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Published in: Journal of Diabetes & Metabolic Disorders 1/2021

01-06-2021 | Type 2 Diabetes | Research article

Effect of apple peel extract on diabetes-induced peripheral neuropathy and wound injury

Authors: Sandesh P. Kamdi, Amit Raval, Kartik T. Nakhate

Published in: Journal of Diabetes & Metabolic Disorders | Issue 1/2021

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Abstract

Purpose

Diabetic peripheral neuropathy (DPN) affects up to 50 % diabetic patients. Moreover, uncontrolled diabetes associated with impaired wound healing. The present study was aimed at exploring the effect of apple peel extract (APE) on type 2 diabetes (T2D)-induced DPN and delayed wound healing.

Methods

In adult male Sprague-Dawley rats on high-fat diet, a single low dose streptozotocin (STZ, 35 mg/kg) was administered via intraperitoneal route to induce T2D. Plantar test using Hargreaves apparatus was used to evaluate the DPN. Six different groups of rats were treated orally with saline (naïve control and DPN control), APE (100, 200 and 400 mg/kg) and gabapentin (30 mg/kg) daily for 7 consecutive days and thermal paw withdrawal latency (PWL) was measured. To elucidate the underlying antioxidant effect of APE, the catalase (CAT), glutathione (GSH) and malonaldehyde (MDA) levels were measured. To evaluate the wound healing potential of APE, excision ischemic open wound model was used. Six different groups of rats were applied with 2 % gum acacia (naïve control and diabetic control), 1 % silver sulfadiazine (SSD) cream and APE cream (5, 10 and 20 %) twice daily for 28 days. Dry connective tissue parameters like hydroxyproline and hexosamine were also measured to further confirm the wound healing activity.

Results

Diabetes produced thermal hyperalgesia in rats with a significant decrease in PWL as compared to naive controls indicating induction of DPN. APE and gabapentin significantly improved PWL in diabetic animals. Biochemical analysis revealed a significant improvement in oxidative stress parameters such as catalase, GSH and MDA. Wound closure was significantly more after day 15 of topical application of APE and SSD as compared to control group. APE significantly increased hydroxyproline and hexosamine levels as compared to standard cream. Moreover, histopathology revealed that, topical application of APE cream showed an enhanced healing process.

