open access

Vol 81, No 2 (2022)
Original article
Submitted: 2021-02-24
Accepted: 2021-03-12
Published online: 2021-04-09
Get Citation

Comparing effects of L-carnitine and sildenafil citrate on histopathologic recovery from sciatic nerve crush injury in female albino rats

O. I. Zedan1, M. A. Bashandy1
DOI: 10.5603/FM.a2021.0037
·
Pubmed: 33899209
·
Folia Morphol 2022;81(2):421-434.
Affiliations
  1. Anatomy and Embryology Department, Faculty of Medicine, Menoufia University, Egypt

open access

Vol 81, No 2 (2022)
ORIGINAL ARTICLES
Submitted: 2021-02-24
Accepted: 2021-03-12
Published online: 2021-04-09

Abstract

Background: The sciatic nerve is a peripheral nerve and is more vulnerable to compression with subsequent short- or long-term neuronal dysfunction. The current study was designed to elucidate the possible ameliorative effect of L-carnitine and sildenafil (SIL) on sciatic nerve crush injury. We sought to determine the effects of L-carnitine, a neuroprotective and a neuro-modulatory agent, and SIL citrate, a selective peripheral phosphodiesterases inhibitor, on modulating neuro-degenerative changes due to sciatic nerve compression.
Materials and methods: The comparative effect of L-carnitine (at an oral dose of 20 mg/kg/day) or SIL citrate (20 mg/kg/day orally) administration for 21 days was studied in a rat model of sciatic nerve compression. Sciatic nerve sections were subjected to biochemical, histological, ultrastructure, and immunohistochemical studies to observe the effects of these treatments on neurofilament protein.
Results: The sciatic nerve crush injury group (group II) showed a significant decrease in tissue catalase (CAT), superoxide dismutase (SOD) and increase in malondialdehyde (MDA) as compared to control group (p < 0.01). Histological changes in the form of degenerated and vacuolated axoplasm with areas of nerve fibre loss and pyknotic nuclei were reported. The blood vessels were dilated, congested with areas of haemorrhage and mononuclear cell infiltration. Histo-morphometrically, a statistically significant reduction in the nerve fibres’ number, mean axon cross-sectional area, myelin sheath thickness and a significant increase in collagen fibres’ percentage (p < 0.05) as compared to control group. Immunohistochemically, neurofilament protein was significantly downregulated as proved by a significant reduction in mean area per cent of neurofilament expression. L-carnitine ameliorated the studied parameters through its neuroprotective effect while SIL, a selective peripheral phosphodiesterases (PDE-5) inhibitor, improved crush injury parameters but with less extent than L-carnitine.
Conclusions: These findings indicate the valuable effects of L-carnitine administration compared to that of SIL citrate in alleviating the serious debilitating effects of sciatic nerve crush injury. Our results provide a new insight into the scope of neuroprotective and neuro-regenerative effects of L-carnitine in a sciatic nerve compression model.

