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US20090069444A1 - Method to Ameliorate Oxidative Stress and Improve Working Memory Via Pterostilbene Administration - Google Patents

Method to Ameliorate Oxidative Stress and Improve Working Memory Via Pterostilbene Administration Download PDF

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US20090069444A1
US20090069444A1 US12/136,341 US13634108A US2009069444A1 US 20090069444 A1 US20090069444 A1 US 20090069444A1 US 13634108 A US13634108 A US 13634108A US 2009069444 A1 US2009069444 A1 US 2009069444A1
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pterostilbene
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recited
effective amount
administered
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James A. Joseph
Agnes M. Rimando
Barbara Shukitt-Hale
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US Department of Agriculture USDA
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Priority to US12/136,341 priority Critical patent/US20090069444A1/en
Assigned to AGRICULTURE, UNITED STATES OF AMERICA, THE, AS REPRESENTED BY THE SECRETARY reassignment AGRICULTURE, UNITED STATES OF AMERICA, THE, AS REPRESENTED BY THE SECRETARY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JOSEPH, JAMES A., RIMANDO, AGNES M., SHUKITT-HALE, BARBARA
Priority to CN201210421008.6A priority patent/CN103083288B/zh
Priority to AU2008296293A priority patent/AU2008296293A1/en
Priority to PCT/US2008/075170 priority patent/WO2009032870A2/fr
Priority to CN2008801103188A priority patent/CN101820869B/zh
Priority to EP20080799127 priority patent/EP2200597B1/fr
Priority to CA2698661A priority patent/CA2698661C/fr
Priority to JP2010524125A priority patent/JP5608082B2/ja
Priority to HK11101728.4A priority patent/HK1148932B/xx
Priority to KR20107007002A priority patent/KR20100075468A/ko
Priority to ES08799127.9T priority patent/ES2526648T3/es
Priority to BRPI0816317A priority patent/BRPI0816317A2/pt
Publication of US20090069444A1 publication Critical patent/US20090069444A1/en
Priority to US13/204,891 priority patent/US8809400B2/en
Priority to HK13112566.4A priority patent/HK1185257B/xx
Priority to US14/284,901 priority patent/US9028887B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a method for use of pterostilbene administered to a subject in an effective amount to forestall, prevent, and reverse the effects of neuronal and behavioral aging and development of neurodegenerative diseases.
  • the resveratrol analog pterostilbene is effective in reversing motor deficits and working memory of subjects.
  • Diet supplementation with fruits and vegetables has an impact of preventing and reversing defects associated with an aging subject.
  • Nutritional regimes that involve dietary supplementations with berryfruit e.g., Vaccinium berries such as cranberries and blueberries
  • blueberry supplementation prevents cognitive behavioral deficits in mice having increased amyloid ⁇ -peptide production with APP/PS-1 mutations.
  • the beneficial effects of berryfruits involve direct and indirect actions against oxidative stressors. As such, there is a need to identify compounds in berryfruit that are effective in altering oxidative mediated changes in motor and cognitive function.
  • Trans-3,5,4′-trihydroxystilbene (hereinafter referred to as resveratrol) has been identified as having a plurality of anti-aging properties due to its robust anti-oxidant activity.
  • resveratrol is an effective free radical scavenger and inhibits low density lipoprotein oxidation (Brito P. et al., 2002. Free Radic Res. 36(6):621-631).
  • stilbenoids such as pinostilbene, desoxyrhapontigenin, pterostilbene, resveratrol trimethylether, and piceatannol, have varying degree of biological activity and effectiveness for lowering lipid levels by activating a nuclear receptor, peroxisome proliferators activated receptor alpha isoform.
  • Trans-3,5-dimethoxy-4′-hydroxystilbene (hereinafter referred to as pterostilbene), a natural methylether analog of resveratrol, had been demonstrated to have antioxidant activity similar to that of resveratrol (Rimando et al., 2002. J. Agric. Food Chem. 50:3453-3457; Stivala et al., 2001. J. Biol. Chem. 276(25):22586-22594.)
  • Pterostilbene is present in some small fruits such as grapes (Adrian et al., 2000. J. Argic. Food Chem.
