Prsentation PowerPoint

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FLORA
Workpackage 5
Effects of Flavonoids and Related
Phenolics against Age-related Degenerative
Diseases
Marie-Claire Toufekstian, Patricia Salen, Michel
de Lorgeril TIMC-IMAG, Cur et Nutrition UMR CNRS
5525 Université Joseph Fourier, Grenoble, France
Istanbul May 25-26, 2009
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Main Objectives

• To evaluate the protective effects of dietary
  polyphenols in rat models
• of ex vivo and in vivo myocardial infarction
• of vascular reactivity
• of diabetes-induced cardiac dysfunction
• of brain ethanol toxicity
• 2. To examine potential interactions between
  polyphenols, ethanol n-3 PUFAs
• 3. To study the cellular mechanisms of protection
  if any

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Collaboration with FLORA partners
Bio. Samples Analysis PRI - Netherlands Resveratr
ol detection
Plant/Food/Extract Biochemical Analysis IPK -
Germany Seeds, pellets and FlavoMix
Bio. Samples Analysis UCSC - Italy ACN detection
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Cardioprotective effects of dietary flavonoids
corn-derived anthocyanins

• Chronic consumption of corn-derived anthocyanins
  increases myocardial resistance against ex vivo
  and in vivo ischemia-reperfusion injury in rats
• No significant effect of dietary anthocyanins on
  vascular reactivity (basal endothelial function)

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Cardioprotective effects of dietary flavonoids
FlavoMix

• Short term oral treatment with FlavoMix capsules
• ( flavones anthocyanins catechines)
• did not protect against in vivo myocardial
  infarction
• did not significantly alter vascular reactivity
• ? Importance of polyphenol source/quality, and
  dose as well as duration of the treatment

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Interactions between flavonoids, ethanol n-3
PUFAs

• Long-chain n-3 PUFAs such as EPA and DHA are
  known for their cardioprotective effects
• Like flavonoids, n-3 PUFAs are important
  components of the healthy Mediterranean diet
• Alcohol and other components of wine
  (polyphénols) increase blood omega-3 PUFAs
• ? Do polyphenols interact with fatty acid
  metabolism independent of alcohol?

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Polyphenols and cardiac complications of
metabolic syndromes

• Metabolic syndrome (MS) obesity, insulin
  resistance and hypertension
• MS ? metabolic cardiac complications
• Polyphenols display beneficial effects against MS

? Do polyphenols prevent cardio-metabolic
disturbances associated with MS?
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Metabolic syndrome
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Objectives

• To develop a rodent model of dietary-induced
  insulin resistance (IR) associated with DCM

• To evaluate the effects of resveratrol (RSV) in
  a pilot study

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Experimental Protocol
Oral treatment

• Chow Excipient ( n 10)
• WD Excipient (n 10)
• - WD RSV (5mg/kg/d) (n 10)

Echocardiography cardiac geometry function
Blood glucose, insulin and lipids
Hemodynamic Nuclear imaging of cardiac IR Cardiac
TNF-a and lipids
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Metabolic parameters
Before treatment with RSV
P lt 0.05 vs. Chow diet
? The WD diet induced insulin resistance
dyslipidemia
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Metabolic hemodynamic parameters
After RSV treatment
P lt 0.05 vs. Chow diet under anesthezia
? RSV did not improve metabolic and hemodynamic
parameters
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Evaluation of cardiac dysfunction by
echocardiography
12 MHz ultrasound transducer
HP Sonos 5500 echocardiographic system
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Evaluation of cardiac dysfunction by
echocardiography CINE
Example of 2-D echocardiographic imaging of the
rat heart
? Follow-up of the cardiac function before (wks 6
- 11) and after RSV treatment (wk 14)
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Evaluation of cardiac dysfunction by
echocardiography
M-mode measurements of cardiac geometry and
function
Stress (dobutamine)
Baseline
LVIDd
LVIDs
FS () (LVIDd-LVIDs)/LVIDd X 100
Allows to reveal cardiac dysfunction undetectable
under baseline conditions
Index of cardiac geometry (LVID) and performances
(FS)
LVID Left Ventricular Internal Dimension in
diastole (d) and in systole (s). FS Fractional
Shortening
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Evolution of cardiac geometry function
LVID Left Ventricular Internal Dimension in
diastole (d) and in systole (s). FS Fractional
Shortening Plt0.05 vs. Chow Plt0.05 vs. WD
? RSV slightly improved cardiac dysfunction
associated with chronic consumption of the WD
diet
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Cardiac function under stress (dobutamine)
FS Fractional Shortening under dobutamine
stress Plt0.05 vs. Chow
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In vivo nuclear imaging of cardiac Insulin
Resistance (IR)

• - Anesthetized rats
• Injection of a radioactive tracer
• - SPECT imaging (g camera)
• Blood sample g counting
• - Image analysis modelisation

Determination of cardiac IR
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Assessment of cardiac IR
Index 2 sensitivity to insulin is normal Index
1 strong insulin resistance
P lt 0.05 vs. chow diet
? RSV did not significantly improve cardiac IR
induced by chronic dietary intake of the WD diet
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Conclusions

• The WD (western-type) diet induced metabolic
  disorders and a progressive cardiac dysfunction
• Short-term oral treatment with resveratrol
  improves cardiac dysfunction but did not prevent
  the evolution of cardio-metabolic perturbations
  induced by the WD diet

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Interactions between alcohol polyphenols
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Alcohol and brain toxicity (1)Impact on fatty
acids

• Alcohol drinking might induce a leak of n-3
  from the brain

• Wine polyphenols might reduce the oxidative
  stress associated with brain aging and
  neurodegenerative diseases

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Brain fatty acids after treatment
Data (Mean SD of n 12 to 14/ group) are
expressed as of the total lipid content. P NS
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Alcohol and brain toxicity (2) Impact on
mitochondrial DNA?

• Alcohol drinking is associated with increased
  oxidative stress in many tissues including brain

• Mitochondrial DNA depletion and deletions are
  markers of DNA oxidative damage

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Effects of Alcohol /- flavonoids on mtDNA
/- EthOH (12 V/V)
Measurement of total and deleted mtDNA by
Real-time PCR on brain tissue lysates
Deleted zone
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Total mitochondrial DNA
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Deleted mitochondrial DNA
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Conclusions

• Moderate drinking does not induce significant
  loss of brain essential PUFAs (DHA, AA) in rats
• Dietary anthocyanins does not alter brain fatty
  acids
• Moderate drinking increases brain oxidative
  stress (increased deleted mtDNA ) in rats
• Anthocyanins partly prevent the increase in brain
  deleted mtDNA

? Dietary anthocyanins seem to exert protective
effects against alcohol-induced brain toxicity
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THANK YOU
FLORA PARTNERS IPK, Gatersleben, Germany UNIMI,
Milan, Italy UCSC, Campobasso, Italy PRI,
Wageningen, Netherlands

• TIMC-PRETA Cur et Nutrition UMR , UJF Grenoble
• Dr. Marie-Claire Toufektsian
• Patricia Salen
• Norbert Nagy
• Stéphane Grauzam
• Departement de Biologie Intégrée, Grenoble
• Pr. François Laporte
• Laura Folliet
• INSERM U877, Radiopharmaceutiques Biocliniques,
  Grenoble
• Service de Cardiologie, CHU, Grenoble
• Pr. Olivier Ormezzano
• Laboratoire de Bioénergétique Fondamentale et
  Appliquée, UJF, Grenoble
• Dr. Christine Demeilliers