Antioxidant and Neuroprotective Effect of a Grape Pomace Extract on Oxaliplatin-Induced Peripheral Neuropathy in Rats: Biochemical, Behavioral and Histopathological Evaluation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals and Experimental Design
2.2. Oxaliplatin Preparation
2.3. Grape Pomace Extract Preparation
2.4. UHPLC-HRMS Analysis of the Grape Extract
2.5. Grape Pomace Extract Administration
2.6. Behavioral Evaluation
2.7. Blood Sample Collection and Oxidative Stress Biomarkers Evaluation
2.8. Tissue Preparation and Immunohistochemistry
2.9. Morphometrical Analysis
2.10. Statistical Analysis
3. Results
3.1. Oxaliplatin and GPE Administration Effect on General Appearance, Locomotion and Exploratory Activity of Experimental Animals
3.2. Oxaliplatin Administration and GPE Consumption Have No Effect on Body Weight
3.3. Animals Receiving GPE Show NORMAL Sensorimotor Reflexes Whereas in Animals Receiving Only Oxaliplatin Certain Reflexes Were Severely Harmed
3.4. GPE Administration Has Not Altered Gait Analysis Measurements of Oxaliplatin Treated Animals
3.5. Effect of GPE Administration on Sensorimotor Tasks
3.6. Oxidative Stress Biomarkers Evaluation
3.7. Oxaliplatin or GPE Administration Have No Effect on Total Number of Lumbar DRG Sensory Neurons
3.8. GPE Protects Large Lumbar DRG Sensory Neurons from Oxaliplatin Induced Atrophy
3.9. Histological and Immunofluorescent Staining Revealed Increase in the Satellite GFAP-Stained Cells in the Oxaliplatin Alone Treated Animals
4. Discussion
4.1. Oxaliplatin and GPE Administration Effect on General Appearance, Locomotion and Exploratory Activity of Experimental Animals
4.2. Oxaliplatin Administration and GPE Consumption Have No Effect on Body Weight
4.3. GPE Rescues the Oxaliplatin-Induced Damage on Corticospinal Funtion
4.4. Oxaliplatin and GPE Administration Has Not Altered Gait Analysis Measurements of Oxaliplatin Treated Animals
4.5. Beneficial Effect of GPE Administration on Sensorimotor Tasks
4.6. GPE Effect on the Oxidative STRESS Induced by Oxaliplatin
4.7. Oxaliplatin or GPE Administration Have No Effect on Total Number of Lumbar DRG Sensory Neurons
4.8. GPE Protects Large Lumbar DRG Sensory Neurons from Oxaliplatin Induced Atrophy
4.9. Histological and Immunofluorescent Staining Revealed Increase in the Satellite GFAP-Stained Cells in the Oxaliplatin Alone Treated Animals
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Rt (min) | Compounds | Theoretical [M-H]− m/z | Experimental [M-H]− m/z | Molecular Formula | RDBeq. | Delta (ppm) | |
---|---|---|---|---|---|---|---|
1 | 0.75 | Gluconic acid | 195.0510 | 195.0511 | C6H12O7 | 1.5 | 0.50 |
2 | 1.10 | Gallic acid | 169.0142 | 169.0145 | C7H6O5 | 5.5 | 1.32 |
3 | 1.90 | Protocatechuic acid | 153.0193 | 153.0195 | C7H6O4 | 5.5 | 1.29 |
4 | 2.17 | Dihydroxybenzoic acid hexoside isomer 1 | 315.0722 | 315.0724 | C13H16O9 | 6.5 | 0.84 |
5 | 3.01 | Procyanidin B1 or B2 | 577.1351 | 577.135 | C30H26O12 | 18.5 | −0.20 |
6 | 3.03/3.34 | Caffeic acid hexoside | 341.0878 | 341.087 | C15H18O9 | 7.5 | −2.36 |
7 | 3.17 | Caffeoyltartaric acid | 311.0409 | 311.041 | C13H12O9 | 8.5 | 0.30 |
8 | 3.24 | 2-Isopropylmalic acid | 175.0612 | 175.0612 | C7H12O5 | 2.5 | 0.10 |
9 | 3.32 | Catechin or Epicatechin | 289.0718 | 289.0717 | C15H14O6 | 9.5 | −0.03 |
10 | 3.67 | Coumaric acid hexoside isomer 1 | 325.0929 | 325.093 | C15H18O8 | 7.5 | 0.49 |
11 | 3.69 | Caffeic acid | 179.035 | 179.0352 | C9H8O4 | 6.5 | 1.50 |
