wine, which comprise epicatechin and derivatives, demonstrated anti-neurodegenerative actions, such as the increase of eNOS, downregulation of iNOS activity and inhibition of the synthesis of endothelin-1, well-known as a vasoactive peptide [102,103]. Furthermore, the attenuation of release of IL-1β and TNF-α, and the inhibition of ERK and NF-κB pathways already demonstrated by epicatechin also protect and/or improve physiological brain functions [101,104]. These facts are in accordance with Mohamed and co-workers [105] study, which referred that pre-treatment of adult rats with (-)-epicatechin diminished doxorubicin's neurotoxicity by reducing TNF-α, iNOS, and NF-κB expression, as well as by reducing the total nitrite levels in the brains. ...
Chapter
Phenolic compounds are phytochemicals extensively distributed by fruits, vegetables and other food products. Recently, they have been gaining great scientific interest due to their great antioxidant capacity. According to their chemical structure, they can be divided into phenolic acids, stilbenes and flavonoids like as anthocyanins, flavonols, flavanones, flavanonols, flavones, isoflavones and flavan-3-ols. These last ones are the most structurally complex subclass of flavonoids, ranging from simple monomers (+)-catechin and its isomers (-)-epicatechin, to complex structures, as oligomeric and polymeric proanthocyanidins (condensed tannins). (+)-Catechin and (-)-epicatechin are present in several vegetables and fruits, being (-)-epicatechin widely present in chocolates, red wine, green and black teas, broad beans, pears, apples, black grapes, apricots, and in raspberry, blackberry, cherry and bilberry fruits, and are responsible for the astringent taste and the bitter note. As like the others flavonoids, (-)-epicatechin shows the C6-C3-C6 structure, which is the major responsible for their displayed health benefits. Recent studies reported that (-)-epicatechin is very effective against free radical scavenging and lipid peroxidation, possess anti-hemorrhagic properties, and proved to have metabolic and physiologic effects in protection against worldwide pandemic pathologies, like cancer, diabetes, osteoporosis, cardiovascular and neurodegenerative diseases. Thus, this chapter will be focused in principal sources and health benefits associated with food consumption rich in (-)-epicatechin, highlighting their chemical structure, bioavailability, biological potential and health benefits currently described.
... Therefore, these compounds might exhibit positive effects on health. 10,11 The aim of the present study was to investigate the effects of grape seed extract (GSE) administration after exposure to hypobaric hypoxia on the brain levels of some oxygen and nitrogen reactive species and inflammatory cytokine and molecules involved in the angiogenesis process. ...
... 34,35 Additionally, red wine polyphenols were demonstrated to inhibit brain NADPHoxidase activation, an important source of superoxide radical. 10 The reduction of the brain NO level after GSE administration was also evidenced in our study. Probably, this extract had an inhibitory effect on n-NOS a result of its epigallocatechin gallate content. ...
Article
Abstract Hypoxia induces a wide range of deleterious effects at the cellular level due to an increased production of reactive oxygen species (ROS). Polyphenols from grape seeds, which are potent antioxidants might protect the brain against oxidative stress produced by hypobaric hypoxia. The brain effects of three doses of grape seed extract intraperitoneally (i.p.) administered in rats after exposure to hypobaric hypoxia corresponding to 5500 m altitude were investigated. Some oxygen and nitrogen reactive species, inflammatory cytokine (IL-6) and molecules involved in angiogenesis (vascular endothelial growth factor [VEGF], matrix metalloproteinase 2 [MMP2], and tissue inhibitors of metalloproteinase 1 [TIMP1]) were determined. Forty-two rats were divided in seven groups: group 1, control; groups 2, 3, and 4 were exposed to hypobaric hypoxia for 24 h in a hypobaric chamber; groups 5, 6, and 7 were exposed to hypobaric hypoxia for 5 days. After returning to normal atmospheric pressure, rats from groups 2 and 5 were sacrificed without other treatment. Animals from groups 3 and 6 were i.p treated with carboxymethyl cellulose (CMC) vehicle and those from groups 4 and 7 were i.p. treated with grape seed extract (GSE) (50 mg gallic acid equivalents/kg body weight in 0.5 mL CMC suspension/animal). The treatment was applied at 2, 24, and 72 h from returning to normoxia. Hypobaric hypoxia produced increased brain levels of ROS, nitric oxide (NO), IL-6, and VEGF after both time intervals (P<.05). The MMP2 concentration was significantly increased in groups treated only with vehicle, whereas TIMP1 was slightly changed. GSE produced a significant reduction of ROS and NO levels proving its antioxidant capacity. It also decreased IL-6 and MMP2 concentrations to values similar to controls. The VEGF concentration was also significantly reduced. These effects are indicative for anti-inflammatory and antiangiogenic properties of GSE.
... Elle renferme des taux élevés en alphatocophérol ou vitamine E, le plus protecteur contre les radicaux libres et à effets antioxydants largement décrits [6]. De plus, les polyphénols contenus dans l'huile d'argan sont des antioxydants aidant à lutter contre le stress oxydatif à l'origine des pathologies cardiovasculaires, désordres immunitaires, cancers mais aussi de maladies neurodégénératives et de mort neuronale [7,8]. Par ailleurs, l'huile d'argan contient des stérols végétaux dont les propriétés hypocholestérolémiantes ne sont plus à prouver [9]. ...
... En effet, plusieurs travaux ont montré que l'huile d'argan obtenue par pressage de l'amande torréfiée est riche en acides gras, en tocophérols, en stérols et en caroténoïdes (xanthophylles) [19][20][21]. Ces molécules sont de plus en plus connues par leur fort potentiel pharmacologique intéressant, les études entreprises sur ces composés ont révélé de fortes propriétés anti-inflammatoires et antioxydantes [8], ce qui peut expliquer l'effet anti-inflammatoire des huiles Témoin 2 0,458 ± 0,017* (6) 0,71 ± 0,014* (6) 0,55 ± 0,014* (6) Indo (20 mg/kg IP) 0,06 ± 0,014* (6) 0,113 ± 0,016* (6) 0,135 ± 0,010* (6) HP (3 ml/kg VO) 0,4 ± 0,014* (6) 0,492 ± 0,017* (6) 0,443 ± 0,025* (6) HP (5 ml/kg VO) 0,34 ± 0,017* (6) 0,385 ± 0,010* (6) 0,35 ± 0,012* (6) HT (3 ml/kg) 0,298 ± 0,011* (6) 0,36 ± 0,014* (6) 0,332 ± 0,014* (6) HT (5 ml/kg) 0,235 ± 0,010* (6) 0,28 ± 0,014* (6) 0,257 ± 0,012* (6) Les valeurs sont exprimées en moyenne ± écart-type (n = 6) * statistiquement significatif à p < 0,001 par rapport au contrôle et à l'anti-inflammatoire de référence (indométacine 20 mg/kg IP) testées. Cependant, les différences observées entre l'huile d'argan traditionnelle et l'huile d'argan de presse ne pourraient être liées qu'à l'influence de certains facteurs comme l'origine des graines, la méthode d'extraction et les conditions de conservation de l'huile comme cela a été rapporté par plusieurs travaux [22]. ...
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L’huile d’argan se distingue par un profil biochimique particulier, riche en acides gras oléique et linoléique, en tocophérols, en stérols, en polyphénols et en alcools triterpéniques, lui conférant des propriétés nutritionnelles, thérapeutiques et préventives contre certaines affections dermatologiques, métaboliques et prolifératives. L’objectif de ce travail est de savoir si la composition de l’huile d’argan pourrait également lui conférer une activité anti-inflammatoire éventuellement influencée par le mode d’extraction de l’huile. Les propriétés anti-inflammatoires de l’huile d’argan extraite selon deux différents procédés, traditionnel à la meule et moderne par presse, ont été évaluées in vivo sur des œdèmes induits par la carragénine et par traumatisme expérimental chez le rat Wistar. L’administration orale de l’huile d’argan traditionnelle à la dose de 5 ml/kg révèle une réduction significative du volume de la patte des rats de 70,52 % (œdème à la carragénine) et de 60,56 % (œdème par traumatisme), comparativement aux rats témoins et aux rats traités par l’indométacine molécule de référence, administrée à 10 et 20 mg/kg VO. En revanche, l’huile d’argan obtenue par presse à 5 ml/kg VO provoque une réduction significativement plus faible des œdèmes, soit de 48,24 % (œdème à la carragénine) et de 45,77 % (œdème par traumatisme). Nos résultats révèlent ainsi une activité antiinflammatoire de l’huile d’argan avec une meilleure efficacité de l’huile d’argan traditionnelle par rapport à l’huile d’argan de presse.
... 15 Flavonols epicathec combining physical activity can increase the retention of rats' spatial memory with a mechanism involving angiogenesis in the hippocampus and increased regulation of genes associated with the learning process in the hippocampus. 16 Interaction of polyphenols with protein kinases and lipid kinases can activate the extracellular signal-regulated kinase (ERK1/2) signaling pathway and protein kinase B/Akt, leading to activation of cAMP response element-binding (CREB) protein, a transcription factor that plays a role in increasing the number of neurotrophin expressions to improve memory and cognitive function. 16 Another study conducted by Grodstein 17 proved that beta-carotene functions as an antioxidant that can scavenge free radicals in lipidoxidation nerve cells and produce The treatment group 5 (EESL 400mg/kg BW) showed a significant increase in spatial memory, but not significant compared to the other treatment groups, due to the use of higher dosage of vegetables does not always show better results than smaller dosage. ...
... 16 Interaction of polyphenols with protein kinases and lipid kinases can activate the extracellular signal-regulated kinase (ERK1/2) signaling pathway and protein kinase B/Akt, leading to activation of cAMP response element-binding (CREB) protein, a transcription factor that plays a role in increasing the number of neurotrophin expressions to improve memory and cognitive function. 16 Another study conducted by Grodstein 17 proved that beta-carotene functions as an antioxidant that can scavenge free radicals in lipidoxidation nerve cells and produce The treatment group 5 (EESL 400mg/kg BW) showed a significant increase in spatial memory, but not significant compared to the other treatment groups, due to the use of higher dosage of vegetables does not always show better results than smaller dosage. Smaller dosage can provide more effective results. ...
