黃酮類化合物和腦健康課件

1、2021年11月1日星期一黃酮類化合物和腦健康1flavonoids and brain health: flavonoids and brain health: multiple effects underpinned by common mechanismsmultiple effects underpinned by common mechanismsdr. jeremy p e spencerdr. jeremy p e spencer黃酮類化合物和腦健康210.880-893.270-790.360-690.235-59prevalenceof ad (%)age (years)6.

2、21.720.180.07prevalenceof pd (%)190019201940196019802000202040455055606570758085life expectancy at birthyear men women increased health care costs and general demand on the nhs. reduced quality of life for the elderly population.ageing and incidence of ageing and incidence of neurodegenerative disea

3、sesneurodegenerative diseaseslife expectancyis increasing黃酮類化合物和腦健康3diet and brain functiondiet and brain functionmolecular mechanisms?flavonoids asneuroprotective agentsanimal investigationsflavonoid extracts from fruit and vegetables have been reported to attenuate cognitive decline and neuronal d

4、ysfunction in animal models and humans. joseph et al. (1998, 1999) j. neurosci. unno et al (2004) exp. gerontol. haque et al (2006) j. nutr. williams et al (2008) free radic. biol. med.human studiesflavonoids, in particular flavanols, influenceneural activity, measured with fmri francis et al (2006)

5、 j. cardiovasc. pharmacol. fisher et al (2006) j. cardiovasc. pharmacol. kuriyama et al (2006) ajcn黃酮類化合物和腦健康4flavonoids: sourcefruit and vegetables:(all classes)red wine:(flavanol, flavonols)cocoa:(flavanols and procyanidins)tea:(flavanols)berries:(anthocyanins)citrus:(flavanone)黃酮類化合物和腦健康5flavonoi

6、ds: structureflavanolflavanolflavonolflavonolisoflavoneisoflavoneflavanoneflavanoneanthocyaninanthocyaninr r2 2hohoo or r1 1r r3 3ohohohoho oo or r1 1r r2 2r r4 4r r3 3r r5 5o o+ +ohohhohoohohohohr r1 1r r2 2o oo ohohoohohohohr r1 1r r2 2r r3 3o ohohoohoho or r1 1r r2 2r r3 3黃酮類化合物和腦健康6plant-derived

7、 flavonoids and plant-derived flavonoids and brain functionbrain function黃酮類化合物和腦健康7correct choices (all trials)02468baseline3 weeks6 weeks9 weeks12 weeksnumber correct (out of 8)youngold effects of a blueberry-rich diet on spatial working memoryblueberry*williams et al: frbm, 2008黃酮類化合物和腦健康8effects

8、 of flavonoid supplementation on spatial memory in older animals黃酮類化合物和腦健康9human human interventiointervention ncognitiveteststest drinkplaceboday 1day 2day 3blood sampleblood sampleblood sampleblood sampleblood sampleblood sampleurine collected 09.00 - 13.00 hoursurine collected 13.00 - 17.00 hours

9、urine collected 17.00 - 09.00 hours the next dayurine collected 09.00 - 13.00 hoursurine collected 13.00 - 17.00 hoursurine collected 17.00 - 09.00 hours the next dayblood samplecognitivetestscognitivetestsday 1day 2day 3cognitivetestscognitivetestscognitivetestscognitivetestscognitivetests黃酮類化合物和腦健

10、康10 memory:working memory: serial sevens taskexplicit and implicit long-term memory: immediate cued word recall and word-stem completion, respectivelyspatial memory: brooks grid, computerised 3d mazevisual memory: face recognition test executive function: computerised stroop test, go-nogo task mood:

11、 visual analogue scales. motor skill: static balance and dynamic balancecognitive testscognitive tests黃酮類化合物和腦健康11improvements in human improvements in human executive function (attention)executive function (attention)mean no. of correctly detected targetssustained ability to correctly detect target

12、 stimuli following flavonoid supplementation compared to the placebo (* p 0.05; n=14). subjects : 18-30 yrssubjects: 60-75 yrs36404448525660flavonoidplacebo*go-nogo task: measures executive function/attentionpre-drink1h post5h postflavonoidplacebo*36404448525660 pre-drink1h post5h postmean no. of co

13、rrectly detected targets黃酮類化合物和腦健康12how are these effects mediated?how are these effects mediated?黃酮類化合物和腦健康13proposed mechanisms underlying the neuroprotective effects of flavonoidsantioxidanteffectsmodulation ofreceptor functionmodulation ofneuronal and glial signallingmodulation ofmembrane fluidi

