Brain-Targeted Proanthocyanidin Metabolites for Alzheimer's Disease Treatment Page: 5,147
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Wang et al. * Proanthocyanidin Metabolites and Cognition
750 750 750 750
(-)-C-O-0-glucuroNide 3'-O-Me-(-)-C-O-gucurorde (-)-EC-O-.3-glucuroride 3'-O-Me (-)-EC-O-p3-<ucuronide
E60o 600 600 600
-450 O GP 450 GP 450 GP 450 GP
T, Mo E o I Mo = Mo
300 APo 300 APO 300 APo 300 APo
150 150 150 150
0 0 0 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Time (h) Time (h) Time (h) Time (h)B
D
-GP
;;PoC-Gluc
rIA
t , ,4 +"EC Gluc M.-C-Gluc M-EC Gluc
C OCH3
2, OH
HO 8 .O 5
6 6
6 N. OH
HOOCO
HOH
OH H4
Rodent plasma
MeO-EC metabolites
3
o 10 20 . 4
Acquisition Time (nmin)
Biosynthetic
u MeO-EC metabolite0........ . . ...... 191 ........ 111 ........ 0
20Acquisition Time(in
Acquisition Time (min)119.039
MS-TOF Spectra
Peak 4479.130
100 200 300 400 500 600
Counts vs. Mass-to-Charge (rnyz)MS-TOF Spectra
Peak M479.131
119 039
100 200 300 400 500 600
Counts vs. Mass-1to-Charge(niz)Figure 2. Plasma pharmacokinetics, brain levels of C and EC metabolites, and structural characterization of biosynthetic EC metabolite. A, Plasma pharmacokinetic profile of major C and EC
metabolites following repeated dosing of rats by treatment with GP, Mo, and Po. B, Concentration of C and EC metabolites in brain tissue following 10 d of treatment. Inset, LC-MS/MS separation
of major C and EC metabolites detected in extracts of rat brain tissue collected after 10 d of treatment. MRM trace is shown for C/EC--0/3-glucuronide (465.1--289.1 m/z) and MeO-C/EC-0-/3
glucuronide (479.1--303.1 m/z). Peak identifications: peak 1:()-C-0-/3-glucuronide; peak 2: (-)-EC-0-/3-glucuronide; peak 3:3'-O-Me-()-C-0-/3-glucuronide; peak4:3'-O-Me-(-)-EC-0-/3-
glucuronide. ***p < 0.001, n - 5 per group. C, Proposed structure of the primary EC metabolite identified as 3'-O-Me-(-)-EC-5-0-/3-glucuronide present in blood and brain tissues following
repeated dosing of rats by treatment with GP or Mo fraction. D, LC-MS-TOF separation and online spectra of C and EC metabolites detected in extracts of rat plasma (black) and biosynthetic EC
metabolite (red). Extracted ion chromatogram is shown for MeO-C/EC-0-/3-glucuronide (479.13). Peak identifications: peak 3: 3'-O-Me-()-C-5-0-/3-glucuronide; peak 4: 3'-O-Me-(-)-EC-5-O-
/3-glucuronide; peak M: 3'-0-Me-(-)-EC-5-0-/3-glucuronide.
Table 1. Eight-hour pharmacokinetic parameters from male Sprague Dawley rats (n = 5) treated with a single dose of GP (41 mg/kg BW), Mo (17 mg/kg BW), or Po (28.3
mg/kg BW) or after repeated exposure to extracts for 10 d
Single acute dose Acute dose following 10 d repeated exposure
AUC(o- 8 h) AUC(o - 8 h)
Metabolite Treatment (nmol/L*h) Cmax (nmol/L) T1/2 (h) (nmol/L*h) Cmax (nmol/L) T1/2(h)
(-)-C-0-/3-glucuronide GP 142.2 33.9a 65.8 13.4a 1.5 0.4a 711.8 35.2*a 407.8 35.4*a 0.9 0.2a
Mo 151.2 24.1a 70.8 9.3a 1.3 0.2a 807.4 131.4*a 394.6 48.7*a 0.9 0.1a
Po ND ND 179.3 73.9 154.5 67.9b ' ND
(-)-EC--0/3-glucuronide GP 223.9 58.2a 91.0 17.5a 1.3 0.1a 1063.4 98.3*a 532.9 29.2*a 1.1 0.4a
Mo 282.2 31.2a 110.8 14.4a 1.6 0.3a 1445.1 237.4*a 586.6 78.8*a 0.9 0.2a
Po ND ND ND 311.1 138.5b 251.9 104.2b ' ND
3'-O-Me-(-)-C-0-j3-glucuronide GP 141.8 31.6a 44.8 6.0a 1.8 0.2a 220.3 51.5*a 68.0 15.5*a 1.3 0.3a
Mo 183.2 25.3a 42.8 5.1a 3.1 0.3b 938.5 598.7*b 177.4 70.4*b 2.4 0.7'
Po ND ND ND 6.5 6.5c 8.7 8.7c ND
3'-O-Me-(-)-EC-0-j3-glucuronide GP 187.7 42.5a 51.9 5.9a 2.0 0.2a 241.7 64.6*a 72.4 16.8*a 1.4 0.3a
Mo 216.0 32.2a 46.7 4.4a 2.8 0.2b 952.0 513.9*b 184.2 66.3*b 2.4 0.3
Po ND ND ND 7.3 7.3C 9.7 9.7c ND
Doses of GP, Mo and Po were administered as a single intragastric gavage as described in the Materials and Methods section. AUC(o_8 h), Plasma area under the curve; Cmax, maximum plasma concentration; ~T,, elimination half life; ND,
not determined.
S'b'Significant difference between single-dose treatments (p <0.05). *Significant difference (p <0.01) between single acute dose and repeated dose parameters.140
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J. Neurosci., April 11, 2012.32(15):5144-5150 * 5147
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Wang, Jun; Ferruzzi, Mario G.; Ho, Lap; Blount, Jack W.; Janle, Elsa M.; Gong, Bing et al. Brain-Targeted Proanthocyanidin Metabolites for Alzheimer's Disease Treatment, article, April 11, 2012; [Washington, DC]. (https://digital.library.unt.edu/ark:/67531/metadc279694/m1/4/: accessed April 19, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT College of Arts and Sciences.