Article
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Background: Spatial memory reduction in elderly is predicted to increase up to twice every 20 years. Spinach (Amaranthus hybridus) is widely consumed by Indonesian people and is believed to prevent declined spatial memory function. The aim of this study was to determine the effects of spinach on spatial memory in wistar rat induced by diazepam Methods: An experimental study was conducted during the period of October to November 2012 in Pharmacology and Therapy Laboratory, Faculty of Medicine, Universitas Padjadjaran. Twenty five wistar rats were divided into 5 groups; two groups as controls, and 3 groups were given 100, 200, and 400mg/kg BW ethanolic extract of spinach (EESL), respectively. On day 7, group 3, 4, and 5 were given 1 mg/kg BW diazepam injection. Morris water maze tests and calculations of escape latency time (ELT) were performed on day 7 and 8. Data were analyzed using analysis of variance (ANOVA) and least significance difference (LSD) test. Results: On day 7, group 2 experienced acceleration in ELT compared to group 4 and group 5. On day 8, group 2 experienced acceleration in ELT compared to group 3 and group 4. There was no significant increase in spatial memory in group 5 (EESL 400mg/kg BW) that due to the use of higher dosage does not always show better results. Conclusions: EESL can prevent impairment of spatial memory with an effective dose of 200 mg/kg BW.
... This is mainly due to studies showing conclusive results in vitro but not in vivo [4,27]. As chemical entities, polyphenols have been shown to have antioxidant [28], neuroprotective [29,30], chemo protective [31], anti-inflammatory [32], arthero protective [33] properties and may decrease the risk of cardiovascular disease [34] and type 2 diabetes [10]. In addition, data from epidemiologic studies indicate the presence of an inverse relationship between human disease and dietary polyphenol [35], and recently, a large study investigating the effect of consumption of diet rich in polyphenols [36] reported an inverse association between the consumption of polyphenol-rich foods and the risk of cardiovascular disease or overall mortality. ...
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Natural plant remedies have been used for thousands of years to offer prevention, relief and cure for all types of illnesses, and people in the ancient times believed that good and sufficient food was vital for the body survival, to perform better and deter various dis-eases. Epidemiological studies suggest that diets high in polyphenols may have a protective effect against oxidative stress and play a critical role in the prevention of some common diseases such as hypertension, diabetes and obesity. However, the diversity and com-plexity of these compounds implies that much remains to be elucidated concerning the mechanisms by which these compounds influ-ence health. We have recently reported that dark chocolate (Barry Callebout, Belgium) and pomegranate juice or extract consump-tion can reduce fasting blood glucose levels, insulin resistance, systolic and diastolic blood pressure. The effects of green coffee bean extract, green tea and grape juice on blood pressure and glucocorticoids were also investigated and compared in healthy volunteers of different age, gender and BMI. There is now growing evidence that polyphenols supplements and food rich in polyphenols may play a critical role in the prevention of several contemporary diseases such as obesity and cancer. I suggest that it is absolutely vital to realize that the intake of polyphenols-rich foods has to be considered as protective measure against the development of the epidemic of chronic diseases rather than a cure, at least for the present time. Therefore, changing the dietary habits and culture has to start at an earlier stage in life, particularly in the UK and Europe. In conclusion, over the last few decades, there has been tremendous surge of attention in the action of natural polyphenols and their effects on various body functions and metabolic processes. However despite the huge increased research throughout the world and interest by the public, the majority of the health benefits and physiological ac-tivities attributed to nutrients and food products require further research to elucidate the mechanism/s of action, and side effects. (10) (PDF) Emad AS Al-Dujaili. “Natural Polyphenols: Potential for Disease Prevention”. Review Article, EC Nutrition 2.2 (2015): 337-345.. Available from: https://www.researchgate.net/publication/288182361_Emad_AS_Al-Dujaili_Natural_Polyphenols_Potential_for_Disease_Prevention_Review_Article_EC_Nutrition_22_2015_337-345 [accessed May 21 2020].
... It is supposed that activation of NF-κB in spontaneously hypertensive rats is accelerated by increased production of reactive oxygen species (ROS) in this type of rats. Increased ROS production likely accelerates the inactivation of NO and accounts for the apparent decrease in bioactive NO as it was documented also in several studies (Noll et al 1997;Bouloumie et al 1997;Kovacsova et al 2010;Pechanova 2010). Thus, the concentration of NO in the brain parts of SHR might be lower despite comparable NO synthase activity with normotensive rats. ...
Article
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Recently, alterations in cerebellar nuclear factor kappaB (NF-κB) expression and nitric oxide (NO) generation were documented to be associated with increased locomotor activity in spontaneously hypertensive rats (SHR). We aimed to analyze whether changes in cerebellar NF-κB pathway in hypertension associated with metabolic syndrome (MS) may affect locomotor activity of MS rats. Furthermore, the age-dependent changes were investigated as well. Male Wistar Kyoto rats (WKY, 9 weeks old), spontaneously hypertensive rats (SHR, 9 weeks old), and rats with MS aged 9 and 12 weeks were analyzed. Blood pressure was measure by tail-cuff plethysmography. Locomotor activity was tested by the open field method. Protein expression of NF-κB (p65 subunit), inducible NOS (iNOS) and NOS activity were determined in the cerebellum. In SHR, despite no changes in NOS activity, increased NF-κB (p65) expression was associated with increased of both horizontal and vertical motor activities. Similarly, in young MS rats, increased NF-κB (p65) expression led to increased horizontal motor activity despite decreased NOS activity. On the other hand, no significant changes in NF-κB (p65) expression were demonstrated in adult MS rats. Horizontal and vertical motor activities as well as NOS activity were markedly reduced in this group of rats. In conclusion, increased cerebellar NF-κB (p65) expression was associated with increased horizontal motor activity in both SHR and young MS rats, despite the obesity which accompanied also young rats with metabolic syndrome. Downregulated NF-κB pathway together with increased weight of rats may belong to the causes of decreased locomotor activity of adult MS rats.
... Several of our own studies have shown [44][45][46][47] that administration of polyphenols may evoke following effects in the animal brain: (1) antioxidant activity, mainly inhibition of the NADPH oxidase and subsequent reactive oxygen species generation; (2) an activator effect on endothelial and inhibitory action upon both neuronal (nNOS) and inducible nitric oxide synthase activity; (3) downregulation of the proinflammatory transcription factors such as NF-B; and (4) modulation of signalling pathways such as mitogen-activated protein kinase cascade and cAMP response element-binding protein leading to the improvement of memory and cognitive performance. Nevertheless, the question still remains whether the polyphenols may have also an influential general beneficial effect in relation to the behavioural and brain functions of senior persons. ...
Article
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It is known that endothelial dysfunction plays an important role in the development and progression of cardiovascular diseases implicated also in cognitive decline. Experimental studies pointed to the fact that the modification of NO levels via NOS activity may affect the blood pressure level as well as several higher nervous functions—for example, learning and memory. There are emerging evidences from in vitro and animal studies suggesting that polyphenols may potentially have a protective effect on the development of neurodegenerative diseases and may improve cognitive function as well as positively affecting the blood pressure regulatory mechanisms. This review accentuates the need for precisely defined clinically controlled studies as well as for use of adequate experimental procedures discriminating between the human higher brain functions and the only overall activation of the brain cortex. The physiological neurocardiovascular interactions are implicated in the increased healthy life span as well.
... Thus, attention has been recently focused on searching for natural products that can protect cells from oxidative damage. Phenolic compounds are an important class of plant-derived secondary metabolites with recognized neuroprotective ability (Kovacsova et al., 2010). They can act in different molecular targets and by different mechanisms due to their redox potential. ...
Article
We investigated the neuroprotective effect of Lavandula viridis extracts (infusion, water:ethanol and methanol) and rosmarinic acid, the major compound present in the extracts, against oxidative damage induced by hydrogen peroxide (H2O2) in A172 human astrocyte cell line regarding the neurotoxic effect, intracellular reactive oxygen species (ROS) production and the activity of the antioxidant enzyme catalase (CAT). We found that L viridis extracts and rosmarinic acid protected A172 astrocytes against H2O2 and reduced intracellular ROS accumulation. Furthermore, the protection effect was not caused by modulation of CAT suggesting that other intracellular mechanisms are involved in the neuroprotective effect. Our results highlight that L viridis extracts and rosmarinic acid have beneficial effects against oxidative damage associated with neurodegenerative diseases.
... This protective effect of natural polyphenols may be important in the prevention of brain damage due to ischemic stroke, neuronal apoptosis and neurodegenerative diseases. 20 Currently, extensive research showed that glutamate concentrations were reduced in the CSF of patients suffering with schizophrenia. ...
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Foeniculum vulgare (Fennel), generally known as Saunf belonging to Apiacae family is one of the most popular and widely used medicinal plants in traditional medicine. Fennel contains volatile compounds, flavonoids, phenolic compounds, fatty acids, and amino acids. There is no documented report on utility of Fennel in psychiatric disorders in literature. Therefore, this study was undertaken to explore anti-psychotic potential of Fennel using Ketamine-induced stereotypic behaviour in mice, pole climbing avoidance in rats and swim induced grooming in mice. Fennel, when administered orally to rodents in two different concentrations of 500mg/kg and 1000mg/kg for 21 days, inhibited Ketamine-induced stereotypic behaviour, reduced swim-induced grooming behaviour and decreased pole-climb avoidance behaviour. In our biochemical estimations both, brain dopamine level and acetyl cholinesterase activity were significantly reduced by Fennel whereas, brain glutathione levels were remarkably increased by Fennel. These findings taken together reveal anti-psychotic potential of Fennel.