Abstract

Background: The sciatic nerve is a peripheral nerve and is more vulnerable to compression with subsequent short- or long-term neuronal dysfunction. The current study was designed to elucidate the possible ameliorative effect of L-carnitine and sildenafil (SIL) on sciatic nerve crush injury. We sought to determine the effects of L-carnitine, a neuroprotective and a neuro-modulatory agent, and SIL citrate, a selective peripheral phosphodiesterases inhibitor, on modulating neuro-degenerative changes due to sciatic nerve compression.
Materials and methods: The comparative effect of L-carnitine (at an oral dose of 20 mg/kg/day) or SIL citrate (20 mg/kg/day orally) administration for 21 days was studied in a rat model of sciatic nerve compression. Sciatic nerve sections were subjected to biochemical, histological, ultrastructure, and immunohistochemical studies to observe the effects of these treatments on neurofilament protein.
Results: The sciatic nerve crush injury group (group II) showed a significant decrease in tissue catalase (CAT), superoxide dismutase (SOD) and increase in malondialdehyde (MDA) as compared to control group (p < 0.01). Histological changes in the form of degenerated and vacuolated axoplasm with areas of nerve fibre loss and pyknotic nuclei were reported. The blood vessels were dilated, congested with areas of haemorrhage and mononuclear cell infiltration. Histo-morphometrically, a statistically significant reduction in the nerve fibres’ number, mean axon cross-sectional area, myelin sheath thickness and a significant increase in collagen fibres’ percentage (p < 0.05) as compared to control group. Immunohistochemically, neurofilament protein was significantly downregulated as proved by a significant reduction in mean area per cent of neurofilament expression. L-carnitine ameliorated the studied parameters through its neuroprotective effect while SIL, a selective peripheral phosphodiesterases (PDE-5) inhibitor, improved crush injury parameters but with less extent than L-carnitine.
Conclusions: These findings indicate the valuable effects of L-carnitine administration compared to that of SIL citrate in alleviating the serious debilitating effects of sciatic nerve crush injury. Our results provide a new insight into the scope of neuroprotective and neuro-regenerative effects of L-carnitine in a sciatic nerve compression model.

Get Citation

Keywords

sciatic nerve, compression, L-carnitine, sildenafil citrate, histopathology, oxidative stress, immunohistochemistry

About this article
Title

Comparing effects of L-carnitine and sildenafil citrate on histopathologic recovery from sciatic nerve crush injury in female albino rats

Journal

Folia Morphologica

Issue

Vol 81, No 2 (2022)

Article type

Original article

Pages

421-434

Published online

2021-04-09

Page views

1397

Article views/downloads

857

DOI

10.5603/FM.a2021.0037

Pubmed

33899209

Bibliographic record

Folia Morphol 2022;81(2):421-434.

Keywords

sciatic nerve
compression
L-carnitine
sildenafil citrate
histopathology
oxidative stress
immunohistochemistry