  • a plurality of botanicals contain pterostilbene, including Anogeissus acuminata, Dracaena cochinchinensis, Dracaena loureiri, Guibourtia tessmannii, Pterocarpus macrocarpus, Pterocarpus marsupium, Pterocarpus santalinus, Vaccinium ashei, Vaccinium corymbosum, Vaccinium deliciosum, Vaccinium membranaceum, Vaccinium ovatum, Vaccinium ovalifoilum, Vaccinium parviflorum, Vaccinium stamineum, Vaccinium uliginosum, and Vitis vinifrea.
  • Pterostilbene is also found in non-botanical sources such as propolis.
  • the level of pterostilbene can vary from species of Vaccinium berries. As reported by Rimando et al., 2004. J. Argic. Food Chem. 52:4713-4719, pterostilbene concentrations via cultivars of Vaccinium berries were reported having 99 ng/gm to 520 ng/gm of dry sample. Additionally, as reported by Rimando et al., Acta Hort. ( ISHS ). 680:137-143, lyophilized berries from Vaccinium nine cultivars species exhibited 0.12 ⁇ g to 2.74 ⁇ g of pterostilbene per gram of berries. Similarly, blueberry species vary in the amount of pterostilbene concentration. It has been reported that a range of 99 ng to 475 ng of pterostilbene can be derived from one gram of lyophilized blueberries.
  • antioxidants have linked the effects of antioxidants with deleterious effects of brain aging and behavior.
  • secondary chemicals not generally involved in the plant primary metabolism
  • the compound pterostilbene has shown moderate inhibition of cyclooxygenase-1, and weak inhibition of cyclooxygenase-2 to suggest anti-inflammatory activity. (Rimando, et al., 2002. J. Agric. Food Chem. 50: 3453-3457.)
  • pterostilbene has been identified to activate peroxisome proliferator-activated alpha isoform, (PPAR ⁇ ) a receptor proposed to mediate lowering lipid and glucose levels. Details of the PPAR ⁇ agonist effect of pterostilbene is disclosed in Rimando et al., 2005. J. Agric. Food Chem. 53:3403-3407 and US2006/005723A1, both incorporated herein by reference.
  • Pterostilbene has been identified to inhibit colon carcinogenesis. Particularly, pterostilbene has suppressed azoxymethane-induced colonic aberrant crypt foci growth in weanling male F344 rats. Additionally, pterostilbene inhibits the expression of inducible nitric oxide synthase (iNOS) in HT-29 human adenocarcinoma cell lines. (Suh et al., 2007. Clin Cancer Res. 13(1) 350-355.)
  • iNOS inducible nitric oxide synthase
  • Muscarinic cholinergic receptors mediate the actions of the neurotransmitter acetylcholine in the central and peripheral nervous systems, gastrointestinal system, heart, endocrine glands, lungs, and other tissues.
  • Five distinct muscarinic receptor subtypes have been identified as m1-m5. The m1 subtype is the predominant subtype found in the cerebral cortex and is believed to be involved in the control of cognitive functions.
  • Conditions associated with cognitive impairment are accompanied by loss of acetylcholine in the brain. This is believed to be the result of degeneration of cholinergic neurons in the basal forebrain, which innervate areas of the association cortex, and hippocampus, which is involved in higher cognitive processes.
  • pterostilbene is administered in an amount between about 2.5 mg to about 10 mg per kilogram of subject body weight.
  • the therapeutic effective amount of pterostilbene is administered via a diet of Vaccinium berries.
  • the Vaccinium berries are blueberries.
  • oxidative stress comprising administering a therapeutically effective amount of a substantially pure compound of the formula:
  • pterostilbene is administered in an amount comprising about 2.5 mg to about 10 mg per kilogram of subject body weight.
  • the compound increases subject acetylcholine receptor activity.
  • the amount of compound administered protects against inhibition of dopamine release upon subjecting the subject to an oxidative stressor.
  • pterostilbene is administered via a diet of Vaccinium berries.
  • the Vaccinium berries are blueberries.
  • pterostilbene increases calcium buffering ability of muscarinic receptor subtypes, such as subtype is m-1.
  • Also disclosed is a method for increasing the working memory of a subject comprising administrating an effective amount of a substantially pure pterostilbene, wherein the working memory for a subject increases.
  • the therapeutic effective amount of pterostilbene is about 10 mg of compound per kilogram of subject body weight.