... Several of our own studies have shown [44][45][46][47] that administration of polyphenols may evoke following effects in the animal brain: (1) antioxidant activity, mainly inhibition of the NADPH oxidase and subsequent reactive oxygen species generation; (2) an activator effect on endothelial and inhibitory action upon both neuronal (nNOS) and inducible nitric oxide synthase activity; (3) downregulation of the proinflammatory transcription factors such as NF-B; and (4) modulation of signalling pathways such as mitogen-activated protein kinase cascade and cAMP response element-binding protein leading to the improvement of memory and cognitive performance. Nevertheless, the question still remains whether the polyphenols may have also an influential general beneficial effect in relation to the behavioural and brain functions of senior persons. ...
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Background: The beneficial effects of natural polyphenols upon hypertension are explained by complex biochemical, pharmacological and physiological interventions with cardiovascular (CV) regulatory mechanisms (1). As neural CV regulatory mechanisms the sympathetic and parasympathetic are taken into account. The question remains whether the higher brain regulatory mechanisms could be affected by polyphenols also. Their effects upon CV regulatory mechanisms are usually thought over as psychosomatic component of certain CV problems. Methods: The red wine polyphenols were administered to healthy undergraduate volunteers (4 mg/kg of body weight). The blood pressure, EEG and accuracy of eye movements in the visual and memory space tasks were recorded before and 2 hours after drug administration. The accuracy of eye movements as well as the EEG power spectra were analyzed. Results: The performance of subjects in experimental tasks was significantly better (higher accuracy of eye movements, less number of corrections, diminished extent of inaccuracy) after polyphenols administration. The EEG alpha spectra pointed to changed level of overall CNS activation. As expected, the single dose of polyphenols did not affect the blood pressure. Conclusions: It was shown that the polyphenols increase the overall CNS activation as well as positively affect the given cognitive function. The question remains whether this is a specific effect or rather general effect of particular integrative brain functions (e.g. attention). The results clearly suggest that the effects of natural polyphenols upon CV functions are complex and may include the higher brain regulatory mechanisms as well. Reference 1. Garthwaite, J.: Eur.J.Neurosci., 27, 2783-802 (2008).
... The mechanism of neuroprotection involves: antioxidant activity, mainly inhibition of the NADPH oxidase and subsequent reduction of reduced NADPH oxidase-mediated generation of reactive oxygen species (Zhang et al. 2010); scavenging activity and the ability to activate key antioxidant enzymes in the brain, and thus limiting oxidative stress and tissue damage (Lau et al. 2005); activation of endothelial nitric oxide release and inhibitory action on both neuronal and inducible nitric oxide synthase activity and subsequent NO production (Ritz et al. 2008;Pechanova et al. 2004); reduction of neuroinflammation via the inhibition of the release of inflammatory mediators like cytokines, interleukin-1beta, and tumor necrosis factoralpha and the downregulation of the pro-inflammatory transcription factors such as nuclear factor-kappaB (NF-jB); and modulation of signaling pathways leading to the improvement of memory and cognitive performance (Kovacsova et al. 2010). Selective interactions with protein kinase and lipid kinase signaling cascades (i.e., phosphoinositide-3 kinase/Akt and mitogen-activated protein kinase pathways), which regulate transcription factors and gene expression; activation of the extracellular signalregulated kinase (ERK1/2) and the protein kinase B/Akt signaling pathways, leading to the activation of the cAMP response element-binding protein (CREB), represent the key pathways leading to neuroprotection (Spencer 2010). ...
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The generation of free radicals and oxidative stress has been linked to several neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic lateral sclerosis. The use of free radical scavenging molecules for the reduction of intracellular reactive oxygen species is one of the strategies used in the clinical management of neurodegeneration. Fungal secondary metabolism is a rich source of novel molecules with potential bioactivity. In the current study, bikaverin was extracted from Fusarium oxysporum f. sp. lycopersici and its structural characterization was carried out. Further, we explored the protective effects of bikaverin on oxidative stress and its anti-apoptotic mechanism to attenuate H2O2-induced neurotoxicity using human neuroblastoma SH-SY5Y cells. Our results elucidate that pretreatment of neurons with bikaverin attenuates the mitochondrial and plasma membrane damage induced by 100 µM H2O2 to 82 and 26 % as evidenced by MTT and LDH assays. H2O2 induced depletion of antioxidant enzyme status was also replenished by bikaverin which was confirmed by Realtime Quantitative PCR analysis of SOD and CAT genes. Bikaverin pretreatment efficiently potentiated the H2O2-induced neuronal markers, such as BDNF, TH, and AADC expression, which orchestrate the neuronal damage of the cell. The H2O2-induced damage to cells, nuclear, and mitochondrial integrity was also restored by bikaverin. Bikaverin could be developed as a preventive agent against neurodegeneration and as an alternative to some of the toxic synthetic antioxidants.
... However, the effect may be attributed to flavonoids, whose presence was confirmed in preliminary phytochemical tests. Flavonoids are polyphenolic compounds (Kovacsova et al. 2010), being the most significant compounds for the antioxidant properties of plant raw materials (Kratchanova et al. 2010). Selection of a particular food plant, plant tissue or herb for its potential health benefits, rely on flavonoid composition (Hatti et al. 2009). ...
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Human African trypanosomiasis is prevalent in Sub-sahara African countries that lie between 14° North and 29° south of the equator. Sixty million people are at risk of infection. Trypanosoma brucei gambesience occurs in West and Central Africa while Trypanosoma brucei rhodesience occurs in East and Southern Africa. The neurological stage of the disease is characterized by neuroinflammation. About 10 % of patients treated with the recommended drug, melarsoprol develop post treatment reactive encephalopathy, which is fatal in 50 % of these patients, thus melarsoprol is fatal in 5 % of all treated patients. This study was aimed at establishing the potential activity of Erythrina abyssinica in reducing neuroinflammation following infection with Trypanosoma brucei brucei. Swiss white mice were divided into ten groups, two control groups and eight infected groups. Infected mice received either methanol or water extract of Erythrina abyssinica at 12.5, 25, 50 or 100 mg/kg body weight. Parasite counts were monitored in peripheral circulation from the third day post infection up to the end of the study. Brains were processed for histology, immunohistochemistry scanning and transmission electron microscopy. Following infection, trypanosomes were observed in circulation 3 days post-infection, with the parasitaemia occurring in waves. In the cerebrum, typical brain pathology of chronic trypanosomiasis was reproduced. This was exhibited as astrocytosis, perivascular cuffing and infiltration of inflammatory cells into the neuropil. However, mice treated with Erythrina abyssinica water extract exhibited significant reduction in perivascular cuffing, lymphocytic infiltration and astrocytosis in the cerebrum. The methanol extract did not have a significant difference compared to the non-treated group. This study provides evidence of anti-inflammatory properties of Erythrina abyssinica and may support its wide use as a medicinal plant by various communities in Kenya.
... Common mechanisms include increased levels of stress, mitochondrial dysfunction, inflammatory changes, iron accumulation, and excitotoxicity (Seidl and Potashkin 2011). Kovacsova et al. 2010 have shown that antioxidants, inhibition of NADPH oxidase, production of nitric oxide, and down regulation of nuclear factor-kappa B plays important role in the neuroprotective effect. PD patients have reduced mitochondrial complex I activity in the substantia nigra (Schapira et al. 1990). ...
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Medicinal plants have been a rich source of medicines. Mucuna pruriens is extensively used in Ayurveda to treat kampavat (Parkinson’s disease in modern medicine), a disease characterized by excess of Vata. Clinical and preclinical studies have substantiated claims on its efficacy and safety in PD and there are indications that it is more effective than the levodopa in reducing dyskinesias. Several constituents of Mucuna seeds such as genistein, gallic acid, unsaturated acids, nicotine, bufotenin, harmin alkaloids, lecithin, etc. have been isolated which possess neuroprotective activity and support the antiPD activity of levodopa. The review describes various constituents of Mucuna pruriens seeds in context to therapeutic utility in treating Parkinson’s disease. Since the conventional treatment of PD using levodopa with other add-on drugs is very expensive and Mucuna pruriens seeds are easily available and economic, the use of standardized extract of Mucuna seeds may drastically reduce the cost of treatment and also reduce the progression of disease. The review emphasizes the importance of holistic approach of Ayurveda in using the Mucuna pruriens in treatment of PD. Further studies may provide an approach to understand the mechanisms involved in treating PD with lesser adverse effects.
... Particularly, oxidative damage is the most marked in the brain due to its high oxygen consumption, high fatty acids levels, and low antioxidant enzyme levels. Moreover, neurons are largely postmitotic, so they cannot be replaced readily via mitosis when damaged [15,16]. Thus, the antioxidant properties certainly contribute to their neuroprotective effects. ...
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Quercetin has been isolated for the first time from ethyl acetate extract of Caesalpinia mimosoides Lamk. C. mimosoides Lamk. (Fabaceae) or Cha rueat (Thai name) is an indigenous plant found in mixed deciduous forest in northern and north-eastern parts of Thailand. Thai rural people consume its young shoots and leaves as a fresh vegetable, as well as it is used for medicinal purposes.The antioxidant capacity in terms of radical scavenging activity of quercetin was determined as IC50 of 3.18 ± 0.07 µg/mL, which was higher than that of Trolox and ascorbic acid (12.54 ± 0.89 and 10.52 ± 0.48 µg/mL, resp.). The suppressive effect of quercetin on both purified and cellular acetylcholinesterase (AChE) enzymes was investigated as IC50 56.84 ± 2.64 and 36.60 ± 2.78 µg/mL, respectively. In order to further investigate the protective ability of quercetin on neuronal cells, P19-derived neurons were used as a neuronal model in this study. As a result, quercetin at a very low dose of 1 nM enhanced survival and induced neurite outgrowth of P19-derived neurons. Furthermore, this flavonoid also possessed significant protection against oxidative stress induced by serum deprivation. Altogether, these findings suggest that quercetin is a multifunctional compound and promising valuable drugs candidate for the treatment of neurodegenerative disease.
