Can Early Electrical Stimulation Accelerates the Neural Regeneration by Increasing the Expression of BDNF and GDNF in Distal Part of Injured Peripheral Nerve? An Animal Experimental Study

Agus Roy Rusly Hariantana  Hamid; Sri Maliawan; DPG Purwa  Samatra; I Nyoman Mantik  Astawa; I Made Bakta; I Made Jawi; Ida Bagus Putra  Manuaba; I Dewa Made Sukrama; David Sontani  Perdanakusuma

doi:10.3889/oamjms.2021.7500

Authors

Agus Roy Rusly Hariantana Hamid Department of Surgery, Division of Plastic Reconstructive and Aesthetic Surgery, Faculty of Medicine, Udayana University, Sanglah General Hospital Bali, Denpasar, Indonesia
Sri Maliawan Department of Neurosurgery, Division of Neurosurgery, Faculty of Medicine, Udayana University, Sanglah General Hospital Bali, Denpasar, Indonesia
DPG Purwa Samatra Department of Neurology
I Nyoman Mantik Astawa Department of Animal Disease
I Made Bakta Department of Internal Medicine
I Made Jawi Department of Pharmacology and Therapy
Ida Bagus Putra Manuaba Department of Chemistry, Udayana University, Bali, Indonesia
I Dewa Made Sukrama Department of Clinical Microbiology, Faculty of Medicine, Udayana University, Bali, Indonesia
David Sontani Perdanakusuma Department of Plastic Reconstructive and Aesthethic Surgery, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia

DOI:

https://doi.org/10.3889/oamjms.2021.7500

Keywords:

Axons, Electric stimulation, Nerve regeneration

Abstract

BACKGROUND: The role of neurotrophic factors (brain-derived neurotrophic factors and glial cell line-derived neurotrophic factors) and early electrical stimulation (EES) in the injured nerve has found promising in several studies. However, there is still limited knowledge about the effect of EES in the distal part of the nerve to sustain this level of expression of growth factors.

AIM: We aim to evaluate the effects of EES in in neural regeneration by measuring the expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in animal model.

METHODS: The research was conducted starting from April to May 2021 using male Wistar rats. Using general anesthesia, the sciatic nerve was cut. The intervention group was treated with EES in the distal stump, right after nerve resection (20 Hz, 1–2 mA, 2–5 s), while the control group received no treatment after nerve resection. A reoperation on day 3 was performed in both groups to measure BDNF and GDNF expression level of the distal nerve tissue by ELISA as well as histopathological examination of sprouting axons of the injured proximal nerve.

RESULTS: A total of 32 samples were included in the study. A statistically significant levels of GDNF is found higher in the EES group (n = 16) than the control group (n = 16) (35. 71 pg/100 mg, confidence interval (CI) 95% 23.93, 47.48, p < 0.05). The number of sprouting axons is found lower in the EES group (p < 0.05). The BDNF level is similar between the two groups, however not significant. After a subgroup analysis, it was found that the greater the level of GDNF, the fewer the axon sprouts in both groups (fewer axon group 58.35 [n = 22, CI 95% 45.14, 71.55] vs. more axon group 47.14 [n = 10, CI 95% 35.33, 58.95]), p < 0.05.

CONCLUSION: The EES proves its benefit in accelerating the axonal regeneration by increasing the expression GDNF in the distal nerve stumps in the electrical excited degenerated sciatic nerve in the rat model.

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References

McGregor CE, English AW. The role of BDNF in peripheral nerve regeneration: Activity-dependent treatments and val66met. Front Cell Neurosci. 2019;12:522. https://doi.org/10.3389/fncel.2018.00522 PMid:30687012 DOI: https://doi.org/10.3389/fncel.2018.00522

Gordon T. The role of neurotrophic factors in nerve regeneration. Neurosurg Focus. 2009;26(2):E3. https://doi.org/10.3171/FOC.2009.26.2.E3 PMid:19228105 DOI: https://doi.org/10.3171/FOC.2009.26.2.E3

Bothwell M. Recent advances in understanding context-dependent mechanisms controlling neurotrophin signaling and function. F1000Res. 2019;8:1658. https://doi.org/10.12688/f1000research.19174.1 PMid:31583078 DOI: https://doi.org/10.12688/f1000research.19174.1