12 | 3.71 | Procyanidin B1 or B2 | 577.1351 | 577.1352 | C30H26O12 | 18.5 | 0.07 |
13 | 3.79 | Coumaroyltartaric acid isomer 1 | 295.0459 | 295.0461 | C13H12O8 | 8.5 | 0.37 |
14 | 3.90 | Ferulic acid pentoside | 325.0929 | 325.093 | C15H18O8 | 7.5 | 0.39 |
15 | 3.93 | Catechin or Epicatechin | 289.0718 | 289.0718 | C15H14O6 | 9.5 | 0.27 |
16 | 4.38 | Myricetin-3-O-galactoside | 479.0831 | 479.0828 | C21H20O13 | 12.5 | −0.67 |
17 | 4.49 | Syringic acid | 197.0455 | 197.0456 | C9H10O5 | 5.5 | 0.32 |
18 | 4.80 | Isoquercitrin | 463.0882 | 463.0881 | C21H20O12 | 12.5 | −0.20 |
19 | 4.85 | Quercetin 3-O-glucuronide | 477.0675 | 477.0675 | C21H18O13 | 13.5 | 0.07 |
20 | 5.59 | p-Hydroxybenzoic acid | 137.0244 | 137.0245 | C7H6O3 | 5.5 | 0.31 |
21 | 5.20 | Isorhamnetin 3-glucoside | 477.1038 | 477.1038 | C22H22O12 | 12.5 | −0.12 |
22 | 6.22 | Quercetin | 301.0354 | 301.0356 | C15H10O7 | 11.5 | 0.57 |
23 | 6.94 | Kaempferol | 285.0405 | 285.0408 | C15H10O6 | 11.5 | 1.08 |
FOB Test | Tested Parameter | Validation | Scale |
---|---|---|---|
Home-cage measurements | |||
Body position | General condition, pain | R | 1 to 3 |
Respiration | Respiration rate, weakness | R | 1 to 6 |
Vocalization | Pain | Y/N | |
Palpebral closure | R | 1 to 3 | |
Hand-held observations | |||
Reactivity | R | 1 to 5 | |
Handling | R | 1 to 4 | |
Palpebral closure | R | 1 to 3 | |
Open field activity | |||
Number of rearings | Exploratory activity | N | |
Gait | Posture | R | 1 to 6 |
Arousal | Activity over time | R | 1 to 6 |
Defecations number | Autonomic system function | N | |
Diarrhea | Autonomic system function | Y/N | |
Urinations number | Autonomic system function | N | |
Stereotypical behavior | Y/N | ||
Sensorimotor reflexes | |||
Approach response | R | 1 to 4 | |
Touch response | R | 1 to 4 | |
Eyelid reflex | Y/N | ||
Sound response | R | 1 to 3 | |
Tail pinch response | Pain response/locomotion | R | 1 to 4 |
Righting reflex | Proprioception | R | 1 to 4 |
Contact placing response | Corticospinal system function/Proprioception | R | 0 to 2 |
Crossed extensor reflex | Corticospinal system function/Proprioception | R | 1 to 2 |
Sensorimotor measurements | |||
Footprint/gait analysis | |||
Stride length | Ataxia, coordination, locomotion | M | |
Stride width | Base of support, locomotion | M | |
Foot rotation (R) | Sciatic nerve function | M | |
Foot rotation (L) | Sciatic nerve function | M | |
Interpedal distance | Ataxia, coordination, locomotion | M | |
Landing foot splay | Vestibular and proprioceptive sensation/motor efferent fibres | M | |
Grip strength | Touch and proprioceptive sensation/motor efferent fibres | M | |
Sticky paper | Touch receptors/motor efferent fibres | M | |
Von Frey hair pinch test | Mechanoreceptors, pain receptors/motor efferent fibres | M |
Group | Pre-Treatment | Mid-Treatment | End-Treatment | Post-Treatment |
---|---|---|---|---|
Control (group A) | 213 ± 15.62 | 228 ± 12.5 | 225 ± 9.75 | 232 ± 9.3 |
Group B | 196 ± 10.77 | 201 ± 11.77 | 207 ± 11.79 | 221 ± 4.3 |
Group C | 226 ± 10.77 | 220 ± 10.25 | 218 ± 10.07 | 227 ± 15.46 |
Group D | 199 ± 1.05 | 202 ± 10.9 | 192.5 ± 7.77 | 212.5 ± 6 |
Group A | Group B | Group C | Group D | |
---|---|---|---|---|
Foot rotation R | 7.9 ± 1.63 | 11.15 ± 1.63 | 8.3 ± 1.4 | 11.68 ± 1.44 |
Foot rotation L | 10.7 ± 1.9 | 11.85 ± 1.9 | 11.57 ± 1.6 | 12.51 ± 1.65 |
Stride length R | 10.65 ± 0.44 | 11.08 ± 0.35 | 11.03 ± 0.3 | 10.9 ± 0.33 |
