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Cognitive Function

Biofactors. 2017 Nov 23. doi: 10.1002/biof.1396.

Resveratrol, pterostilbene, and dementia.

Lange KW1, Li S2.

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Abstract
Resveratrol is a natural phytoestrogen with neuroprotective properties. Polyphenolic compounds including resveratrol exert in vitro antioxidant, anti-inflammatory, and antiamyloid effects. Resveratrol and its derivative pterostilbene are able to cross the blood-brain barrier and to influence brain activity. The present short review summarizes the available evidence regarding the effects of these polyphenols on pathology and cognition in animal models and human subjects with dementia. Numerous investigations in cellular and mammalian models have associated resveratrol and pterostilbene with protection against dementia syndromes such as Alzheimer’s disease (AD) and vascular dementia. The neuroprotective activity of resveratrol and pterostilbene demonstrated in in vitro and in vivo studies suggests a promising role for these compounds in the prevention and treatment of dementia. In comparison to resveratrol, pterostilbene appears to be more effective in combatting brain changes associated with aging. This may be attributed to the more lipophilic nature of pterostilbene with its two methoxyl groups compared with the two hydroxyl groups of resveratrol. The findings of available intervention trials of resveratrol in individuals with mild cognitive impairment or AD do not provide evidence of neuroprotective or therapeutic effects. Future clinical trials should be conducted with long-term exposure to preparations of resveratrol and pterostilbene with high bioavailability.

© 2017 BioFactors, 2017.

KEYWORDS:
cognition; dementia; polyphenols; pterostilbene; resveratrol

PMID: 29168580 DOI: 10.1002/biof.1396

Cogn Neurodyn. 2017 Feb;11(1):35-49. doi: 10.1007/s11571-016-9413-1. Epub 2016 Sep 30.

Pterostilbene ameliorates intracerebroventricular streptozotocin induced memory decline in rats.

Naik B1, Nirwane A1, Majumdar A1.

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Abstract
There is strong evidence that mitochondrial dysfunction mediated oxidative stress results in aging and energy metabolism deficits thus playing a prime role in pathogenesis of Alzheimer’s disease, neuronal death and cognitive dysfunction. Evidences accrued in empirical studies suggest the antioxidant, anticancer and anti-inflammatory activities of the phytochemical pterostilbene (PTS). PTS also exhibits favourable pharmacokinetic attributes compared to other stilbenes. Hence, in the present study, we explored the neuroprotective role of PTS in ameliorating the intracerebroventricular administered streptozotocin (STZ) induced memory decline in rats. PTS at doses of 10, 30 and 50 mg/kg, was administered orally to STZ administered Sprague-Dawley (SD) rats. The learning and memory tests, Morris water maze test and novel object recognition test were performed which revealed improved cognition on PTS treatment. Further, there was an overall improvement in brain antioxidant parameters like elevated catalase and superoxide dismutase activities, GSH levels, lowered levels of nitrites, lipid peroxides and carbonylated proteins. There was improved cholinergic transmission as evident by decreased acetylcholinesterase activities. The action of ATPases (Na+ K+, Ca2+ and Mg2+) indicating the maintenance of cell membrane potential was also augmented. mRNA expression of battery of genes involved in cellular mitochondrial biogenesis and inflammation showed variations which extrapolate to hike in mitochondrial biogenesis and abated inflammation. The histological findings corroborated the effective role of PTS in countering STZ induced structural aberrations in brain.

KEYWORDS:
AChE; ATPases; Brain; Fenofibrate; IL-6; Inflammation; Learning and memory; PGC1α; PPARα; Protein carbonylation; Pterostilbene; Rats; Streptozotocin; TNF-α

PMID: 28174611 PMCID: PMC5264756 [Available on 2018-02-01] DOI: 10.1007/s11571-016-9413-1

Bioorg Med Chem. 2017 Feb 15;25(4):1471-1480. doi: 10.1016/j.bmc.2017.01.010. Epub 2017 Jan 11.