14、tyinfluences on gene expressioninhibitors of neuroinflammation黃酮類化合物和腦健康14biotransformation of flavonoidsoral ingestionof flavonoidmonomericunitsoligomericflavonoidsstomachsmall intestinejejunumileumcolonliverkidneyurineportalveinrenal excretionof glucuronides oligomerscleaved cellsblood-brainbarrie

15、rneuronsgliaglucuronidesa-ring glucuronidesaglyconeo-methylated glucuronideso-methylatedglucuronideso-methylatedsulphatesfurthermetabolismphenolic acidsgut microfloraflavonoidspencer , et al: antiox redox signal, 2001; j nutr, 2003; biochem j, 2003; abb, 2004; brit. j. nutr. 2008黃酮類化合物和腦健康153-o-meth

16、yl-epicatechinoch3ohohoohohepicatechin-7-sulphateohohooohohsoooepicatechin-7-b-d-glucuronideohohoohohcoohohooohohepicatechinohohohoohoh0.1-30.9-250.1-80.9-5plasmaconcentrationm mmmajor flavonoid metabolites黃酮類化合物和腦健康16brain uptake of flavonoids00.511.522.53totalgshvitaminevitamincm mmol/g brain tiss

17、uepelargonidinnmol/g brain tissueabd el mohsen et al: frbm, 2002; free radic res., 2004 ; br j nutr., 2006 黃酮類化合物和腦健康17inhibition of neuronal injury by flavonoidscontrolox. stress (steady-state peroxide)ec + ox. stressme-ec + ox. stress% mtt reduction% mtt reduction* * * * * * *0 0202040406060808010

18、0100120120controlox. stressecme-ecec-glucvehiclespencer et al: biochem j, 2001; frbm, 2004黃酮類化合物和腦健康18neurotransmitter receptorpkcpi 3-kinasetyrosine kinasemap kinase cascadesjnk p38erk1/2akt/pkbneuronal survival and plasticityneuronal apoptosiscrebc-junbrain ageingincreases in cognition performance

19、 and memorywilliams et al: frbm, 2004spencer et al: genes & nutr, 2007; brit j nutr, 2008; chem soc rev, 2009黃酮類化合物和腦健康19flavonoid attenuation of death signalling*00.40.81.21.6band intensity*00.40.81.21.6band intensity00.40.81.21.6band intensity00.40.81.21.6band intensitybasal54h2o23mec46active

20、jnktotal jnkflavonoid: 0.3 flavonoid: 0.3 m mm mos: peroxide: 50 os: peroxide: 50 m mm mh2o2h2o2ecbasalh2o23mech2o2h2o2ecspencer et al: biochem j, 2001; frbm, 2004; schroeter et al: biochem j, 2001黃酮類化合物和腦健康20flavonoid activation of pro-survival signalling vehicle0.10.31.0m mm4442perk1/2total erk(15

21、 min; 310 k; n=4)0.00.20.40.60.81.01.2vehicleec 0.1m mmec 0.3ec 1ec 3ec 10relative band intensityperk2perk1*黃酮類化合物和腦健康21flavonoids mediate creb activationpcreb (ser-133)total crebbasal0.10.31310epicatechin m mmepicatechin: 300 nm; 15 min;o126: 10 m mm; ly294002: 35 m mm 00.40.81.21.6basalec 300 nmec

22、 300 nmuo126ec 300 nmly294002ec 300 nmly294003uo126relative band intensitypcreb (ser-133)mek inhibitorpi3k inhibitor黃酮類化合物和腦健康22oohohohhoohoonoly294002ooohh2npd98059epicatechinpi3 kinaseinhibitormek inhibitoroohohohohhooquercetinsimilarity between flavonoids and kinase inhibitors黃酮類化合物和腦健康23flavonoi

23、d interactions with neuronal and glial signallingifn il-1b btnf-a acd23p38stat-1inosnotnf-a acaspase-8caspase-9caspase-3neuronalapoptosis ros/rnsmicroglia/astrocyteneuronneuronask1jnk1/2badbcl-xldhbt-1erk1/2aktmek1/2pi3kcrebactivation by flavonoidsactivation by flavonoidsscavenging by scavenging by