  • FIG. 1 depicts chemical structures of various stilbene derivatives
  • FIG. 2 is a graph Mean Ca 2+ Recovery in M1-transfected COS-7 cells control cells, and those pre-treated with blueberry, resveratrol, pinostilbene, desoxyrhapontigenin, pterostilbene, pterostilbene glucoside, resveratrol trimethylether, or piceatannol, following 0 dopamine ( ⁇ dopamine) or 1 mM dopamine (+dopamine) treatment.
  • FIG. 3 is a graph of latency to platform measurement in seconds of subjects administered a low supplement of pterostilbene (0.004% w/w), a high supplement of pterostilbene (0.016% w/w), or no pterostilbene in their diet (control).
  • FIG. 4 is a graph of distance to platform measurement in meters for subjects administered a low supplement of pterostilbene (0.004% w/w), a high supplement of pterostilbene (0.016% w/w), or no pterostilbene in their diet (control).
  • FIG. 5 is a graph of oxotremorine enhancement of dopamine release from striatal slices (change in pmol/mg protein) prepared from subjects maintained on the control, low dose pterostilbene (0.004%), and high dose pterostilbene (0.016%) diets, under basal levels ( ⁇ H 2 O 2 ) and under conditions of oxidative stress (+H 2 O 2 , 50 ⁇ M) treatment.
  • FIG. 6A is a graph depicting pterostilbene amount (ng) in the hippocampus of subjects as a function of latency in finding a platform (seconds) performed in a Morris Water Maze. Pterostilbene was measured in the hippocampus of subjects and correlated with the performance of subjects of Trial 2 from days 3 and 4 .
  • FIG. 6B is a graph depicting pterostilbene amount (ng) in the hippocampus of subjects as a function of distance (meters) traversed by a subject in reaching a platform performed in a Morris Water Maze. Pterostilbene was measured in the hippocampus of subjects of Trial 2 from days 3 and 4 .
  • Senescent subjects were administered a plurality of pterostilbene doses supplementing their diet. Pterostilbene-supplemented subjects exhibited improved psychomotor and cognitive performance as compared to those without pterostilbene supplementation. In another embodiment, subjects were administered with a low dose of pterostilbene at 2.5 mg of pterostilbene per kilogram of subject weight. In another embodiment, subjects were administered with a high dose of pterostilbene at 10 mg of pterostilbene per kilogram of subject weight and exhibited the greatest improved cognitive performance in tests assessing working memory.
  • pterostilbene pre-treatment antagonized the negative effect of dopamine treatment on calcium clearance following oxotremorine-induced depolarization in an M1-transfected COS-7 cell line.
  • a therapeutic amount of pterostilbene was administered wherein said cell lines transfected with oxidative stress sensitive muscarinic acetylcholine receptors protected against dopamine-induced decreases in recovery time.
  • pterostilbene administered in subject diet increases the sensitivity of subject muscarinic receptors of post-mortem striatal slices wherein dopamine release does not decrease upon subjection to an oxidative stressor.
  • a cell includes a plurality of cells, including mixtures thereof.
  • stilbene is used to describe a chemical class of compounds having the general formula of trans-1,2-diphenylethylene, having the molecular formula C 6 H 5 CH ⁇ CHC 6 H 5 .
  • Stilbenes have the general structure of 1,2-diphenylethylene with two phenyl groups branching as side chains.
  • One chemical derivate from the stilbene chemical class is resveratrol, which is trans-3,5,4′-trihydroxystilbene and depicted in FIG. 1 .
  • Another chemical derivative from the stilbene chemical class is pterostilbene, which can be described as trans-3,5-dimethoxy-4′-hydroxystilbene and depicted in FIG. 1 .
  • stilbene examples include pinostilbene (trans-3,4′-dihydroxy-5-methoxystilbene), desoxyrhapontigenin (trans-3,5-dihydroxy-4′-methoxystilbene), pterostilbene glucoside, resveratrol trimethylether (trans-3,5,4′-trimethyletherstilbene), and piceatannol(trans-3,4,3′,5′-tetrahydroxystilbene).
  • oxidative stressor refers to reactive oxygen species that react with various substances in the body causing disorders. Generally, hydroxyl radical indiscriminately reacts with a plurality of organic substrates. Examples of oxidizing stressor are hydrogen peroxide and ozone.
  • working memory refers to the fast memory process for storage and retrieval, including processes required to retain incoming information in short-term memory before it is converted to long-term memory, including the processes that support the retrieval of established long-term (episodic) memories.