Design, synthesis and evaluation of some N-methylenebenzenamine derivatives as selective acetylcholinesterase (AChE) inhibitor and antioxidant to enhance learning and memory.

Shrivastava SK1, Srivastava P2, Upendra TVR2, Tripathi PN2, Sinha SK3.

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Abstract
Series of some 3,5-dimethoxy-N-methylenebenzenamine and 4-(methyleneamino)benzoic acid derivatives comprising of N-methylenebenzenamine nucleus were designed, synthesized, characterized, and assessed for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory, and antioxidant activity thereby improving learning and memory in rats. The IC50 values of all the compound along with standard were determined on AChE and BChE enzyme. The free radical scavenging activity was also assessed by in vitro DPPH (2,2-diphenyl-1-picryl-hydrazyl) and hydrogen peroxide radical scavenging assay. The selective inhibitions of all compounds were observed against AChE in comparison with standard donepezil. The enzyme kinetic study of the most active compound 4 indicated uncompetitive AChE inhibition. The docking studies of compound 4 exhibited the worthy interaction on active-site gorge residues Phe330 and Trp279 responsible for its high affinity towards AChE, whereas lacking of the BChE inhibition was observed due to a wider gorge binding site and absence of important aromatic amino acids interactions. The ex vivo study confirmed AChE inhibition abilities of compound 4 at brain site. Further, a considerable decrease in escape latency period of the compound was observed in comparison with standard donepezil through in vivo Spatial Reference Memory (SRM) and Spatial Working Memory (SWM) models which showed the cognition-enhancing potential of compound 4. The in vivo reduced glutathione (GSH) estimation on rat brain tissue homogenate was also performed to evaluate free radical scavenging activity substantiated the antioxidant activity in learning and memory.

KEYWORDS:
Acetylcholinesterase inhibitor; Antioxidant; Learning and memory; Pterostilbene; Schiff base

PMID: 28126439 DOI: 10.1016/j.bmc.2017.01.010

Neurochem Int. 2015 Oct;89:227-33. doi: 10.1016/j.neuint.2015.07.017. Epub 2015 Jul 26.

Effects of pterostilbene and resveratrol on brain and behavior.

Poulose SM1, Thangthaeng N1, Miller MG1, Shukitt-Hale B2.

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Abstract
Age is the greatest universal risk factor for neurodegenerative diseases. During aging, these conditions progress from minor loss of function to major disruptions in daily life, loss of independence and ultimately death. Because approximately 25% of the world population is expected to be older than age 65 by 2050, and no treatments exist to halt or reverse ongoing neurodegeneration, the need for effective prevention strategies is more pressing that ever before. A growing body of research supports the role of diet in healthy aging, particularly diets rich in bioactive phytochemical compounds. Recently, stilbenes such as resveratrol (3, 5, 4′-trans-trihydroxystilbene) and its analogue, pterostilbene, have gained a significant amount of attention for their potent antioxidant, anti-inflammatory, and anticarcinogenic properties. However, evidence for the beneficial effects of stilbenes on cerebral function is just beginning to emerge. In this review, we summarize the current knowledge on the role of resveratrol and pterostilbene in improving brain health during aging, with specific focus on antioxidant and anti-inflammatory signaling and behavioral outcomes.

KEYWORDS:
Aging; Brain-signaling; Inflammation; Polyphenols; Pterostilbene; Resveratrol

PMID: 26212523 DOI: 10.1016/j.neuint.2015.07.017

Crit Rev Clin Lab Sci. 2013 May-Jun;50(3):65-78. doi: 10.3109/10408363.2013.805182. Epub 2013 Jul 1.

Pterostilbene: Biomedical applications.

Estrela JM1, Ortega A, Mena S, Rodriguez ML, Asensi M.