Conclusions

On the basis of the findings, we conclude that APE has a potential to be used as a therapeutic intervention for the management of DPN and delayed wound healing in the diabetic condition.
Literature
1.
go back to reference Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843.
2.
go back to reference Tesfaye S, Selvarajah D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev. 2012;28(1):8–14.PubMed Tesfaye S, Selvarajah D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev. 2012;28(1):8–14.PubMed
4.
go back to reference Dyck PJ. Detection, characterization, and staging of polyneuropathy: assessed in diabetics. Muscle Nerve. 1988;1(1):21–32. Dyck PJ. Detection, characterization, and staging of polyneuropathy: assessed in diabetics. Muscle Nerve. 1988;1(1):21–32.
5.
go back to reference Vinik AI, Emley MS, Megerian JT, Gozani SN. Median and ulnar nerve conduction measurements in patients with symptoms of diabetic peripheral neuropathy using the NC-stat system. Diabetes Technol Ther. 2004;6(6):816–24.PubMed Vinik AI, Emley MS, Megerian JT, Gozani SN. Median and ulnar nerve conduction measurements in patients with symptoms of diabetic peripheral neuropathy using the NC-stat system. Diabetes Technol Ther. 2004;6(6):816–24.PubMed
6.
go back to reference Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28(4):956–62.PubMed Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28(4):956–62.PubMed
7.
go back to reference Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care. 2004;27(6):1458–86.PubMed Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care. 2004;27(6):1458–86.PubMed
8.
go back to reference Oso BJ, Abey N, Oyeleke MO, Olowookere B. Comparative study of the in vitro antioxidant properties of methanolic extracts of Chromolaena odorata and Ageratum conyzoides use in wound healings. Int Ann Sci. 2019;6(1):8–12. Oso BJ, Abey N, Oyeleke MO, Olowookere B. Comparative study of the in vitro antioxidant properties of methanolic extracts of Chromolaena odorata and Ageratum conyzoides use in wound healings. Int Ann Sci. 2019;6(1):8–12.
9.
go back to reference Mekonnem W, Sidamo T, Asres K, Engidawork E. In vivo wound healing activity and phytochemical screening of the crude extract and various fractions of Kalanchoe petiana. J Ethnophramacol. 2013;145(2):638–46. Mekonnem W, Sidamo T, Asres K, Engidawork E. In vivo wound healing activity and phytochemical screening of the crude extract and various fractions of Kalanchoe petiana. J Ethnophramacol. 2013;145(2):638–46.
10.
go back to reference Thakur R, Jain N, Pathak R, Sandhu SS. Practices in wound healing studies of plants. Evid Based Complement Alternat Med. 2011;2011:1–17. Thakur R, Jain N, Pathak R, Sandhu SS. Practices in wound healing studies of plants. Evid Based Complement Alternat Med. 2011;2011:1–17.
11.
go back to reference Caskey RC, Zgheib C, Morris M, Allukiahj M, Dorsett-Martin W, Xu J, et al. Dysregulation of collagen production in diabetes following recurrent skin injury:Contribution to the development of chronic wound. Wound Repair Regen. 2014;22(4):515–20.PubMed Caskey RC, Zgheib C, Morris M, Allukiahj M, Dorsett-Martin W, Xu J, et al. Dysregulation of collagen production in diabetes following recurrent skin injury:Contribution to the development of chronic wound. Wound Repair Regen. 2014;22(4):515–20.PubMed
12.
go back to reference Agyare C, Boakye YD, Bekoe EO, Hensel A, Oteng S, Appiah T. Review: African medicinal plants with wound healing properties. J Ethnopharmacol. 2016;177(4):85–100.PubMed Agyare C, Boakye YD, Bekoe EO, Hensel A, Oteng S, Appiah T. Review: African medicinal plants with wound healing properties. J Ethnopharmacol. 2016;177(4):85–100.PubMed
13.
go back to reference Bahadoran Z, Mirmiran P, Azizi F. Dietary polyphenols as potential nutraceuticals in management of diabetes: a review. J Diabetes Metab Disord. 2013;12(1):43.PubMedPubMedCentral Bahadoran Z, Mirmiran P, Azizi F. Dietary polyphenols as potential nutraceuticals in management of diabetes: a review. J Diabetes Metab Disord. 2013;12(1):43.PubMedPubMedCentral
14.
go back to reference Oszmiansk J, Wolniak M, Wojdyto A, Wawer I. Influence of apple purée preparation and storage on polyphenol contents and antioxidant activity. Food Chem. 2008;107(4):1473–84. Oszmiansk J, Wolniak M, Wojdyto A, Wawer I. Influence of apple purée preparation and storage on polyphenol contents and antioxidant activity. Food Chem. 2008;107(4):1473–84.