24、flavonoidsflavonoidsinhibition byinhibition byflavonoidsflavonoidsactivationinhibitioncysdavafeiadou et al: emid drug targets, 2007; abb, 2009vauzour et al: j neurochem, 2007; genes & nutr, 2008; abb, 2008 黃酮類化合物和腦健康24lee et al (2006)frbm 40, 323-334flavonoid-induced signalling in cancer prevent

25、ionlee et al: frbm, 2006nguyen et al: frbm, 2006vauzour et al: abb, 2007黃酮類化合物和腦健康25interaction of flavonoids with interaction of flavonoids with the brains architecture of the brains architecture of memorymemory黃酮類化合物和腦健康26the sensory input to the hippocampusrendeiro et al: genes & nutr, 2009黃酮

26、類化合物和腦健康27newly acquiredsensory informationshort-termmemoryconsolidationlong-termmemorymemoryrecallslower retrievalrapid retrievaltraining/practicememorylossacquisitionpost-translationalmodification ofproteinsde novo protein synthesishippocampuscortexstoragespencer et al: proceed nutr soc, 2006;chem

27、 soc rev, 2009黃酮類化合物和腦健康28erk1/2/5crebcamk ii/ivpkapkb/aktpkcneurotrophinsi.e. bdnfenosnoangiogenesismtorarc/arg3.1b-actinsynaptic plasticitymemory and learningneurogenesissynapse re-modellingtranslationefficiencycontrol of memory at the molecular levelspencer et al: chem soc rev, 2009黃酮類化合物和腦健康29ch

28、anges in hippocampal crebpcreb1 (ser 133) creb1yyobobhippocampuscortexpcreb1 (ser 133) creb101234hippocampuscortexa*relative bandintensitypcreb/crebagedyoungaged + bba = p 0.001* = p 0.001williams et al: frbm, 2008黃酮類化合物和腦健康30 pro-neurotrophin precursors also mediate biological functions polymorphis

29、m that replaces valine for methionine at position 66 of the pro domain, is associated with memory defects and abnormal hippocampal function in humans hippocampal changes in pro- and mature bdnfyyobobpro-bdnfbdnfgapdh*ayobrelativebandintensity0.00.51.01.5*bpro-bdnfmature ddnfa/b = p 0.001* = p 0.001黃

30、酮類化合物和腦健康31changes in hippocampal erk1/2perk 44perk 42yyoboberk2perk 44perk 42a*b*relativebandintensityperk/erk0.00.51.01.52.0agedyoungaged + bba/b = p 0.001* = p 0.001* = p 0.01erkpkccrebpkacamk黃酮類化合物和腦健康32hippocampal changes in aktpakt (ser 473)aktpka ccamkiv (thr 196)camkivyyobobpakt (ser 473)cam

31、kiv(thr 196)pka (thr 197)*brelativebandintensity0.00.51.01.52.0aaagedyoungaged + bba/b = p 0.001* = p 0.001pi3ktrkbaktbdnf黃酮類化合物和腦健康33enhancement of hippocampal protein synthesiserkpi3ktrkbmtorhomer2arc/arg3.1aktbdnfmtor(ser 2448)0.00.20.40.60.81.01.2*arelativebandintensityphospho-mtor/total mtormto

32、r(ser 2481)arc/arg3.1nr4a20.00.51.01.52.02.5bandintensity*aagedyoungaged + bb黃酮類化合物和腦健康34erkpkccrebpi3kbdnftrkbmtorhomer2postsynapticnmda-rpkacamkarc/arg3.1aktbdnfenhancementof protein synthesispresynapticglutamatereleaseampa-r(1)(2)(3)proposed mechanism of action ispencer et al: chem soc rev, 2009黃

33、酮類化合物和腦健康35postsynapticpresynaptictrkbnmda-rampa-rincreased synaptic receptor densitydendritic spinal growth- mushroom spinessynapse following ltperkpi3kmtorhomer2arc/arg3.1aktglutamatereleasef-actinexpansioncofilinsustainedactivation of arc, mtorproposed mechanism of action ii黃酮類化合物和腦健康36interactio

34、ns with the architecture of memory and cognitionnew nerve cell growth (neurogenesis)increased neuronal communication(synaptic plasticity)plant bioactivescell signalling and gene expressionvascular effectsneuronal morphology黃酮類化合物和腦健康37flavonoids improve peripheral and cerebral blood flownitric oxide-dependentvasodilatation acute changes in brain blood flowmodulation of vascular signalling and fa