Al-Majed AA, Brushart TM, Gordon T. Electrical stimulation accelerates and increases expression of BDNF and trkB mRNA in regenerating rat femoral motoneurons. Eur J Neurosci. 2000;12(12):4381-90. PMid:11122348 DOI: https://doi.org/10.1046/j.1460-9568.2000.01341.x

Zuo KJ, Gordon T, Chan KM, Borschel GH. Electrical stimulation to enhance peripheral nerve regeneration: Update in molecular investigations and clinical translation. Exp Neurol. 2020;332:113397. https://doi.org/10.1016/j.expneurol.2020.113397 PMid:32628968 DOI: https://doi.org/10.1016/j.expneurol.2020.113397

Su HL, Chiang CY, Lu ZH, Cheng FC, Chen CJ, Sheu ML, et al. Late administration of high-frequency electrical stimulation increases nerve regeneration without aggravating neuropathic pain in a nerve crush injury. BMC Neurosci. 2018;19(1):1-12. https://doi.org/10.1186/s12868-018-0437-9 PMid:29940857 DOI: https://doi.org/10.1186/s12868-018-0437-9

Willand MP, Nguyen MA, Borschel GH, Gordon T. Electrical stimulation to promote peripheral nerve regeneration. Neurorehabil Neural Repair. 2016;30(5):490-6. https://doi.org/10.1177/1545968315604399 PMid:26359343 DOI: https://doi.org/10.1177/1545968315604399

Nayak R, Banik RK. Current innovations in peripheral nerve stimulation. Pain Res Treat. 2018;2018:1-5. https://doi.org/10.1155/2018/9091216 PMid:30302288 DOI: https://doi.org/10.1155/2018/9091216

Gordon T. Peripheral nerve regeneration and muscle reinnervation. Int J Mol Sci. 2020;21(22):8652. https://doi.org/10.3390/ijms21228652 PMid:33212795 DOI: https://doi.org/10.3390/ijms21228652

Almani SA, Memon IA, Shaikh TZ, Khoharo HK, Ujjan I. Berberine protects against metformin-associated lactic acidosis in induced diabetes mellitus. Iran J Basic Med Sci. 2017;20:511-5. https://doi.org/10.22038/IJBMS.2017.8675 PMid:28656086

Radtke C, Vogt PM. Peripheral nerve regeneration: A current perspective. Eplasty. 2009;9:e47. PMid:19907643

Liu P, Peng J, Han GH, Ding X, Wei S, Gao G, et al. Role of macrophages in peripheral nerve injury and repair. Neural Regen Res. 2019;14(8):1335-42. https://doi.org/10.4103/1673-5374.253510 PMid:30964051 DOI: https://doi.org/10.4103/1673-5374.253510

Burnett MG, Zager EL. Pathophysiology of peripheral nerve injury: A brief review. Neurosurg Focus. 2004;16(5):1-7. https://doi.org/10.3171/foc.2004.16.5.2 PMid:15174821 DOI: https://doi.org/10.3171/foc.2004.16.5.2

Tam SL, Gordon T. Mechanisms controlling axonal sprouting at the neuromuscular junction. J Neurocytol. 2003;32(5-8):961-74. https://doi.org/10.1023/B:NEUR.0000020635.41233.0f PMid:15034279 DOI: https://doi.org/10.1023/B:NEUR.0000020635.41233.0f

Sakuragi S, Tominaga-Yoshino K, Ogura A. Involvement of TrkB- and p75NTR-signaling pathways in two contrasting forms of long-lasting synaptic plasticity. Sci Rep. 2013;3(1):3185. https://doi.org/10.1038/srep03185 PMid:24212565 DOI: https://doi.org/10.1038/srep03185

Keefe K, Sheikh I, Smith G. Targeting neurotrophins to specific populations of neurons: NGF, BDNF, and NT-3 and their relevance for treatment of spinal cord injury. Int J Mol Sci. 2017;18(3):548. https://doi.org/10.3390/ijms18030548 PMid:28273811 DOI: https://doi.org/10.3390/ijms18030548

Ibáñez CF, Paratcha G, Ledda F. RET-independent signaling by GDNF ligands and GFRα receptors. Cell Tissue Res. 2020;382(1):71-82. https://doi.org/10.1007/s00441-020-03261-2 PMid:32737575 DOI: https://doi.org/10.1007/s00441-020-03261-2