15.
go back to reference Hyson DA. A comprehensive review of apples and apple components and their relationship to human health. Adv Nutr. 2011;2(5):408–20.PubMedPubMedCentral Hyson DA. A comprehensive review of apples and apple components and their relationship to human health. Adv Nutr. 2011;2(5):408–20.PubMedPubMedCentral
16.
go back to reference Arabbi PR, Genovese MI, Lajolo FM. Flavonoids in vegetable foods commonly consumed in Brazil and estimated ingestion by the Brazilian population. J Agric Food Chem. 2004;52(5):1124–31.PubMed Arabbi PR, Genovese MI, Lajolo FM. Flavonoids in vegetable foods commonly consumed in Brazil and estimated ingestion by the Brazilian population. J Agric Food Chem. 2004;52(5):1124–31.PubMed
17.
go back to reference Balasuriya N, Rupasinghe V, Sweeney M, McCarron S, Gottschall-Pass K. Antihypertensive effects of apple peel extract on spontaneously hypertensive rats. Pharmacologia. 2015;6(8):371–376. Balasuriya N, Rupasinghe V, Sweeney M, McCarron S, Gottschall-Pass K. Antihypertensive effects of apple peel extract on spontaneously hypertensive rats. Pharmacologia. 2015;6(8):371–376.
18.
go back to reference Tian J, Wu X, Zhang M, Zhou Z, Liu Y. Comparative study on the effects of apple peel polyphenols and apple flesh polyphenols on cardiovascular risk factors in mice. Clin Exp Hypertens. 2018;40(1):65–72.PubMed Tian J, Wu X, Zhang M, Zhou Z, Liu Y. Comparative study on the effects of apple peel polyphenols and apple flesh polyphenols on cardiovascular risk factors in mice. Clin Exp Hypertens. 2018;40(1):65–72.PubMed
19.
go back to reference Manzano M, Giron MD, Vilchez JD, Sevillano N, El-Azem N, Rueda R, et al. Apple polyphenol extract improves insulin sensitivity in vitro and in vivo in animal models of insulin resistance. Nutr Metab (Lond). 2016;13:32. Manzano M, Giron MD, Vilchez JD, Sevillano N, El-Azem N, Rueda R, et al. Apple polyphenol extract improves insulin sensitivity in vitro and in vivo in animal models of insulin resistance. Nutr Metab (Lond). 2016;13:32.
20.
go back to reference Fathy SM, Drees EA. Protective effects of Egyptian cloudy apple juice and apple peel extract on lipid peroxidation, antioxidant enzymes and inflammatory status in diabetic rat pancreas. BMC Complement Altern Med. 2016;16:8.PubMedPubMedCentral Fathy SM, Drees EA. Protective effects of Egyptian cloudy apple juice and apple peel extract on lipid peroxidation, antioxidant enzymes and inflammatory status in diabetic rat pancreas. BMC Complement Altern Med. 2016;16:8.PubMedPubMedCentral
21.
go back to reference Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res. 2005;52:313–20.PubMed Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res. 2005;52:313–20.PubMed
22.
go back to reference Nakhate KT, Yedke SU, Bharne AP, Subhedar NK, Kokare DM. Evidence for the involvement of neuropeptide Y in the antidepressant effect of imipramine in type 2 diabetes. Brain Res. 2006;1646:1–11. Nakhate KT, Yedke SU, Bharne AP, Subhedar NK, Kokare DM. Evidence for the involvement of neuropeptide Y in the antidepressant effect of imipramine in type 2 diabetes. Brain Res. 2006;1646:1–11.
23.
go back to reference Goyal SN, Reddy NM, Patil KR, Nakhate KT, Ojha S, Patil CR, Agrawal YO. Challenges and issues with streptozotocin-induced diabetes - A clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics. Chem Biol Interact. 2016;244:49–63.PubMed Goyal SN, Reddy NM, Patil KR, Nakhate KT, Ojha S, Patil CR, Agrawal YO. Challenges and issues with streptozotocin-induced diabetes - A clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics. Chem Biol Interact. 2016;244:49–63.PubMed
24.
25.
go back to reference Fang JY, Lin CH, Huang TH, Chuang SY. In vivo rodent models of type 2 diabetes and their usefulness for evaluating flavonoid bioactivity. Nutrients. 2019;28(3):530. Fang JY, Lin CH, Huang TH, Chuang SY. In vivo rodent models of type 2 diabetes and their usefulness for evaluating flavonoid bioactivity. Nutrients. 2019;28(3):530.
26.
go back to reference Hargreaves, et al.,A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32(1):77–88. Hargreaves, et al.,A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32(1):77–88.