  • the term also refers to a short-term memory, primary memory, immediate memory, operant memory, and provisional memory.
  • a therapeutically effective amount is defined as an amount of a compound that, when administered to a subject, is sufficient to effect such treatment of a conditioned state.
  • the “therapeutically effective amount” may vary depending on the compound, and condition being treated, the age and relative health of the subject, the route and form of administration, the judgment of the one having ordinary skill in the art, and other factors.
  • FIG. 1 A plurality of stilbene analogs were utilized in a calcium recovery assay in M1-transfected cell line following dopamine administration, those stilbene analogs are depicted in FIG. 1 .
  • Resveratrol was purchased from Sigma-Aldrich (St. Louis, Mo.) while piceatannol was purchased from Calbiochem-Novabiochem Corp. (San Diego, Calif.).
  • Pterostilbene trans-3,5-dimethoxy-4′-hydroxystilbene
  • was synthesized (as modified from Pettit et al., 1988, J. Nat. Prod. 51:517-527) by condensation of 3,5-dimethoxybenzaldehyde and 4-hydroxyphenylacetic acid in acetic anhydride and triethylamine.
  • the reaction mixture was heated (150° C.) under an atmosphere of nitrogen, and continuously stirred. After 20 hours, the reaction was stopped, cooled to room temperature, and concentrated hydrochloric acid (5 mL) was added.
  • the formed precipitate was dissolved in 50 mL chloroform and extracted with 10% aqueous sodium hydroxide.
  • the aqueous extract was acidified to pH 1 with concentrated hydrochloric acid, and stirred for at least 6 hours, resulting in the precipitation of the intermediate product, ⁇ -[(3,5-dimethoxyphenyl)methylene]-4-hydroxy-( ⁇ Z)-benzeneacetic acid.
  • This intermediate product was heated with 1.0 g of copper in 10 mL quinoline (200° C., 6 hours, under nitrogen). The reaction mixture was cooled to room temperature and filtered. 5N hydrochloric acid (25 mL) was added to filtrate, stirred for 1 hour, and extracted with chloroform.
  • the chloroform extract containing impure pterostilbene was purified by flash chromatography on a Horizon HPFC system (Biotage, Inc., Charlottesville, Va.), using silica gel column, and solvent system ethyl acetate:hexane (linear gradient from 15:85 to 100% ethyl acetate). Fractions containing pure pterostilbene were combined and concentrated in vacuum. Pterostilbene was recrystallized in hexane, and its structure confirmed from its spectroscopic data (UV, mass spectrometry, and nuclear magnetic resonance spectroscopy).
  • Pterostilbene glucoside was synthesized via pterostilbene (20 mg) mixed with 40 mg of acetobromo- ⁇ ,D-glucose (Sigma-Aldrich, St. Louis, Mo.) and potassium hydroxide (5 mg) in 1 mL of ethanol, and stirred for two days in room temperature. Pterostilbene glucoside was purified by preparative layer chromatography using methanol:chloroform as developing solvent (20:80). The structure of pterostilbene glucoside was determined by mass spectrometry and 1 H-nuclear magnetic resonance spectroscopy.
  • the pterostilbene diets were prepared at Harlan Teklad (Madison, Wis.) by adding crystalline pterostilbene to the control diet, of 40 mg/kg diet, 0.004% w/w for low dose, 160 mg/kg diet, 0.016% w/w for high dose. See Table 1 for diet composition. The amount of corn in the control diet was adjusted to compensate for the added volume of the pterostilbene. The rats were maintained on either the control or pterostilbene diet for eight weeks before motor testing and nine weeks before cognitive testing at 21 months.
  • COS-7 cells a cell line derived from African green monkey kidney, were grown in Dulbecco's Modified Eagle's Medium (D-MEM) supplemented with 10% fetal bovine serum (FBS) and containing 100 U/ml penicillin and 100 ug/ml streptomycin sulfate. Twenty four hours prior to transfection, cells were harvested with trypsin, counted, and plated on 100 mm 2 tissue culture plates at 5 ⁇ 10 6 cells/plate. Cells were transiently transfected with rat muscarinic receptor subtype 1 DNA by the DEAE-dextran method. After transfection, cells were incubated 2.5 hours in growth medium containing 80 ⁇ M chloroquine to minimize degradation of the DNA. Transfected cells were then maintained in growth medium for 48 hours, harvested with trypsin, plated to coverslips in 35 mm plates for calcium imaging, and incubated overnight.