... NADPH oxidase has been identified as one of the major producers of ROS in the brain (Bokoch et al 2003). NADPH oxidase–dependent production of superoxide radical (O 2 – ) was documented to be responsible for a majority of oxidative injury in the brain (Bokoch & Knaus 2003; Kovacsova et al 2010). It is hypothetised that angiotensin II, similarly like in the peripheral tissues, activates NADPH oxidase leading to increased superoxide generation. ...
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The contribution of the central nervous system (CNS) to the development and mainte-nance of high blood pressure is well established. Increased activity of the sympathetic nervous system during hypertensive conditions has been demonstrated experimentally and clinically. Different types of dysregulation in CNS, as seen by alterations in neurotrans-mitter production and baroreceptor reflex function, have been detected in early stages of hypertension. It was demonstrated that centrally acting drugs such as a-methyldopa, clonidine or reserpine effectively lower blood pressure. Moreover, in animal experi-ments renal hypertension could be prevented by central chemical sympathectomy. And psychosocial stress-induced sustained hypertension is well-known present phenomenom. The biochemical mechanisms contributing to the blood pressure increase by means of CNS are however lesser-known. Since lowering of blood pressure by the inhibition of the renin-angiotensin-aldosterone system within peripheral but also central nervous system was documented by several studies, it seems that brain angiotensin II may play a key role in the contribution of CNS to hypertension. On the other hand, sufficient production of nitric oxide within the system may effectively prevent increase in blood pressure.
... ); Bickford et al. (2000); Youdim and Joseph (2001); Rabin et al. (2002) Seeram et al. (2001) Bilberry and blackcurrant @BULLETDecreasing the ratio of insoluble amyloid beta-42/40 @BULLETAlleviating behavioral abnormalities Vepsalainen et al. (2013) Bilberry @BULLETFree radical scavenging activity @BULLETAlleviating memory deficits Kovacsova et al. (2010) Blackberry @BULLETReducing intracellular reactive oxygen species levels, modulating glutathione levels and inhibiting caspases activity @BULLETImproving behavioral performance in motor tests and Morris water maze (cognitive test) Shukitt-Hale et al. (2009); Tavares et al. (2013) Blueberry @BULLETChanges in brain-derived neurotrophic factor @BULLETDecreasing Aβ levels @BULLETDecreasing the levels of interleukin-1β, tumor necrosis factor-α and transcription factor nuclear factor-kappaB @BULLETEnhancing motor and memory performances @BULLETSignificant cognitive enhancement Youdim et al. (2000); Casadesus et al. (2004) Papandreou et al. (2009) Mulberry @BULLETDecreasing the infarct volume of the brain @BULLETNeuroprotection Kang et al. (2006) ...
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Recent clinical research has demonstrated that berry fruits can prevent age-related neurodegenerative diseases and improve motor and cognitive functions. The berry fruits are also capable of modulating signaling pathways involved in inflammation/cell survival and enhancing neuroplasticity. The neuroprotective effects of berry fruits on neurodegenerative diseases are related to phytochemicals such as anthocyanin, caffeic acid, catechin, quercetin, kaempferol and tannin. In this review, we made an attempt to clearly describe the beneficial effects of various types of berries as promising neuroprotective agents.
... This protective effect of natural polyphenols may be important in the prevention of brain damage due to ischemic stroke, neuronal apoptosis and neurodegenerative diseases. 20 Currently, extensive research showed that glutamate concentrations were reduced in the CSF of patients suffering with schizophrenia. ...
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Foeniculum vulgare (Fennel), generally known as Saunf belonging to Apiacae family is one of the most popular and widely used medicinal plants in traditional medicine. Fennel contains volatile compounds, flavonoids, phenolic compounds, fatty acids, and amino acids. There is no documented report on utility of Fennel in psychiatric disorders in literature. Therefore, this study was undertaken to explore antipsychotic potential of Fennel using Ketamine- induced stereotypic behaviour in mice, pole climbing avoidance in rats and swim induced grooming in mice. Fennel, when administered orally to rodents in two different concentrations of 500mg/kg and 1000mg/kg for 21 days, inhibited Ketamine -induced stereotypic behaviour, reduced swim -induced grooming behaviour and decreased pole - climb avoidance behaviour. In our biochemical estimations both, brain dopamine level and acetyl cholinesterase activity were significantly reduced by Fennel whereas, brain glutathione levels were remarkably increased by Fennel. These findings taken together reveal anti-psychotic potential of Fennel.
... s suggesting that polyphenols may potentially have a protective effect on the development of neurodegenerative diseases and may improve cognitive function in patients when such diseases are established. These authors stressed also that research in this area is still in its early stages and human studies are needed to substantiate potential effects. Kovacsova et al. (2010) summarized the most important neuroprotective actions of natural polyphenolic compounds in the brain. They accentuated the evidences suggesting that their mechanism of action involves: 1) antioxidant activity, mainly inhibition of the NADPH oxidase and subsequent reactive oxygen species generation; 2) an activator effect on endothelial ...
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Several natural polyphenols exert effects upon the cardiovascular as well as nervous system. In vitro and animal studies suggest that polyphenols may potentially affect the human cognitive function. The aim was to study the effect of Provinols™, the polyphenolic compounds isolated from red wine, upon the human higher brain functions. The accuracy of space memory was assessed by means of visually-guided and memory-guided saccadic eye movements. The EEG and blood pressure were registered also. The healthy undergraduates served as subjects. They were divided into the control, placebo and Provinols™ groups. The amplitudes of saccades, EEG spectral density, evoked potentials time-locked to saccadic onset and blood pressure were analyzed in control condition and 2 hours later, after administration of placebo, Provinols™ (4 mg/kg of body weight) or nothing. After the Provinols™ administration the memory-guided saccades were significantly more accurate and the significant decrease in the slow EEG bands, alpha power mainly, was registered over the broad regions of temporo-parietal cortex. No changes in saccadic eye movement related potentials as well as in blood pressure were found after the single dose Provinols™ administration. Even a single dose of the Provinols™ was able to affect positively the space memory for limited time duration. The improvement in space memory function and/or the positive role of attentional mechanisms may be taken into account mainly. More sensitive analysis of the particular participation of attentional and memory components demands the further study.
... In addition, they can inhibit COXs' activity, and enhancing GTPase activity, causing dopamine release, and avoiding losses of sensitivity in Purkinje cells, improving cognitive performance and preventing neural cell damage [177]. Furthermore, flavonoids also can modulate glutathione levels and gene expression, inhibit caspase activity, decrease neuroinflammatory markers (such as the levels of IL-1β, NF-κB and TNF-α), and stop amyloid aggregation in brain of mice models [103,[178][179][180][181][182]. ...
... Melatonin is able to increase the activity and/or mRNA of glutathione peroxidase, copper-zinc super- oxide dismutase, manganese superoxide dismutase and reduced glutathione in different brain regions, observed during both acute and chronic treatment with melatonin (Tomas-Zapico et al 2005;Kotler et al 1998). Furthermore, melatonin, similarly like different polyphenolic compounds, directly affects the assembly of NADPH oxidase in microglia, potentially through the inhibition of NADPH oxidase phosphorylation via a PI3K/Akt-dependent signaling pathway, blockade of p47(phox) and p67(phox) subunits translocation to the membrane, and down-regulation of p47(phox) binding to gp91(phox) ( Zhou et al 2008;Kovacsova et al 2010;Pechanova et al 200). ...
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The dysbalance between the sympathetic and parasympathetic vegetative system and increased free radical burden in the central nervous system (CNS) are the important pathophysiological disorders and therapeutic targets in hypertension. Besides the effects on cardiovascular system, the pineal hormone, melatonin (N-acetyl-5-methoxytryptamine) may exert part of its antihypertensive action just through its interaction with the CNS. Melatonin may be protective in CNS on several different levels: it reduces production of reactive oxygen species, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. Increased level of serum melatonin observed in some types of hypertension may represent a counterregulatory adaptive mechanism against the sympathetic overstimulation. All these effects of melatonin may include increased production of nitric oxide in their mechanisms of protection. In different experimental models of hypertension upregulation of nitric oxide synthase (NOS) activity and NOS isoform expression in different parts of brain after melatonin treatment have been documented. Thus, it is supposed that the correction of absolute or relative melatonin deficiency by exogenous melatonin administration in conditions of increased blood pressure, may help to attenuate the excessive catecholamine outflow providing a rational background for therapeutic application of melatonin in hypertension treatment.
... Dietary flavonoids inhibited LPS-induced production of proinflammatory mediators such as Interleukin-1a (IL-1a ), Tumor Necrosis Factor-a (TNFa ), and NO in activated microglia. Catechin, EGCG, quercetin, and kaempferol demonstrated reduced microglia-or astrocyte-mediated neuro-inflammation inhibiting inducible iNOS expression, COX-2, NO production, cytokine release, NADPH oxidase activation, and subsequent ROS generation in activated microglia [101][102][103]. ...
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Huntington’s disease (HD) is a neurodegenerative disorder characterized by progressive loss of neurons, which leads to behavioral systems and mental decline. HD is linked to repeat expansions of cytosine, adenine, and guanine in the Huntingtin (HTT) gene that give rise to mutation, leading to the formation of the HTT protein product. Oxidative stress also provokes the initiation and progression of HD as it leads to protein misfolding that results in the formation of inclusion which clumps together and alters neurotransmission. Despite the advancement in the field of pharmaceutical sciences, current therapeutic approaches suppress only the severity of symptoms and no therapy exists that can cure HD from its root cause. Flavonoids are the most abundant polyphenols widely present in daily dietary sources. Dietary flavonoids have a wide range of pharmacological bioactivities and many therapeutic applications. Dietary flavonoids including hesperidin, naringin, quercetin, rutin, fisetin, myricetin, luteolin, and epigallocatechin 3-O-gallate can prevent and manage HD through exerting antioxidant and anti-inflammatory activities, altering intracellular pathways, genetic alterations, and metal ion chelation. This review highlights flavonoids as therapeutic options for HD and will open new dimensions for flavonoids as safe and effective therapeutic agents in diminishing HD.
