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Extracellular Matrix Remodeling and Modulation of Inflammation and Oxidative Stress by Sulforaphane in Experimental Diabetic Peripheral Neuropathy

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Abstract

The peripheral nervous system is one of many organ systems that can be profoundly impacted in diabetes mellitus. Diabetic peripheral neuropathy has a significant negative effect on patients’ quality of life as it begins with loss of limbs’ sensation and may result in lower limb amputation. This investigation aimed at exploring the effect of sulforaphane on peripheral neuropathy in diabetic rats. Experimental diabetes was induced through single intraperitoneal injections of nicotinamide (50 mg/kg) and streptozotocin (52.5 mg/kg). Rats were divided into five groups. Two groups were treated with saline or sulforaphane (1 mg/kg, p.o.). Three diabetic groups were either untreated or given sulforaphane (1 mg/kg, p.o.) or pregabalin (10 mg/kg, i.p.). Two weeks after drugs’ administration, biochemical, behavioral, histopathological, and immunohistochemical investigations were carried out. Treatment with sulforaphane restored animals’ body weight, reduced blood glucose, glycated hemoglobin, and increased insulin levels. In parallel, it normalized motor coordination and the latency withdrawal time of tail flick test, increased the latency withdrawal time of cold allodynia test, and ameliorated histopathological changes. Treatment of sulforaphane, likewise, decreased sciatic nerve malondialdehyde, nitric oxide, interleukin-6, and matrix metalloproteinase-2 and -9 contents. Similarly, it reduced sciatic nerve DNA fragmentation and expression of cyclooxygenase-2 and nuclear factor kappa-B p65. Meanwhile, it increased sciatic nerve superoxide dismutase and interleukin-10 contents. These results reveal the neuroprotective effect of sulforaphane against peripheral neuropathy in diabetic rats possibly through modulating oxidative stress, inflammation, and extracellular matrix remodeling.

Diagram that illustrates the effects of sulforaphane in treating experimental diabetic peripheral neuropathy. In NA-STZ model of diabetes mellitus, sulforaphane, restored animals’ body weight, reduced blood glucose, glycated hemoglobin and increased insulin levels. In parallel, it normalized motor coordination and the latency withdrawal time of tail flick test, increased the latency withdrawal time of cold allodynia test and ameliorated histopathological changes. Treatment of sulforaphane, likewise, decreased sciatic nerve malondialdehyde, nitric oxide, interleukin-6, matrix metalloproteinase-2 and -9 contents. Similarly, it reduced sciatic nerve DNA fragmentation and expression of cyclooxygenase-2 and nuclear factor kappa-B p65. Meanwhile, it increased sciatic nerve superoxide dismutase and interleukin-10 contents.

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Abbreviations

AD:

Alzheimer’s disease

AGEs:

Advanced glycation end products

ANOVA:

Analysis of variance

COX-2:

Cyclooxygenase-2

DM:

Diabetes mellitus

DPN:

Diabetic peripheral neuropathy

ECM:

Extracellular matrix

ERK1/2:

Extracellular signal-regulated protein kinases 1 and 2

GHBA1c:

Glycated hemoglobin

H&E:

Hematoxylin and eosin

HPWL:

Hind paw withdrawal latency

IL-10:

Interleukin-10

IL-6:

Interleukin-6

iNOS:

Nitric oxide synthase

Keap1:

Kelch-like ECH associated protein 1

MDA:

Malondialdehyde

MMP-2:

Matrix metalloproteinase-2

MMP-9:

Matrix metalloproteinase-9

NA:

Nicotinamide

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-κB:

Nuclear factor kappa B

NO:

Nitric oxide

PD:

Parkinson’s disease

PGB:

Pregabalin

PKC:

Protein kinase C

ROS:

Reactive oxygen species

SFN:

Sulforaphane

SOD:

Superoxide dismutase

STZ:

Streptozotocin

TWL:

Tail withdrawal latency

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Acknowledgments

The authors are thankful to Dr. Adel Bakeir (Histology Department, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt) for carrying out the histopathological and immunohistochemical examinations of this study.

Funding

This study was funded by the National Research Centre, Cairo, Egypt.

Author information

Author notes

  1. Passant E. Moustafa

    Present address: Department of Pharmacology, National Research Centre, 33 El Buhouth St., Dokki, Cairo, 12311, Egypt

Authors and Affiliations

  1. Department of Pharmacology, National Research Centre, 33 El Buhouth St., Dokki, Cairo, 12311, Egypt

    Sally A. El Awdan & Osama A. El-Shabrawy

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Noha F. Abdelkader & Hala F. Zaki

Authors
  1. Passant E. Moustafa
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  2. Noha F. Abdelkader
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  3. Sally A. El Awdan
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  4. Osama A. El-Shabrawy
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  5. Hala F. Zaki
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Corresponding author

Correspondence to Passant E. Moustafa.

Ethics declarations

This study conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) and was approved by the Ethics Committees of Faculty of Pharmacy, Cairo University (permit number 1393) and National Research Centre (permit number 15/047).

Conflict of Interest

The authors affirm that there were no conflicts of interest associated with this research work.

Additional information

Highlights

• Sulforaphane is neuroprotective against diabetic peripheral neuropathy

• Sulforaphane has anti-hyperglycemic, anti-oxidant, anti-inflammatory activities

• Sulforaphane suppressed matrix metalloproteinases involved in the neuropathic pain

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Moustafa, P.E., Abdelkader, N.F., El Awdan, S.A. et al. Extracellular Matrix Remodeling and Modulation of Inflammation and Oxidative Stress by Sulforaphane in Experimental Diabetic Peripheral Neuropathy. Inflammation 41, 1460–1476 (2018). https://doi.org/10.1007/s10753-018-0792-9

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  • DOI: https://doi.org/10.1007/s10753-018-0792-9

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