Authors

O. I. Zedan
M. A. Bashandy

References (76)
  1. Abd-El-Hafez A. Effect of leflunomide on sciatic nerve of adult albino rats. Egypt J Histol. 2014; 37(2): 258–268.
  2. Abd ElS, Raafat M, Shokry Y. ogical study on the role of bone marrow derived mesenchymal stem cells on the sciatic nerve and the gastrocnemius muscle in a model of sciatic nerve crush injury in albino rats. Egypt J Histol. 2015; 38(3): 438–451.
  3. Abdul HM, Butterfield DA. Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. Free Radic Biol Med. 2007; 42(3): 371–384.
  4. Alqalla M, Tawfik M, Grawish M. The effects of low-level laser treatment on recovery of nerve conduction after sciatic nerve compression injury (experimental study). J Am Sci. 2016; 12(9): 5–11.
  5. American Heart Association. Viagra Helps Men with Heart Failure. Science Daily. http://www.sciencedaily.com/ releases/2002/ 08/0208070 64924.htm (2002; 7 August).
  6. Avsar UZ, Avsar U, Aydin A, et al. L-carnitine alleviates sciatic nerve crush injury in rats: functional and electron microscopy assessments. Neural Regen Res. 2014; 9(10): 1020–1024.
  7. Babicová A, Havlínová Z, Hroch M, et al. In vivo study of radioprotective effect of NO-synthase inhibitors and acetyl-L-carnitine. Physiol Res. 2013; 62(6): 701–710.
  8. Bagdatoglu C, Saray A, Surucu HS, et al. Effect of trapidil in ischemia/reperfusion injury of peripheral nerves. Neurosurgery. 2002; 51(1): 212–9; discussion 219.
  9. Bancroft JD, Gamble M. Theory and practice of histological techniques, 6th ed. Churchill Livingstone Elsevier, Philadelphia 2008: 126, 150, 440.
  10. Burnett M, Zager E. Pathophysiology of peripheral nerve injury: a brief review. Neurosurgical Focus. 2004; 16(5): 1–7.
  11. Cavallini G, Caracciolo S, Vitali G, et al. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology. 2004; 63(4): 641–646.
  12. Cetinkaya A, Bulbuloglu E, Kantarceken B, et al. Effects of L-carnitine on oxidant/antioxidant status in acetic acid-induced colitis. Dig Dis Sci. 2006; 51(3): 488–494.
  13. Chen CJ, Ou YC, Liao SL, et al. Transplantation of bone marrow stromal cells for peripheral nerve repair. Exp Neurol. 2007; 204(1): 443–453.
  14. Chiechio S, Copani A, Gereau RW, et al. Acetyl-L-carnitine in neuropathic pain: experimental data. CNS Drugs. 2007; 21 Suppl 1: 31–8; discussion 45.
  15. Di Cesare Mannelli L, Ghelardini C, Calvani M, et al. Neuroprotective effects of acetyl-L-carnitine on neuropathic pain and apoptosis: a role for the nicotinic receptor. J Neurosci Res. 2009; 87(1): 200–207.
  16. El-Azab NE, El-Mahalaway A, Mostafa O, et al. Histological and immunohistochemical study of the potential therapeutic impacts of bone marrow mesenchymal stem cells and exosomes for sciatic nerve crush injury model in rats. J Histotechnol. 2018; 41(4): 160–176.
  17. El Desoky ES, Fouad IA. Pharmacological evidence for the role of nitric oxide-CGMP in antinociception. J Appl Res. 2005; 5: 451–459.
  18. Emmez H, Yildirim Z, Kale A, et al. Anti-apoptotic and neuroprotective effects of α-lipoic acid on spinal cord ischemia-reperfusion injury in rabbits. Acta Neurochir (Wien). 2010; 152(9): 1591–600; discussion 1600.
  19. Emel E, Ergün SS, Kotan D, et al. Effects of insulin-like growth factor-I and platelet-rich plasma on sciatic nerve crush injury in a rat model. J Neurosurg. 2011; 114(2): 522–528.
  20. Eto M, Sumi H, Fujimura H, et al. Pioglitazone promotes peripheral nerve remyelination after crush injury through CD36 upregulation. J Peripher Nerv Syst. 2008; 13(3): 242–248.
  21. Feng X, Yuan W. Dexamethasone enhanced functional recovery after sciatic nerve crush injury in rats. Biomed Res Int. 2015; 2015: 627923.
  22. Galeotti N, Bartolini A, Calvani M, et al. Acetyl-L-carnitine requires phospholipase C-IP3 pathway activation to induce antinociception. Neuropharmacology. 2004; 47(2): 286–294.
  23. Gao Y, Weng C, Wang X. Changes in nerve microcirculation following peripheral nerve compression. Neural Regen Res. 2013; 8(11): 1041–1047.