... Furthermore, polyphenols, even including those from cocoa, exert antioxidant effects, thus increasing neurological functions also preventing age-dependent damage (193). In synthesis, by analogy to other plant-derived polyphenols, cocoa flavanols may exert beneficial effects via activation of eNOS, inhibition of the NADPH oxidase and ROS production, downregulation of NF-κB, and regulation of MAPK and cAMP response element-binding protein pathways (194)(195)(196)(197). In aging, especially neurological functions become deteriorated, and NO and aging seem to be interconnected. ...
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It is well known that cocoa and dark chocolate possess polyphenols as major constituents whose dietary consumption has been associated to beneficial effects. In fact, cocoa and dark chocolate polyphenols exert antioxidant and anti-inflammatory activities switching on some important signaling pathways such as toll-like receptor 4/nuclear factor κB/signal transducer and activator of transcription. In particular, cocoa polyphenols induce release of nitric oxide (NO) through activation of endothelial NO synthase which, in turn, accounts for vasodilation and cardioprotective effects. In the light of the above described properties, a number of clinical trials based on the consumption of cocoa and dark chocolate have been conducted in healthy subjects as well as in different categories of patients, such as those affected by cardiovascular, neurological, intestinal, and metabolic pathologies. Even if data are not always concordant, modifications of biomarkers of disease are frequently associated to improvement of clinical manifestations. Quite interestingly, following cocoa and dark chocolate ingestion, cocoa polyphenols also modulate intestinal microbiota, thus leading to the growth of bacteria that trigger a tolerogenic anti-inflammatory pathway in the host. Finally, many evidences encourage the consumption of cocoa and dark chocolate by aged people for the recovery of the neurovascular unit.
... In addition, they can inhibit COXs' activity, and enhancing GTPase activity, causing dopamine release, and avoiding losses of sensitivity in Purkinje cells, improving cognitive performance and preventing neural cell damage [177]. Furthermore, flavonoids also can modulate glutathione levels and gene expression, inhibit caspase activity, decrease neuroinflammatory markers (such as the levels of IL-1β, NF-κB and TNF-α), and stop amyloid aggregation in brain of mice models [103,[178][179][180][181][182]. ...
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Abstract: Background: Sweet cherries are one of the most appreciated fruits worldwide as well as one of the great sources of several active substances, as phytochemical compounds (carotenoids, serotonin, melatonin and phenolic compounds) as well as in nutritive compounds (sugars and organic acids). Accumulating research demonstrate that their supplementation in our daily diet can contradict oxidative stress, mitigating or even attenuating chronic diseases, as cancerous processes, antiinflammatory-related disorders, diabetes, and neurological and cardiovascular pathologies. Therefore, the aims of this review are to present an overview on the effects of sweet cherries as health promotors, giving emphasis to the health benefits of their bioactive compounds, particularly their antimicrobial, antioxidant, antidiabetic, anticancer, anti-neurodegeneration, anti-inflammatory and cardiovascular effects. Methods: Research and online content about sweet cherry fruits is reviewed. The information available has been read several times to avoid inconsistencies. In addition, according what we read, original figures were done and added to facilitate understanding and to enrich the paper. Results: In this review, a total of 202 original reports were used. In respect to health benefits, it is possible to confirm by several studies that, in fact, the consumption of sweet cherries has positive impacts in human health, owing to their wealthy and vast constitution, particularly in phenolic compounds, vitamins and carotenoids whose health properties were already documented. Conclusion: The findings of this review support the evidence that sweet cherries can be applied in pharmaceutical and food formulations, since they are able to diminish free radical species and proinflammatory markers, preventing and/ or ameliorating oxidative-stress disorders.
... In fact, the brain is susceptible to oxidative stress more than other organs, because of its low antioxidant natural defense (Rahman, 2007;Uttara et al., 2009), and consequently it is suscepti- ble to oxidative-stress-related neurological disease. Many epidemiological studies have shown that regular flavonoid intake is associated with delayed onset of neurological diseases such as ischemic diseases, Parkinson's disease (PD), aging effects, and Alzheimer's disease (AD) ( Ono et al., 2003;Marambaud et al., 2005;Savaskan et al., 2005;Alzheimer's Association, 2008;Pandey and Rizvi, 2009), but flavonoids are also able to significantly ameliorate the mammalian cognitive function and may reverse the declines in memory and learning with aging ( Kovacsova et al., 2010;Angeloni et al., 2012). In particular, phyto- chemicals of berry fruits have demonstrated a beneficial effect in neurodegenerative diseases and in brain aging, due to their antiproliferative, anti-inflammatory, antiox- idative, and antiviral properties (Youdim and Joseph, 2001). ...
... [10] Phenols protect other antioxidants from oxidative effects and promote the release of antioxidant enzymes. [11] Phenolic compoundsnatural antioxidants acting with various mechanisms are necessary for human health because they have anticancer [12] , anti-inflammatory [13] neuroprotective [14] , blood cholesterol and triglyceride lowering [15] , antiviral [16] , for improving cardiovascular activity [17] , an antidiabetic [18] and many other body-enhancing effects. Another significant group of biologically active compounds found in quince organs is triterpenic compounds. ...
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Japanese quince (Chaenomeles japonica (Thunb.)) is a very important ornamental plant that is rich in many biochemical compounds such as antioxidants and secondary metabolites that have positive effects on human health. The aim of the study was to evaluate the biochemical compounds in the leaves of three Japanese quince (Chaenomeles japonica (Thunb.)) Lindl. ex Spach cultivars (ʻRasaʼ, ʻDariusʼ and ʻRondoʼ). The results showed that the leaves of Japanese quince have strong antiradical activity (1091 ± 22–1135 ± 15 µmol TE/g) in the CUPRAC reaction system. The analysis by the HPLC method revealed that the major polyphenol group in Japanese quince cultivars leaves was phenolic acids and the most common polyphenol compound is chlorogenic acid (11.2– 52.4 mg/g DW). The most common triterpene is ursolic acid (3.7– 6.8 mg/g DW). Japanese quince leaf powder can be used as a food or beverage additive and enriches our diet with compounds with strong antioxidant activity.
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Current therapeutic drugs for Alzheimer's disease (AD) can only offer limited symptomatic benefits and do not halt disease progression. Multitargeted directed ligands (MTDLs) have been considered to be a feasible way to treat AD due to the multiple neuropathological processes in AD. Previous studies proposed that compounds containing two aromatic groups connected by a carbon chain should act as effective amyloid β (Aβ) aggregation inhibitors although the optimal length of the carbon chain has not been explored. In the current study, a series of naphthalimide analogs were designed and synthesized based on the proposed structure and multiple bioactivities beneficial to the AD treatment were reported. In vitro studies showed that compound 8, which has two aromatic groups connected by a two‐carbon chain, exhibited significant inhibition of Aβ aggregation through the prevention of elongation and association of Aβ fibril growth. Furthermore, this compound also displayed antioxidative activities and neuroprotection from Aβ monomer induced toxicity in primary cortical neurons. The results of the present study highlight a novel naphthalimide‐based compound 8 as a promising MTDL against AD. Its structural elements can be further explored for enhanced therapeutic capabilities. Inhibition of both early and late stages of Aβ monomer aggregation, antioxidation through increased ORAC and reduction of inducible nitric oxygen synthase production, neuroprotective activity on Aβ monomer induced primary cortical neuron injury.
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Introduction: Oleuropein is the most important phenolic compound in olive leaves which has several pharmacological properties. So far, this compound has been shown to have antioxidant, anti-inflammatory, anti-atrogenic, antimicrobial, and antiviral properties. Scopolamine is a muscarinic antagonist used as standard medication for inducing cognitive deficits in humans and animals. This study was performed to investigate the effect of oleuropein on the function of passive avoidance memory, malondialdehyde level, and expression of GluN2B gene in the model of memory impairment caused by scopolamine. Materials & Methods: In total, 35 male mice were randomly divided into five groups (n=7). The control group received normal saline, and the Sco (scopolamine) group received intraperitoneal scopolamine at a dose of 1 mg/kg for three weeks. The treatment groups received oleuropein in three doses of 5, 10, and 20 mg/kg. At the end of the shuttle box test, the brain tissues of the animals were removed for the determination of oxidative stress and molecular tests. Findings: The results of our study showed that scopolamine significantly decreased memory and induced oxidative stress (P
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Exploiting the potential of natural compounds to attenuate endogenous redox status to achieve neuroprotection is a novel concept in human disease therapy. This has necessitated a need to identify newer efficient phytochemicals possessing propensity to act on various biochemical therapeutic targets with low or no toxicity. Selaginella is a lithophytic pteridophyte which grows on constantly irrigated rocks in high altitude zones in different parts of the world. It is appraised to be "Sanjeevani" (the resurrection herb) based on its mythological reference in the Indian epic "Ramayana". Due to the presence of a unique disaccharide, trehalose, most species of Selaginella can survive severe drought conditions, maintaining the plant's structural stability and resurrect during rains. Several species of the genus are used in ethnic medicine for the therapy of jaundice, chronic trachitis, lung cancer, labor pain and wound healing. The major natural compounds in the genus Selaginella are characteristic flavonoid-dimers, called 'biflavonoids'. Although various biological effects of Selaginella have been documented in vitro, studies on its neuromodulatory properties are non-existing despite the presence of potentially therapeutic biflavonoids. We have reviewed the existing literature on the possible pharmacological properties of Selaginella. Further, recent evidence gathered from our laboratory on the neuromodulatory propensity of S. delicatula employing in vivo models of chemically induced neurodegenerative diseases in rodents and Drosophila are discussed. Our findings point to a mechanism which modulates redox status and mitochondrial dysfunction suggesting their possible therapeutic use in oxidative stress-mediated neurodegenerative diseases including Parkinson's disease.