  • D-MEM Dulbecco's Modified Eagle's Medium
  • FBS fetal bo
  • Blueberry (BB) extract (2 mg/ml), stilbenes [resveratrol (50 ⁇ g/ml), pinostilbene (50 ⁇ g/ml), desoxyrhapontigenin (25 ⁇ g/ml), pterostilbene (10 ⁇ g/ml), pterostilbene glucoside (10 ⁇ g/ml), resveratrol trimethylether (10 ⁇ g/ml), piceatannol (10 ⁇ g/ml)] and dopamine (1 mM) treatments were carried out as described previously in Joseph J. et al., 2004. J. Alz. Dis. 6:403-411, and hereby incorporated by reference.
  • the BB extract and stilbenes were dissolved in growth media and cells were subsequently incubated for 45 minutes at 37° C. with the treated growth medium, followed by dopamine administration for 4 hours. Following these incubations, the cells were washed three times with extract-free growth medium prior to testing.
  • the Morris Water Maze is a method to test spatial learning and memory of subjects.
  • the MWM is an age and diet sensitive learning paradigm that requires a subject to locate a hidden platform (10 cm in diameter) positioned below the surface (2 cm) of a circular pool of water (134 cm in diameter ⁇ 50 cm in height, maintained at 23° C.) based on distal cues, and to remember its location from the previous trial. Accurate navigation is rewarded with escape from the water onto the platform, for which the subject uses distal cues such as posters, the experimenter, a computer, cage racks, to effectively locate.
  • the working memory version of the MWM (Brandeis et al., 1989. Int J Neurosci.
  • Trial 2 (the working memory or retrieval trial) used the same platform location and start position as Trial 1 .
  • Performances were videotaped and analyzed with image tracking software (HVS Image, UK), which allows measurements of latency (sec) (time to find the platform), path length (cm), and swimming speed (cm/sec; latency/path length).
  • image tracking software HVS Image, UK
  • the high dose pterostilbene group showed a significant (p ⁇ 0.05) difference in latency to find the platform between Trial 1 and Trial 2 , i.e., Trial 2 latencies were significantly less than Trial 1 , showing that these rats demonstrated one-trial learning, even with the 10 minute retention interval ( FIG. 3 ).
  • both the low and high dose pterostilbene groups showed significant (p ⁇ 0.05) differences in distance to find the platform between Trial 1 and Trial 2 , i.e., Trial 2 distances were significantly less than Trial 1 ( FIG. 4 ).
  • the control group did not show this improvement from Trial 1 to Trial 2 (p>0.05). Therefore, pterostilbene reversed the deleterious effects of aging on cognitive performance, particularly working memory, in a dose-dependent manner.
  • Hippocampal brain tissue was extracted from subjects that were euthanized 2-3 weeks following Morris Water Maze testing.
  • the tissue samples were stored at ⁇ 80° C. and thawed in ice prior to extraction.
  • Tissues were homogenized in 500 ⁇ L of phosphate buffer (pH 7.4) then centrifuged (7000 g, 4° C., 15 min). The supernatant was collected and homogenization was repeated.
  • the combined supernatant was extracted with ethyl acetate (500 ⁇ L ⁇ 2). The ethyl acetate extract was dried under a stream of nitrogen.
  • the dried extract was treated with 30 ⁇ L of N,O-bis[trimethylsilyl]trifluoroacetamide:dimethylformamide (BSTFA:DMF, 1:1; Pierce Biotechnology, Inc., Rockford, Ill.) and heated at 70° C. for 40 min.
  • BSTFA:DMF N,O-bis[trimethylsilyl]trifluoroacetamide:dimethylformamide
  • the derivatized sample was used for analysis of pterostilbene by gas chromatography-mass spectrometry (GC-MS).
  • GC-MS gas chromatography-mass spectrometry
  • the GC was run under the following temperature program: initial 190° C., increased to 239° C. at 20° C./min rate and held at this temp for 3 min, increased to 242° C. at the rate of 0.2° C./min, then finally increased to 300° C. at the rate of 25° C./min and held at this temperature for 1.5 min.
  • the carrier gas was ultrahigh purity helium, at 1 mL/min flow rate.