27.
go back to reference Hofmann AT, Neumann S, Ferguson J, Red H, Mittermayr R. A rodent excision model for ischemia-impaired wound healing. Tissue Eng Part C Methods. 2017;23(12):995–1002.PubMed Hofmann AT, Neumann S, Ferguson J, Red H, Mittermayr R. A rodent excision model for ischemia-impaired wound healing. Tissue Eng Part C Methods. 2017;23(12):995–1002.PubMed
28.
go back to reference Gupta A, Kirar V, Keshri GK, Gola S, Yadav A, Negi PS, et al. Wound healing activity of an aqueous extract of the Lingzhi or Reishi medicinal mushroom Ganoderma lucidum (higher Basidiomycetes). Int J Med Mushrooms. 2014;16(4):345–54.PubMed Gupta A, Kirar V, Keshri GK, Gola S, Yadav A, Negi PS, et al. Wound healing activity of an aqueous extract of the Lingzhi or Reishi medicinal mushroom Ganoderma lucidum (higher Basidiomycetes). Int J Med Mushrooms. 2014;16(4):345–54.PubMed
30.
go back to reference Murthy S, Gautam MK, Goel S, Purohit V, Sharma H, Goel RK. Evaluation of in vivo wound healing activity of Bacopa monniera on different wound model in rats. Biomed Res Int. 2013;2013:972028.PubMedPubMedCentral Murthy S, Gautam MK, Goel S, Purohit V, Sharma H, Goel RK. Evaluation of in vivo wound healing activity of Bacopa monniera on different wound model in rats. Biomed Res Int. 2013;2013:972028.PubMedPubMedCentral
31.
go back to reference Ellman GL. Tissue sulphydryl groups. Arch Biochem Biophys. 1959;82:70–7.PubMed Ellman GL. Tissue sulphydryl groups. Arch Biochem Biophys. 1959;82:70–7.PubMed
32.
go back to reference Sinha KA. Colorimetric assay of catalase. Anal Biochem. 1972;47:389–94.PubMed Sinha KA. Colorimetric assay of catalase. Anal Biochem. 1972;47:389–94.PubMed
34.
go back to reference McManus JFA, Mowry RW. Stainning methods, histologic and histochemical. New York: Harper Raw; 1965. McManus JFA, Mowry RW. Stainning methods, histologic and histochemical. New York: Harper Raw; 1965.
35.
go back to reference Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest. 2007;117(5):1219–22.PubMedPubMedCentral Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest. 2007;117(5):1219–22.PubMedPubMedCentral
36.
go back to reference da Silveira Vasconcelos M, Gomes-Rochette NF, de Oliveira ML, Nunes-Pinheiro DC, Tome AR, Maia de Sousa FY, et al. Anti-inflammatory and wound healing potential of cashew apple juice (Anacardium occidentale L.) in mice. Exp Biol Med (Maywood). 2015;240(12):1648–55. da Silveira Vasconcelos M, Gomes-Rochette NF, de Oliveira ML, Nunes-Pinheiro DC, Tome AR, Maia de Sousa FY, et al. Anti-inflammatory and wound healing potential of cashew apple juice (Anacardium occidentale L.) in mice. Exp Biol Med (Maywood). 2015;240(12):1648–55.
37.
go back to reference Pang Y, Zhang Y, Huang L, Xu L, Wang K, Wang D, et al. Effects and mechanisms of total flavonoids from Blumea balsamifera (L.) DC. on skin wound in rats. Int J Mol Sci. 2017;18(12):2766.PubMedCentral Pang Y, Zhang Y, Huang L, Xu L, Wang K, Wang D, et al. Effects and mechanisms of total flavonoids from Blumea balsamifera (L.) DC. on skin wound in rats. Int J Mol Sci. 2017;18(12):2766.PubMedCentral
38.
go back to reference Yin G, Wang Z, Wang Z, Wang X. Topical application of quercetin improves wound healing in pressure ulcer lesions. Exp Dermatol. 2018;27(7):779–86.PubMed Yin G, Wang Z, Wang Z, Wang X. Topical application of quercetin improves wound healing in pressure ulcer lesions. Exp Dermatol. 2018;27(7):779–86.PubMed
39.
go back to reference Dwivedi D, Dwivedi M, Malviya S, Singh V. Evaluation of wound healing, anti-microbial and antioxidant potential of Pongamia pinnata in wistar rats. J Tradit Complement Med. 2017;7(1):79–85.PubMed Dwivedi D, Dwivedi M, Malviya S, Singh V. Evaluation of wound healing, anti-microbial and antioxidant potential of Pongamia pinnata in wistar rats. J Tradit Complement Med. 2017;7(1):79–85.PubMed
40.
go back to reference Yu H, Qin C, Zhang P, Ge Q, Wu M, Wu J, et al. Antioxidant effect of apple phenolic on lipid peroxidation in Chinese-style sausage. J Food Sci Technol. 2015;52(2):1032–9.PubMed Yu H, Qin C, Zhang P, Ge Q, Wu M, Wu J, et al. Antioxidant effect of apple phenolic on lipid peroxidation in Chinese-style sausage. J Food Sci Technol. 2015;52(2):1032–9.PubMed
41.