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Japanese quince (Chaenomeles japonica) is one of the most underutilized plant species that have high nutrient value and a positive impact on human health. Due to the high content of bio-compounds, such as phenols, vitamin C, triterpenes, fibers, essential amino acids, and microelements, the fruits, leaves, and seeds are excellent raw materials for functional food production. In addition, their biochemical composition and anti-inflammatory, anticancer, and antibacterial properties expanded their uses in the pharmaceutical field. Moreover, it was demonstrated that quince waste after industrial processing is still valuable and suitable for remanufacturing and developing innovative high value-added products, which can provide economic and ecological benefits. This chapter presents the biochemical composition and possible application of C. japonica cultivars Rasa, Darius, and Rondo. The optimization of processing and extraction parameters was evaluated to increase the extraction efficiency of biologically active compounds and to reduce the extraction time and cost of electricity and environmentally harmful solvents. Moreover, the detailed nutritional and pharmacological value of Japanese quince can help for more selective plant organs application. Our study revealed that cultivars Rasa, Darius, and Rondo are very valuable with many new options for utilization, including food, cosmetic, and pharmaceutical industries.
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Grewia asiatica L. (family-Malvaceae) commonly known as phalsa has been used traditionally as Rasayana which has a role in ameliorating cognitive decline and has a stimulant effect. The present study was conducted with an aim to investigate whether G. asiatica berries ameliorates cognitive deficits induced by scopolamine. In this experimental work, cognition enhancement activity of G. asiatica extracts (200 mg/kg) was assessed against scopolamine-induced amnesia using elevated plus maze model. To assess the protective potential of G. asiatica on scopolamine-induced damages effect on acetylcholinesterase (AChE), lipid peroxidase and superoxide dismutase, contents were estimated in rat brain homogenate spectrophotometrically and histopathological studies were done. Effect of methanol extract of G. asiatica (200 and 400 mg/kg) was assessed on dopamine and serotonin-mediated behavior using haloperidol-induced catalepsy and lithium-induced head twitches model respectively. Results showed that methanol extract of G. asiatica caused restoration of memory caused due to scopolamine-induced amnesia as measured on behavioral paradigms by elevating neurotransmitter acetylcholine, amelioration of oxidative stress markers, restoration of damaged neuronal cells cytoarchitecture and modulation of monoamines mediated behavior eliciting role of phalsa as promising nootropic candidate.
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ABSTRACT Introduction: Parkinsonism is a neurodegenerative disease that is defied by certain symptoms as muscle rigidity, impaired movement, catatonia, tremor and disorientation of body. Aim: The aim is to investigate the effect of red lentil extract on perphenazine-induced Catatonia in model of rat. Materials and Methods: This experimental study was done on 48 male albino rats (weight 180–200g) of the Sprague-Dawley strain. Animals were randomly divided into six groups and were pre-treated with a single dose of red lentil extract (200, 400, 800 and 1000 mg/kg), most effective dose of bromocriptine (30mg/ kg) and normal saline (5ml/kg) via intraperitoneal (IP) route. perphenazine (5 mg/kg) was after 30 minutes, administered (IP) to induce catatonia. The scoring method of Morpurgo was used to determine the muscular rigidity of animals. Results: The results showed that the 200mg/kg red lentil extract treated group had no signifiant reduction in catatonic responses after perphenazine administration in comparison with control group while the groups that received 800 and 1000mg/ kg of red lentil extract showed signifiant difference (p<0.05) at all the time points. Conclusion: The results revealed that hydroalcoholic extract of red lentil has protective effect on Catatonia induced by perphenazine in rats. So this extract may be probably benefiial for catatonia in Parkinsonism.
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Objective: The aim of this study were: (1) To evaluate neuroprotective effect of Resveratrol and Curcumin on NADPH-d (Nicotinamide adenine dinucleotide phosphate diaphorase) activity in neuronal cell in sub regions of mice brain (2) To evaluate the effects on antioxidant status, and (3) To evaluate the protective effects of phytochemicals on learning and memory following fluoride exposure. Method: Young Mice (one month old, B.W. 30±5mg) were provided to 120 ppm sodium fluoride dissolved in drinking water. They were given Curcumin (30mg/kg BW) or Resveratrol (30 mg/kg BW) orally once in a day up to 30 days. Effects of Resv and Cur on spatial learning and memory were studied using Morris water maze (MWM), and classic maze test. Effects on brain antioxidants (LDH, MDA and ROS) status were also studied in vitro. Histochemistry was done to assess the effect of treatments on Nitric oxide neurotransmitter. Result: Our study showed that in fluoride treated animals, number of NADPH-d positive neurons, intracellular Ca²⁺, ROS level, LDH and MDA concentration increased significantly. Interestingly, after treatment with Curcumin or Resveratrol, a significant decrease in number of NADPH-d positive neurons and antioxidant status were observed. This decrease was more considerable in resveratrol treated group. Conclusion: Our study indicates that, both antioxidants, Curcumin and Resveratrol are useful in reducing neurodegeneration in selective areas of CA1, CA3, DG and the cortex, of mice brain, recuperate the loss of memory and learning caused due to fluoride exposure.
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Objective: Recently, differences in brain and cardiac nuclear factor kappaB (NF-κB) expression and nitric oxide (NO) generation were documented in rats treated with NO synthase inhibitor - NG-nitro-L-arginine methyl ester (L-NAME). We aimed to analyse whether changes in brain and cardiac NF-κB expression may be associated with nitric oxide synthase (NOS) activity in spontaneously hypertensive rats (SHR) and rats with metabolic syndrome (MS). Methods: Normotensive 9 weeks old male Wistar Kyoto rats (WKY), age-matched spontaneously hypertensive rats and obese rats with MS were analysed. Blood pressure was measure by tail-cuff plethysmography. Protein expression of NF-κB (p65 subunit), endothelial NOS (eNOS), and inducible NOS (iNOS) as well as NOS activity were determined in the brain and heart. Results: In the brain of SHR, despite no changes in NOS activity, increased expression of NF-κB (p65) was associated with eNOS and iNOS up-regulation. There were no significant changes in the heart in both NF-κB (p65) and NOS isoforms expressions. In MS rats, increased NF-κB (p65) expression in the brain was associated with down-regulation of eNOS and iNOS leading to decreased NOS activity. On the other hand, increased NF-κB (p65) expression in the heart did not develop any significant changes in NOS isoforms expressions. Blood pressure of SHR and MS rats was increased similarly in comparison with normotensive WKY rats. Conclusions: Down-regulated NOS isoforms and decreased NOS activity in the brain of rats with metabolic syndrome may contribute to blood pressure increase in this respective strain of rats.
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Huntington's disease (HD) is a neurological disorder characterized by abnormal body movements (chorea) associated with cognitive and motor dysfunctions, neuropsychiatric disturbances, and striatal damage. 3-Nitropropionic acid (3-NP) triggers cellular energy deficit, nitric oxide (NO) mechanisms, and oxidative stress (OS)-induced neurotoxicity by inhibiting the activity of mitochondrial complex II enzyme and succinate dehydrogenase in irreversible fashion. Chronic systemic administration of 3-NP to animals produces preferential degeneration of the striatum, leading to motor and cognitive deficits, closely resembling HD. Besides 3-NP model of striatal neurodegeneration, a number of transgenic animal models expressing mutant proteins are routinely used in preclinical trials exploring anti-HD therapeutics. In this review, the roles of a number of plant extracts, fractions, and isolated compounds investigated in various neurotoxic animal models and transgenics are discussed, highlighting on their ability to influence signaling pathways, leading to neuromodulation and probable neuroprotection. Since mitochondrial involvement and OS are also common phenomena in etiopathogenesis of a number of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), a few plant-based anti-HD natural products have been found efficacious against such diseases. Therapeutic advancement in screening of natural products against HD suffers from constraints such as limited animal models and giving maximum emphasis on cellular models during experimentations. However, recent progress in animal HD transgenic models expressing mutant proteins may reveal the therapeutic efficacy of natural products against HD, a disease with less elucidated pathogenesis and inadequate treatment strategies.
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In this study, we investigated the in vivo effects of red wine polyphenol compounds (RWPC) in rats that were submitted to middle cerebral occlusion as an experimental model of stroke. Male Wistar rats were given RWPC [30 mg/(kg x d) dissolved in drinking water] or water for 1 wk before being subjected to transient middle cerebral artery occlusion followed by reperfusion. Sham-operated rats were subjected to transient occlusion in which the filament was not completely introduced. The release of amino acids and energy metabolites were monitored by intracerebral microdialysis. The volume of the ischemic lesion was assessed 24 h after reperfusion. Proteomic analysis of brain tissue was performed to study the effects of ischemia and RWPC on specific protein expression. Treatment with RWPC completely prevented the burst of excitatory amino acids that occurred in response to ischemia in untreated rats and significantly reduced brain infarct volumes. Rats chronically treated with RWPC, however, had lower basal concentrations of energy metabolites, including glucose and lactate in the brain parenchyma, compared with untreated rats. Chronic RWPC treatment significantly enhanced the residual cerebral blood flow during occlusion and reperfusion in rats subjected to transient occlusion compared with untreated rats. This effect resulted from arterial vasodilatation, as the internal diameters of several arteries were significantly enlarged after RWPC treatment. Proteomic studies revealed the modulation by RWPC of the expression of proteins involved in the maintenance of neuronal caliber and axon formation, in the protection against oxidative stress, and in energy metabolism. These findings provide an experimental basis for the beneficial effects of RWPC on the neurovascular unit during stroke.
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In the brain, NF-κB has been implicated in both normal processes of synaptic plasticity and memory as well as in pathological mechanisms of neurodegenerative diseases such as Parkinson's disease, Huntington's disease or Alzheimer's disease. The involvement of nitric oxide in the learning, memory, behavioral processes, cognition but also in neurodegenerative processes and disorders was clearly described. Since the similar mechanisms including increase in glutamate and intracellular calcium level lead to activation of both NF-κB and nitric oxide, the mutual regulation of these factors is suggested. It seems that concerning the neurons, the increase in NF-κB expression and activation is accompanied by increased inducible and neuronal NOS isoform expressions and vice versa.