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Abstract
Resveratrol and its naturally dimethylated analog, pterostilbene, show similar biological activities. However, the higher in vivo bioavailability of pterostilbene represents a fundamental advantage. The main focus of this review is on biomedical applications of pterostilbene. The metabolism and pharmacokinetics of this stilbene in inflammatory dermatoses and photoprotection, cancer prevention and therapy, insulin sensitivity, blood glycemia and lipid levels, cardiovascular diseases, aging, and memory and cognition are addressed. Safety and toxicity, as well as recommendations for future research and biomedical uses, are discussed. This review includes comparisons between pterostilbene and other polyphenols, with particular emphasis on resveratrol. Potential benefits of using combinations of different polyphenols are considered. Based on present evidences we conclude that pterostilbene is an active phytonutrient and also a potential drug with multiple biomedical applications.

PMID: 23808710 DOI: 10.3109/10408363.2013.805182

Br J Nutr. 2012 Sep;108(5):794-800. doi: 10.1017/S0007114512000669. Epub 2012 Apr 5.

A berry thought-provoking idea: the potential role of plant polyphenols in the treatment of age-related cognitive disorders.

Cherniack EP1.

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Abstract
Today, tens of millions of elderly individuals worldwide suffer from dementia. While the pathogenesis of dementia is complex and incompletely understood, it may be, at least to a certain extent, the consequence of systemic vascular pathology. The metabolic syndrome and its individual components induce a proinflammatory state that damages blood vessels. This condition of chronic inflammation may damage the vasculature of the brain or be directly neurotoxic. Associations have been established between the metabolic syndrome, its constituents and dementia. A relationship has also been observed between certain dietary factors, such as constituents of the ‘Mediterranean diet’, and the metabolic syndrome; similar associations have been noted between these dietary factors and dementia. Fruit juices and extracts are under investigation as treatments for cognitive impairment. Blueberry, strawberry, blackberry, grape and plum juices or extracts have been successfully tested in cognitively impaired rodents. Published trials of the benefits of grape and blueberry juice in the treatment of small numbers of cognitively impaired persons have recently appeared. The benefits of fruit products are thought to be a result of its polyphenol content. A grape polyphenol found in grapes, resveratrol, now being studied in humans, and one in grapes and blueberries, pterostilbene, have been found to improve cognition in rodents. In the design of future human trials, one ought to consider the poor bioavailability of these products, the possible need to initiate the experimental therapy long before the onset of symptoms, and currently limited knowledge about the appropriate form (e.g. juice, powder or individual polyphenol) of treatment.

PMID: 22475317 DOI: 10.1017/S0007114512000669

J Agric Food Chem. 2008 Nov 26;56(22):10544-51. doi: 10.1021/jf802279h.

Cellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of aging.

Joseph JA1, Fisher DR, Cheng V, Rimando AM, Shukitt-Hale B.

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Abstract
Research suggests that polyphenolic compounds contained in fruits and vegetables that are rich in color may have potent antioxidant and anti-inflammatory activities. The present studies determined if stilbene (e.g., resveratrol) compounds would be efficacious in reversing the deleterious effects of aging in 19 month old Fischer 344 rats. Experiment I utilized resveratrol and six resveratrol analogues and examined their efficacies in preventing dopamine-induced decrements in calcium clearance following oxotremorine-induced depolarization in COS-7 cells transfected with M1 muscarinic receptors (MAChR) that we have shown previously to be sensitive to oxidative stressors. Experiment II utilized the most efficacious analogue (pterostilbene) from experiment I and fed aged rats a diet with a low (0.004%) or a high (0.016%) concentration of pterostilbene. Results indicated that pterostilbene was effective in reversing cognitive behavioral deficits, as well as dopamine release, and working memory was correlated with pterostilbene levels in the hippocampus.

PMID: 18954071 DOI: 10.1021/jf802279h

Neurobiol Aging. 2012 Sep;33(9):2062-71. doi: 10.1016/j.neurobiolaging.2011.08.015. Epub 2011 Oct 7.

Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer’s disease.

Chang J1, Rimando A, Pallas M, Camins A, Porquet D, Reeves J, Shukitt-Hale B, Smith MA, Joseph JA, Casadesus G.

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Abstract
Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer’s disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD. Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1 (SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression. Taken together our findings indicate that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene.

PMID: 21982274 DOI: 10.1016/j.neurobiolaging.2011.08.015