Stride length L | 10.81 ± 0.42 | 11.04 ± 0.32 | 10.98 ± 0.34 | 11.33 ± 0.29 |
Stride width | 4.49 ± 0.2 | 4.35 ± 0.21 | 4.15 ± 0.16 | 4.13 ± 0.17 |
Interpedal distance | 5.47 ± 0.2 | 5.5 ± 0.19 | 5.5 ± 0.15 | 5.48 ± 0.16 |
Sensorimotor Tasks | Group A | Group B | Group C | Group D | |
---|---|---|---|---|---|
Landing foot splay (cm) | 3.99 ± 0.5 | 4.35 ± 0.34 | 4.43 ± 0.29 | 4.58 ± 0.28 | N.S. |
Grip strength (N) | 3.11 ± 0.18 * | 2.81 ± 0.18 **/*** | 3.4 ± 0.15 ** | 3.53 ± 0.15 */*** | * p ≤ 0.1 ** p ≤ 0.05 *** p ≤ 0.01 |
Sticky paper (sec) | 157.7 ± 24 | 124.9 ± 24.3 | 126.8 ± 19 | 161.1 ± 18.5 | N.S. |
Von Frey hair pinch test (grams) | 0.40 ± 0.0 * | 1.04 ± 0.3 */**/*** | 0.43 ± 0.03 | 0.42 ± 0.02 | * p ≤ 0.05 ** p ≤ 0.05 *** p ≤ 0.05 |
TAC (mmol DPPH/L Plasma) | SEM | TBARS (μmol/L Plasma) | SEM | |
---|---|---|---|---|
group A | 0.77 | 0.048 | 48.4 | 2.11 |
group B | 0.77 | 0.006 | 40.3 | 1.07 |
group C | 0.79 | 0.076 | 47.8 | 5.14 |
group D | 0.67 | 0.012 | 40.4 | 4.68 |
Morphometric Parameters | Group A | Group B | Group C | Group D | p |
---|---|---|---|---|---|
Total DRG Neuron Number c | 14.138 ± 1.590.37 | 17.020 ± 2.278.97 | 15.090 ± 2.0000 | 16.782 ± 1.194.75 | N.S. |
Large DRG neurons b | 10.4% | 2.8% | 3.3% | 3.8% | - |
Medium DRG neurons b | 30.8% | 24.1% | 21.2% | 26% | - |
Small DRG neurons b | 58.8% | 73.2% | 75.6% | 70.2% | - |
Mean somatic Area (μm2) a | 526.96 ± 4.24 * | 390.94 ± 2.48 */** | 393.92 ± 3.39 | 428.87 ± 2.82 ** | *,** p < 0.01 |
Area of Large DRG neurons (μm2) a | 1.322.18 ± 10.54 */** | 1.196.91 ± 12.48 */*** | 1.275.81 ± 21.35 *** | 1.237.48 ± 13.27 ** | *,** p < 0.001 *** p < 0.01 |
Diameter a | 24.13 ± 0.48 */** | 20.43 ± 0.79 * | 20.32 ± 0.65 ** | 21.49 ± 0.38 | *,** p < 0.01 |
Perimeter a | 86.25 ± 1.61 */**/*** | 71.97 ± 2.44 * | 72.19 ± 3.21 ** | 75.26 ± 1.88 *** | *,** p < 0.01 *** p < 0.05 |
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Bekiari, C.; Tekos, F.; Skaperda, Z.; Argyropoulou, A.; Skaltsounis, A.-L.; Kouretas, D.; Tsingotjidou, A. Antioxidant and Neuroprotective Effect of a Grape Pomace Extract on Oxaliplatin-Induced Peripheral Neuropathy in Rats: Biochemical, Behavioral and Histopathological Evaluation. Antioxidants 2022, 11, 1062. https://doi.org/10.3390/antiox11061062
Bekiari C, Tekos F, Skaperda Z, Argyropoulou A, Skaltsounis A-L, Kouretas D, Tsingotjidou A. Antioxidant and Neuroprotective Effect of a Grape Pomace Extract on Oxaliplatin-Induced Peripheral Neuropathy in Rats: Biochemical, Behavioral and Histopathological Evaluation. Antioxidants. 2022; 11(6):1062. https://doi.org/10.3390/antiox11061062
Chicago/Turabian StyleBekiari, Chryssa, Fotios Tekos, Zoi Skaperda, Aikaterini Argyropoulou, Alexios-Leandros Skaltsounis, Demetrios Kouretas, and Anastasia Tsingotjidou. 2022. "Antioxidant and Neuroprotective Effect of a Grape Pomace Extract on Oxaliplatin-Induced Peripheral Neuropathy in Rats: Biochemical, Behavioral and Histopathological Evaluation" Antioxidants 11, no. 6: 1062. https://doi.org/10.3390/antiox11061062
APA StyleBekiari, C., Tekos, F., Skaperda, Z., Argyropoulou, A., Skaltsounis, A.-L., Kouretas, D., & Tsingotjidou, A. (2022). Antioxidant and Neuroprotective Effect of a Grape Pomace Extract on Oxaliplatin-Induced Peripheral Neuropathy in Rats: Biochemical, Behavioral and Histopathological Evaluation. Antioxidants, 11(6), 1062. https://doi.org/10.3390/antiox11061062