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Fruits and vegetables are key foods whose high ingestion is associated with the improvement of numerous pathological conditions, including hypertension. Such health promoting actions have been increasingly ascribed to the antioxidant characteristics of different polyphenols in fruits and vegetables. Consequently, based on this assumption, many beverages and foods rich in polyphenols, grape, tea, cocoa, and soy products and many of their chemical constituents purified, are being studied both, as antioxidants and antihypertensive agents. This paper reviews the current evidence linking high polyphenol consumption with reductions in blood pressure. Basic chemical aspects of flavanols, flavonols, isoflavones and stilbenes, as possible responsible for the observed effects of those foods on blood pressure are included. Human interventions studies by using grapes and wine, cocoa and chocolate, black and green tea, soy products, and purified compounds ((+)-catequin, quercetin, (-)-epigallocatechin gallate) are summarized. The discussed hypothesis, strongly supported by experimental data in animals, is that by regulating nitric oxide bioavailability, polyphenols present in fruits and vegetables affect endothelial function and as a consequence, blood pressure. Even when data are not definitive and many questions remain open, the whole evidence is encouraging to start considering diets that can provide a benefit to hypertensive subjects, and those benefits will be more significant in people that do not have controlled his/her elevated blood pressure.
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Endothelin (ET) was first isolated and described by Yanagisawa et al. and has since been described as one of the most potent known vasoconstrictor compounds. ET-1 mediates its effects via two types of receptors, ETA and ETB, which are expressed in the vascular smooth muscle cells, endothelial cells, intestines and brain. Secretion of ET-1 results in long-lasting vasoconstriction, increased blood pressure and, in turn, overproduction of free radicals. As dysregulation of the endothelin system is an important factor in the pathogenesis of several diseases including atherosclerosis, hypertension and endotoxic shock, the ETA and ETB receptors are attractive therapeutic targets for treatment of these disorders. The biosynthesis and release of ET-1 are regulated at the transcriptional level. Studies have shown that p38MAP kinase, nuclear factor kappaB (NF-kappaB), PKC/ERK and JNK/c-Jun all take part in the ROS-activated production of ET-1. Furthermore, administration of ET(A) significantly reduces the generation of free radicals. However, treatment with ETB receptor blockers does not elicit the same effect. Therefore, the effects of endothelin receptor blockers on blood pressure and the generation of free radicals remain debatable. This review summarizes recent investigations into the role of endothelin receptor blockers with respect to the modulation of hemodynamic parameters and the generation of free radicals.
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Quinolinic acid (QUIN) excitotoxicity is mediated by elevated intracellular Ca(2+) levels, and nitric oxide-mediated oxidative stress, resulting in DNA damage, poly(ADP-ribose) polymerase (PARP) activation, NAD(+) depletion and cell death. We evaluated the effect of a series of polyphenolic compounds [i.e. epigallocatechin gallate (EPCG), catechin hydrate, curcumin, apigenin, naringenin and gallotannin] with antioxidant properties on QUIN-induced excitotoxicity on primary cultures of human neurons. We showed that the polyphenols, EPCG, catechin hydrate and curcumin can attenuate QUIN-induced excitotoxicity to a greater extent than apigenin, naringenin and gallotannin. Both EPCG and curcumin were able to attenuate QUIN-induced Ca(2+) influx and neuronal nitric oxide synthase (nNOS) activity to a greater extent compared with apigenin, naringenin and gallotannin. Although Ca(2+) influx was not attenuated by catechin hydrate, nNOS activity was reduced, probably through direct inhibition of the enzyme. All polyphenols reduced the oxidative effects of increased nitric oxide production, thereby reducing the formation of 3-nitrotyrosine and poly (ADP-ribose) polymerase activity and, hence, preventing NAD(+) depletion and cell death. In addition to the well-known antioxidant properties of these natural phytochemicals, the inhibitory effect of some of these compounds on specific excitotoxic processes, such as Ca(2+) influx, provides additional evidence for the beneficial health effects of polyphenols in excitable tissue, particularly within the central nervous system.
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The polyphenolics in fruits and vegetables, when fed to rats from 19-21 months of age, have been shown to retard and even reverse age-related decrements in motor and cognitive performance. These effects may be the result of the polyphenols increasing antioxidant and/or anti-inflammatory levels, or by direct effects on signaling, in the brain. Increased dietary intake of berry fruit, in particular, has a positive and profound impact on human health, performance, and disease. Thus, the present study examined a 2% blackberry-supplemented diet for its effectiveness in reversing age-related deficits in behavioral and neuronal function when fed to aged (19-month-old) Fischer 344 rats for 8 weeks. The results showed that the blackberry diet improved motor performance on three tasks which rely on balance and co-ordination: the accelerating rotarod, wire suspension, and the small plank walk. Results for the Morris water maze showed that the blackberry-fed rats had significantly greater working, or short-term, memory performance than the control rats. These data support our previous investigations in which we have seen improved motor and cognitive performance in aged rats after supplementation with other berry fruits.
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Nitric oxide (NO) produced by the endothelium of cerebral arterioles is an important mediator of endothelium-dependent vasodilation (EDV), and also helps to prevent thrombosis and vascular remodeling. A number of risk factors for ischemic stroke are associated with impaired EDV, and this defect is usually at least partially attributable to a decrease in the production and/or stability of NO. These risk factors include hypertension, high-sodium diets, homocysteine, diabetes, visceral obesity, and aging. Conversely, many measures which may provide protection from ischemic stroke - such as ample dietary intakes of potassium, arginine, fish oil, and selenium - can have a favorable impact on EDV. Protection afforded by exercise training, estrogen replacement, statin drugs, green tea polyphenols, and cruciferous vegetables may reflect increased expression of the endothelial NO synthase. IGF-I activity stimulates endothelial NO production, and conceivably is a mediator of the protection associated with higher-protein diets in Japanese epidemiology and in hypertensive rats. These considerations prompt the conclusion that modulation of NO availability is a crucial determinant of risk for ischemic stroke. Multifactorial strategies for promoting effective cerebrovascular NO activity, complemented by measures that stabilize platelets and moderate blood viscosity, should minimize risk for ischemic stroke and help maintain vigorous cerebral perfusion into ripe old age. The possibility that such measures will also diminish risk for Alzheimer's disease, and slow the normal age-related decline in mental acuity, merits consideration. A limited amount of ecologic epidemiology suggests that both stroke and senile dementia may be extremely rare in cultures still consuming traditional unsalted whole-food diets. Other lines of evidence suggest that promotion of endothelial NO activity may decrease risk for age-related macular degeneration.
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Aging is a major risk factor for neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to oxidative stress which can induce neuronal damage, ultimately leading to neuronal death by apoptosis or necrosis. A large body of evidence indicates that oxidative stress is involved in the pathogenesis of AD, PD, and ALS. An increasing number of studies show that nutritional antioxidants (especially Vitamin E and polyphenols) can block neuronal death in vitro, and may have therapeutic properties in animal models of neurodegenerative diseases including AD, PD, and ALS. Moreover, clinical data suggest that nutritional antioxidants might exert some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed. Particular emphasis will be given to the role played by the nuclear transcription factor-kappaB (NF-kappaB) in apoptosis, and in the pathogenesis of neurodegenerative disorders, such as AD, PD, and ALS. The effects of ROS and antioxidants on NF-kappaB function and their relevance in the pathophysiology of neurodegenerative diseases will also be examined.
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In addition to their role in bacterial killing by leukocytes, reactive oxygen species (ROS) have been increasingly recognized as important components of signaling and host defense in other cell types. The formation of ROS in both phagocytic- and non-phagocytic cells involves membrane-localized NADPH oxidases (Noxs). Nox proteins show structural homology to the cytochrome b(558) of leukocytes but, until recently, their regulation has been poorly understood. Here, we describe our current understanding of Nox function, and discuss emerging paradigms for regulation of Nox activity by Rac GTPase and/or other cytosolic components.
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Objective: The cardioprotective effect of red wine has been attributed to resveratrol. The resveratrol-induced protection against ischemia-reperfusion (I/R) injury has been documented in heart, kidney, and brain. Resveratrol scavenges free O(2) radicals and upregulates nitric oxide (NO). However, the presence of resveratrol-induced spinal cord protection against I/R injury has not been reported in the literature. The objective of this study was to evaluate the effects of resveratrol on neurologic functions, histopathologic changes, and NO metabolism following temporary spinal cord ischemia (SCI) in rabbits. Material and methods SCI was induced with occlusion of the infrarenal aorta in rabbits. In addition to the sham group (group S, n = 7), group C (n = 7) received vehicle 30 minutes before ischemia. Group R1 (n = 7) and R10 (n = 7) received 1 mg/kg and 10 mg/kg resveratrol instead of vehicle, respectively. Blood samples were taken to obtain nitrite/nitrate levels during the surgical procedure. After neurologic evaluation at the 48th hour of reperfusion, lumbar spinal cords were removed for histopathologic examination and malondialdehyde measurement as a marker of oxidative stress. Results: Five animals in group C had paraplegia while 5 in group R10 had normal neurologic functions. The average Tarlov score of group R10 was significantly higher than that the score of group C (4.1 +/- 1.2, vs 1.2 +/- 2.2; P =.014). Histopathologic examination revealed higher neuronal viability index in group R10 compared with that of group C (0.82 +/- 0.24 vs. 0.46 +/- 0.34; P =.018). Nitrite/nitrate levels decreased in group C (from 357 +/- 20.15 micromol/L to 281 +/- 47.9 micromol/L; P <.01) whereas they increased both in group R1 and group R10 (from 287+/-28 micromol/L to 310 +/- 33.9 micromol/L and from 296 +/- 106 micromol/L to 339 +/- 87 micromol/L, respectively) during SCI. Malondialdehyde levels of group R10 was lower than those of group C (55 +/- 12.9 nmol/mg protein vs 83.9 +/- 15.1 nmol/mg protein; P =.001, respectively). Conclusions: In this model of SCI, resveratrol decreased oxidative stress, increased NO release, and protected spinal cord from I/R injury. Resveratrol-induced neuroprotection is probably mediated by its antioxidant and NO promoting properties. Before considering the clinical use of this natural antioxidant, further research is warranted about its mechanism of effects, timing, and optimum dose. Clinical relevance: Paraplegia that results from spinal cord ischemia is a catastrophic complication of thoracic and thoracoabdominal aorta surgical procedures. Despite several surgical modifications and pharmacologic approaches, paraplegia has not been totally eliminated. On clinical grounds, the efficiency of currently used pharmacologic agents to prevent spinal cord injury during thoracic and thoracoabdominal aorta surgery is very limited and their benefit is controversial. Preischemic infusion of resveratrol protects the spinal cord from ischemia reperfusion injury in rabbits. Following clarification of the underlying protective mechanism, optimal dose, and timing, resveratrol may used in humans as an adjunct to eliminate this catastrophic complication.