go back to reference Zangiabadi N. The effect of omega-3 fatty acids on nerve conduction velocity (NCV) and F-wave latency in patients with diabetic polyneuropathy. Am J Pharmacol Toxicol. 2007;2(1):1–3. Zangiabadi N. The effect of omega-3 fatty acids on nerve conduction velocity (NCV) and F-wave latency in patients with diabetic polyneuropathy. Am J Pharmacol Toxicol. 2007;2(1):1–3.
42.
go back to reference Coste TC, Gerbi A, Vague P, Maixent JM, Pieroni G, Raccah D. Peripheral diabetic neuropathy and polyunsaturated fatty acid supplementations: natural sources or biotechnological needs? Cell Mol Biol (Noisy-le-grand). 2004;50(7):845–53. Coste TC, Gerbi A, Vague P, Maixent JM, Pieroni G, Raccah D. Peripheral diabetic neuropathy and polyunsaturated fatty acid supplementations: natural sources or biotechnological needs? Cell Mol Biol (Noisy-le-grand). 2004;50(7):845–53.
43.
go back to reference Greene DA, Stevens MJ, Obrosova I, Feldman EL. Glucose-induced oxidative stress and programmed cell death in diabetic neuropathy. Eur J Pharmacol. 1999;375(1–3):217–23.PubMed Greene DA, Stevens MJ, Obrosova I, Feldman EL. Glucose-induced oxidative stress and programmed cell death in diabetic neuropathy. Eur J Pharmacol. 1999;375(1–3):217–23.PubMed
44.
go back to reference Pocernich CB, Butterfield DA. Elevation of glutathione as a therapeutic strategy in Alzheimer disease. Biochi Biophys Acta. 2012;1822(5):625–30. Pocernich CB, Butterfield DA. Elevation of glutathione as a therapeutic strategy in Alzheimer disease. Biochi Biophys Acta. 2012;1822(5):625–30.
45.
go back to reference Heo HJ, Lee CY. Protective effects of quercetin and vitamin C against oxidative stress-induced neurodegeneration. J Agric Food Chem. 2004;52(25):7514–17.PubMed Heo HJ, Lee CY. Protective effects of quercetin and vitamin C against oxidative stress-induced neurodegeneration. J Agric Food Chem. 2004;52(25):7514–17.PubMed
46.
go back to reference Heo HJ, Kim DO, Shin SC, Kim MJ, Kim BG, Shin DH. Effect of antioxidant flavanone, naringenin, from Citrus junosonneuroprotection. J Agric Food Chem. 2004;52(6):1520–5.PubMed Heo HJ, Kim DO, Shin SC, Kim MJ, Kim BG, Shin DH. Effect of antioxidant flavanone, naringenin, from Citrus junosonneuroprotection. J Agric Food Chem. 2004;52(6):1520–5.PubMed
47.
go back to reference Nakayama T, Yamada M, Osawa T, Kawakishi S. Suppression of active oxygen-induced cytotoxicity by flavonoids. Biochem Pharmacol. 1993;45(1):265–7.PubMed Nakayama T, Yamada M, Osawa T, Kawakishi S. Suppression of active oxygen-induced cytotoxicity by flavonoids. Biochem Pharmacol. 1993;45(1):265–7.PubMed
48.
go back to reference Patil CS, Singh VP, Satyanarayan PS, Jain NK, Singh A, Kulkarni SK. Protective effect of flavonoids against aging- and lipopolysaccharide-induced cognitive impairment in mice. Pharmacology. 2003;69(2):59–67.PubMed Patil CS, Singh VP, Satyanarayan PS, Jain NK, Singh A, Kulkarni SK. Protective effect of flavonoids against aging- and lipopolysaccharide-induced cognitive impairment in mice. Pharmacology. 2003;69(2):59–67.PubMed
49.
go back to reference O’Byrne DJ, Devaraj S, Grundy SM, Jialal I. Comparison of the antioxidant effects of Concord grape juice flavonoids alpha-tocopherol on markers of oxidative stress in healthy adults. Am J Clin Nutr. 2002;76(6):1367–74.PubMed O’Byrne DJ, Devaraj S, Grundy SM, Jialal I. Comparison of the antioxidant effects of Concord grape juice flavonoids alpha-tocopherol on markers of oxidative stress in healthy adults. Am J Clin Nutr. 2002;76(6):1367–74.PubMed
50.
go back to reference Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and Alzheimer’s disease: the Kame Project. Am J Med. 2006;119(9):751–9.PubMedPubMedCentral Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and Alzheimer’s disease: the Kame Project. Am J Med. 2006;119(9):751–9.PubMedPubMedCentral
Metadata
Title
Effect of apple peel extract on diabetes-induced peripheral neuropathy and wound injury
Authors
Sandesh P. Kamdi
Amit Raval
Kartik T. Nakhate
Publication date
01-06-2021
Publisher
Springer International Publishing
Keyword
Type 2 Diabetes
Published in
Journal of Diabetes & Metabolic Disorders / Issue 1/2021
Electronic ISSN: 2251-6581
DOI
https://doi.org/10.1007/s40200-020-00719-6

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