  • the injection port, GC-MS interface and ionization chamber were at 250, 230 and 230° C., respectively.
  • the volume of injection was 1 ⁇ L, splitless injection. Mass spectrum was acquired in positive, electron impact (70 eV), low-resolution mode.
  • Pterostilbene was determined and quantified from a reconstructed ion chromatogram using m/z 328, 313, 297 and 147. Quantitation was performed from calibration curve of a standard sample of pterostilbene (retention time, 12.5 min). GC-MS analyses were performed in duplicates. Hippocampal pterostilbene was only detectable in the high dose pterostilbene group and was 1.352 ⁇ 0.465 ng/tissue sample.
  • hippocampal pterostilbene levels were correlated with Trial 1 and Trial 2 latency and distance performance as detailed in FIG. 6A and 6B .
  • the muscarinic enhancement of K + -evoked dopamine release (K + -ERDA) from superfused striatal slices is an indicator of receptor sensitivity and striatal function and is sensitive to aging and oxidative stress as disclosed in Joseph et al., 1988. Brain Res., 454:140-8; Joseph et al., 1988. Brain Res., 454:149-55; Joseph J., et al., 1990. Brain Res., 537:40-48; Joseph et al., 1996. Free Radic. Biol. Med., 20: 821-30 and herein incorporated by reference. Additionally, muscarinic enhancement of dopamine release is sensitive to dietary supplementation as disclosed in Joseph et al., 1998. J.
  • Dopamine release was conducted 2-3 weeks following behavioral testing on freshly dissected and cross cut (300 ⁇ m, McIlwain tissue chopper) striatal slices from subject brains that were fed a high dose, low dose and control diet.
  • the slices were placed in small glass vials containing modified Krebs-Ringer basal release medium (BRM) that had been bubbled for 30 min with 95% O 2 /5% CO 2 and containing 21 mM NaHCO 3 , 3.4 mM glucose, 1.3 mM NaH 2 PO 4 , 1 mM EGTA, 0.93 mM MgCl 2 , 127 mM NaCl and 2.5 mM KCl (low KCl) (pH 7.4).
  • BRM modified Krebs-Ringer basal release medium
  • Half of the tissue was treated with 50 ⁇ M H 2 O 2 to assess the effect of diet under conditions of oxidative stress.
  • the slices were placed in the perfusion chambers and maintained at 37° C. and perfused with the BRM for 30 minutes. Following this equilibration period, the medium was switched to one containing (in mM) KCl 30 (high KCl), CaCl 2 .2H 2 O 1.26 (in place of EGTA), NaCl 57, and O or 500 ⁇ M oxotremorine and then the enhancement of K + -ERDA was assessed.
  • Dopamine release was quantitated by HPLC coupled to electrochemical detection and expressed as pmoles/mg protein as determined by the Lowry procedure.

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US12/136,341 US20090069444A1 (en) 2007-09-07 2008-06-10 Method to Ameliorate Oxidative Stress and Improve Working Memory Via Pterostilbene Administration
BRPI0816317A BRPI0816317A2 (pt) 2007-09-07 2008-09-04 Método para tratar o estresse oxidativo e melhorar a memória de trabalho pela administração de pterostilbeno
CA2698661A CA2698661C (fr) 2007-09-07 2008-09-04 Procede pour traiter le stress oxydatif et ameliorer la memoire de travail par administration de pterostilbene
HK11101728.4A HK1148932B (en) 2007-09-07 2008-09-04 Method to ameliorate oxidative stress and improve working memory via pterostilbene administration
PCT/US2008/075170 WO2009032870A2 (fr) 2007-09-07 2008-09-04 Procédé pour traiter le stress oxydatif et améliorer la mémoire de travail par administration de ptérostilbène
CN2008801103188A CN101820869B (zh) 2007-09-07 2008-09-04 通过施用紫檀芪减轻氧化应激并改善工作记忆的方法
EP20080799127 EP2200597B1 (fr) 2007-09-07 2008-09-04 Procédé pour traiter le stress oxydatif et améliorer la mémoire de travail par administration de ptérostilbène
CN201210421008.6A CN103083288B (zh) 2007-09-07 2008-09-04 通过施用紫檀芪减轻氧化应激并改善工作记忆的方法
JP2010524125A JP5608082B2 (ja) 2007-09-07 2008-09-04 プテロスチルベン投与を介して酸化的ストレスを改善し、かつ作業記憶を向上させる方法