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Recent studies have shown that (-)-epigallocatechin gallate (EGCG), one of the green tea polyphenols, has a potent antioxidant property. Nitric oxide (NO) plays an important role in the neuropathogenesis induced by brain ischemia/reperfusion and hypoxia. This study aimed to explore the potential neuroprotective effect of EGCG on the ganglionic neurons of the nodose ganglion (NG) in acute hypoxic rats. Thus, the young adult rats were pretreated with EGCG (10, 25, or 50 mg/kg, i.p.) 30 min before they were exposed to the altitude chamber at 10,000 m with the partial pressure of oxygen set at the level of 0.27 atm (pO2=43 Torr) for 4 h. All the animals examined were allowed to survive for 3, 7, and 14 successive days, respectively, except for those animals sacrificed immediately following hypoxic exposure. Nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and neuronal nitric oxide synthase (nNOS) immunohistochemistry were carried out to detect the neuronal NADPH-d/nNOS expression in the NG. The present results show a significant increase in the expression of NADPH-d/nNOS reactivity in neurons of the NG at various time intervals following hypoxia. However, the hypoxia-induced increase in NADPH-d/nNOS expression was significantly depressed only in the hypoxic rats treated with high dosages of EGCG (25 or 50 mg/kg). These data suggest that EGCG may attenuate the oxidative stress following acute hypoxia.
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In the present study, experiments were performed to explore the action of quercetin, the most widely distributed flavonoids, and its major metabolite, quercetin-3'-sulfate, on lipopolysaccharide (LPS)- and interferon-gamma (IFN-gamma)-induced nitric oxide (NO) production in BV-2 microglia. Quercetin could suppress LPS- and IFN-gamma-induced NO production and inducible nitric oxide synthase (iNOS) gene transcription, while quercetin-3'-sulfate had no effect. LPS-induced IkappaB kinase (IKK), nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) activation, and IFN-gamma-induced NF-kappaB, signal transducer and activator of transcription-1 (STAT1) and interferon regulatory factor-1 (IRF-1) activation were reduced by quercetin. Moreover quercetin was able to induce heme oxygenase-1 expression. To address the involvement of heme oxygenase-1 induction in iNOS inhibition, heme oxygenase-1 antisense oligodeoxynucleotide was used. Quercetin-mediated inhibition of NO production and iNOS protein expression were partially reversed by heme oxygenase-1 antisense oligodeoxynucleotide, but was mimicked by hemin, a heme oxygenase-1 inducer. The involvement of signal pathways in quercetin-induced heme oxygenase-1 gene expression was associated with tyrosine kinase and mitogen-activated protein kinases activation. All these results suggest quercetin should provide therapeutic benefits for suppression of inflammatory-related neuronal injury in neurodegenerative diseases.
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Brain aging is characterized by the continual concession to battle against insults accumulated over the years. One of the major insults is oxidative stress, which is the inability to balance and to defend against the cellular generation of reactive oxygen species (ROS). These ROS cause oxidative damage to nucleic acid, carbohydrate, protein, and lipids. Oxidative damage is particularly detrimental to the brain, where the neuronal cells are largely post-mitotic. Therefore, damaged neurons cannot be replaced readily via mitosis. During normal aging, the brain undergoes morphological and functional modifications resulting in the observed behavioral declines such as decrements in motor and cognitive performance. These declines are augmented by neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD). Research from our laboratory has shown that nutritional antioxidants, such as the polyphenols found in blueberries, can reverse age-related declines in neuronal signal transduction as well as cognitive and motor deficits. Furthermore, we have shown that short-term blueberry (BB) supplementation increases hippocampal plasticity. These findings are briefly reviewed in this paper.
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In the 21st century, human aging will be one of the biggest challenges for most societies throughout the world. The decline in human fitness is a typical hallmark of the aging process. Aside from the cardiovascular system, the brain most often suffers significantly from the life-long impact of stressors, such as reactive oxygen and nitrogen species. Oxytosis, i.e. oxidative stress-induced cell death, has been identified to play a major role in the development and onset of chronic diseases. Foods, especially of plant origin, are rich in antioxidants and numerous in vivo data suggest that a diet rich in fruits and vegetables supports the maintenance of animal and human health. These beneficial effects also extend to the central nervous system, which, due to the presence of the blood-brain barrier, tightly controls the influx of metabolites and nutrients. In earlier studies the impact of antioxidant vitamins, such as alpha-tocopherol and ascorbic acid, on brain health has been of interest. Recently, the focus moved to assessing the potential of unsaturated fatty acids and secondary plant metabolites, particularly of polyphenols, to act as neuroprotectants. Considerable experimental evidence suggests that polyphenols and other plant-derived bioactivities affect animal and human brain function not only by directly lowering oxidative stress load but also by modulating various signal transduction pathways.
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Sustained microglial activation in the central nervous system (CNS) has been extensively investigated in age-related neurodegenerative diseases and has been postulated to lead to neuronal cell loss in these conditions. Recent studies have shown that antiinflammatory drugs may suppress microglial activation and thus protect against microglial overactivation and subsequent cell loss. Research also suggests that fruits such as berries may contain both antioxidant and antiinflammatory polyphenols that may be important in this regard. Our previous research showed that blueberry extract was effective in preventing oxidant-induced calcium response deficits in M1 (muscarinic receptor)-transfected COS-7 cells. Extrapolating from these findings, the current study investigated the effect of blueberry extract on preventing inflammation-induced activation of microglia. Results indicated that treatments with blueberry extract inhibited the production of the inflammatory mediator nitric oxide (NO) as well as the cytokines interleukin-1beta and tumor necrosis factor-alpha, in cell conditioned media from lipopolysaccharide (LPS)-activated BV2 microglia. Also, mRNA and protein levels of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-activated BV2 cells were significantly reduced by treatments with blueberry extract. The results suggest that blueberry polyphenols attenuate inflammatory responses of brain microglia and could be potentially useful in modulation of inflammatory conditions in the CNS.
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There is increasing evidence to suggest that neuroinflammatory processes contribute to the cascade of events that lead to the progressive neuronal damage observed in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Therefore, treatment regimes aimed at modulating neuroinflammatory processes may act to slow the progression of these debilitating brain disorders. Recently, a group of dietary polyphenols known as flavonoids have been shown to exert neuroprotective effects in vivo and in neuronal cell models. In this review we discuss the evidence relating to the modulation of neuroinflammation by flavonoids. We highlight the evidence which suggests their mechanism of action involves: 1) attenuation of the release of cytokines, such as interleukin-1beta (IL-1beta and tumor necrosis factor-alpha (TNF-alpha); 2) an inhibitory action against inducible nitric oxide synthase (iNOS) induction and subsequent nitric oxide (NO(*)) production; 3) inhibition of the activation of NADPH oxidase and subsequent reactive oxygen species generation; 4) a capacity to down-regulate the activity of pro-inflammatory transcription factors such as nuclear factor-kappaB (NF-kappaB); and 5) the potential to modulate signalling pathways such as mitogen-activated protein kinase (MAPK) cascade. We also consider the potential of these dietary compounds to represent novel therapeutic agents by considering their metabolism in the body and their ability to access the brain via the blood brain barrier. Finally, we discuss future areas of study which are necessary before dietary flavonoids can be established as therapeutic agents against neuroinflammation.
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Moderate intake of wine may be protective against various neurologic, cardiovascular and gastroenteric diseases. Low concentration of alcohol (wine diluted with water 1:2 to 1:10) exhibits strong antimicrobial activity against majority of gastrointestinal pathogens as well as against Chlamydia pneumoniae. In contrast, higher doses of even diluted alcohol (more than 5-7 glasses a day) may cause severe neuropsychic disorders with major social consequences. Wine contains variety of molecules with cardioprotective effect and antiinfectious properties.
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Oestrogens have neuroprotective properties, resulting in memory and learning preservation. Red wine (RW) has been linked to neuroprotection, but mechanisms are largely unknown. The aim of this work was to test the effect of RW or 13% ethanol solution consumption on the expression of aromatase and estrogen receptors (ER) in the rat hippocampus. Beverages were supplied to male Wistar rats and after 8 weeks of treatment animals were euthanised, hippocampus was removed, aromatase expression assessed by western blotting and aromatase and ER transcription determined by RT-PCR. The effects of treatments on hippocampal aromatase activity were also determined, as well as the effect of several red wine polyphenols in hippocampal homogenates from untreated animals. Aromatase transcription was increased by ethanol (to 158+/-7%) but only significantly by RW (to 180+/-9%). No difference was found in ERalpha expression among groups, whereas RW significantly decreased ERbeta expression (to 63+/-10%). Resveratrol, quercetin, myricetin and kaempferol had no effect on aromatase activity and catechin (300 microM), epicatechin (200 microM), procyanidin extract (200 mg/L) and fractioned procyanidins (FI and FII; 200 mg/L) significantly decreased aromatase activity. The contribution of procyanidins in wine to the effect observed in aromatase was investigated in animals treated for the same period with these compounds (200 mg/L), although no effect was seen in aromatase activity, mRNA or protein levels, meaning that this group of compounds had little contribution, if any, to the effects observed. Nevertheless, the increase in aromatase expression induced by RW may corroborate the neuroprotective ability attributed to this beverage. Alterations in the relative abundance of ER expression may also play an important role in the protection.