AU2008296293A AU2008296293A1 (en) 2007-09-07 2008-09-04 Method to ameliorate oxidative stress and improve working memory via pterostilbene administration
KR20107007002A KR20100075468A (ko) 2007-09-07 2008-09-04 테로스틸벤 투여에 의해 산화적 스트레스를 개선하고 작업 기억을 향상시키는 방법
ES08799127.9T ES2526648T3 (es) 2007-09-07 2008-09-04 Método para mejorar el estrés oxidativo y la memoria de trabajo mediante la administración de pterostilbeno
US13/204,891 US8809400B2 (en) 2007-09-07 2011-08-08 Method to ameliorate oxidative stress and improve working memory via pterostilbene administration
HK13112566.4A HK1185257B (en) 2007-09-07 2013-11-08 Method to ameliorate oxidative stress and improve working memory via pterostilbene administration
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US9975915B1 (en) 2016-11-11 2018-05-22 The Queen's University Of Belfast Crystalline forms of nicotinoyl ribosides, modified derivatives thereof, and phosphorylated analogs thereof, and methods of preparation thereof
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US20110144053A1 (en) * 2009-06-22 2011-06-16 Sunil Bhaskaran Process for Obtaining Purified Pterostilbene and Methods of Use Thereof
US20100119499A1 (en) * 2009-09-17 2010-05-13 Kneller Bruce W Stilbene-based compositions and methods of use therefor
US20130072509A1 (en) * 2011-09-15 2013-03-21 ChromaDex Inc. Pterostilbene and statin combination for treatment of metabolic disease, cardiovascular disease, and inflammation
US11033568B2 (en) 2013-10-30 2021-06-15 ChromaDex Inc. Nicotinamide riboside compositions for topical use in treating skin conditions
US10688118B2 (en) 2013-10-30 2020-06-23 ChromaDex Inc. Nicotinamide riboside compositions for topical use in treating skin conditions
WO2015066382A1 (fr) 2013-10-30 2015-05-07 ChromaDex Inc. Compositions de nicotinamide riboside à usage topique pour traiter les affections cutanées
US9975915B1 (en) 2016-11-11 2018-05-22 The Queen's University Of Belfast Crystalline forms of nicotinoyl ribosides, modified derivatives thereof, and phosphorylated analogs thereof, and methods of preparation thereof
US10689411B2 (en) 2016-11-11 2020-06-23 The Queen's University Of Belfast Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof
US11242364B1 (en) 2016-11-11 2022-02-08 ChromaDex Inc. Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof
US11274117B2 (en) 2016-11-11 2022-03-15 ChromaDex Inc. Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof
US11345720B2 (en) 2016-11-11 2022-05-31 The Queen's University Of Belfast Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof
US11746123B2 (en) 2016-11-11 2023-09-05 The Queen's University Of Belfast Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof
US12195494B2 (en) 2016-11-11 2025-01-14 The Queen's University Of Belfast Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof
US11071747B2 (en) 2016-11-29 2021-07-27 University Of Iowa Research Foundation Use of NAD precursors for breast enhancement
US11633421B2 (en) 2016-11-29 2023-04-25 University Of Iowa Research Foundation Use of NAD precursors for improving maternal health and/or offspring health

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EP2200597A4 (fr) 2010-09-08
CN101820869A (zh) 2010-09-01
KR20100075468A (ko) 2010-07-02
BRPI0816317A2 (pt) 2017-07-25
CN103083288A (zh) 2013-05-08
CN101820869B (zh) 2012-12-12
CA2698661C (fr) 2016-03-29
HK1148932A1 (en) 2011-09-23
HK1185257A1 (zh) 2014-02-14
WO2009032870A3 (fr) 2009-05-22
CN103083288B (zh) 2016-04-13
AU2008296293A1 (en) 2009-03-12
ES2526648T3 (es) 2015-01-14
US20140256827A1 (en) 2014-09-11
WO2009032870A2 (fr) 2009-03-12
US8809400B2 (en) 2014-08-19
EP2200597A2 (fr) 2010-06-30
US9028887B2 (en) 2015-05-12
CA2698661A1 (fr) 2009-03-12
US20120035272A1 (en) 2012-02-09

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