  24. Garcia LA, Hlaing SuM, Gutierrez RA, et al. Sildenafil attenuates inflammation and oxidative stress in pelvic ganglia neurons after bilateral cavernosal nerve damage. Int J Mol Sci. 2014; 15(10): 17204–17220.
  25. Gibson A. Phosphodiesterase 5 inhibitors and nitrergic transmission—from zaprinast to sildenafil. Eur J Pharmacol. 2001; 411(1-2): 1–10.
  26. Góth L. A simple method for determination of serum catalase activity and revision of reference range. Clinica Chimica Acta. 1991; 196(2-3): 143–151.
  27. Gülçin I. Antioxidant and antiradical activities of L-carnitine. Life Sci. 2006; 78(8): 803–811.
  28. Helvacioglu F, Kandemir E, Karabacak B, et al. Effect of creatine on rat sciatic nerve injury: a comparative ultrastructural study. Turk Neurosurg. 2016; 28(1): 128–136.
  29. Hlaing SuM, Garcia LA, Kovanecz I, et al. Sildenafil promotes neuroprotection of the pelvic ganglia neurones after bilateral cavernosal nerve resection in the rat. BJU Int. 2013; 111(1): 159–170.
  30. Duarte I, Lorenzetti BB, Ferreira SH. Peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. Eur J Pharmacol. 1990; 186(2-3): 289–293.
  31. Jeong KH, Lee TW, Ihm CG, et al. Effects of sildenafil on oxidative and inflammatory injuries of the kidney in streptozotocin-induced diabetic rats. Am J Nephrol. 2009; 29(3): 274–282.
  32. Karsidag S, Akcal A, Sahin S, et al. Neurophysiological and morphological responses to treatment with acetyl-L-carnitine in a sciatic nerve injury model: preliminary data. J Hand Surg Eur Vol. 2012; 37(6): 529–536.
  33. Kabiri M, Oraee-Yazdani S, Shafiee A, et al. Neuroregenerative effects of olfactory ensheathing cells transplanted in a multi-layered conductive nanofibrous conduit in peripheral nerve repair in rats. J Biomed Sci. 2015; 22(1).
  34. Khan A, Faruqi N, Ansari M. Effects of hydrocortisone on the sciatic nerve crush injury in adult rat: a light microscopic study. Curr Neurobiol. 2014; 5(1, 2): 11–16.
  35. Khan A, Ajmal M, Faizal M. Effects of vitamin C on regeneration of sciatic nerve crush injury in adult rats: a light microscopic study. JIARM. 2015; 3(8): 68–77.
  36. Kidd PM. Alzheimer's disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Altern Med Rev. 2008; 13(2): 85–115.
  37. Kim TH, Yoon SJ, Lee WC, et al. Protective effect of GCSB-5, an herbal preparation, against peripheral nerve injury in rats. J Ethnopharmacol. 2011; 136(2): 297–304.
  38. Kocaoğlu S, Aktaş Ö, Zengi O, et al. Effects of alpha lipoic acid on motor function and antioxidant enzyme activity of nerve tissue after sciatic nerve crush injury in rats. Turk Neurosurg. 2017 [Epub ahead of print].
  39. Korkmaz MF, Parlakpınar H, Ceylan MF, et al. The effect of sildenafil on recuperation from sciatic nerve injury in rats. Balkan Med J. 2016; 33(2): 204–211.
  40. Li HF, Wang YR, Huo HP, et al. Neuroprotective effects of ultrasound-guided nerve growth factor injections after sciatic nerve injury. Neural Regen Res. 2015; 10(11): 1846–1855.
  41. Li R, Wu J, Lin Z, et al. Single injection of a novel nerve growth factor coacervate improves structural and functional regeneration after sciatic nerve injury in adult rats. Exp Neurol. 2017; 288: 1–10.
  42. Marconi S, Castiglione G, Turano E, et al. Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush. Tissue Eng Part A. 2012; 18(11-12): 1264–1272.
  43. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem. 1978; 86(1): 271–278.
  44. Mixcoatl-Zecuatl T, Aguirre-Bañuelos P, Granados-Soto V. Sildenafil produces antinociception and increases morphine antinociception in the formalin test. Eur J Pharmacol. 2000; 400(1): 81–87.
  45. Morani A, Bodhankar S. Neuroprotective effect of vitamin E acetate in models of mononeuropathy in rats. Neuroanatomy. 2008; 7: 33–37.
  46. Namazi H, Emami MJ, Dehghani Nazhvani F, et al. Simvastatin vs. L-Carnitine: An experimental study on optimizing nerve repair. Turk Neurosurg. 2019 [Epub ahead of print].
  47. Navarro X, Vivó M, Valero-Cabré A. Neural plasticity after peripheral nerve injury and regeneration. Prog Neurobiol. 2007; 82(4): 163–201.
  48. Omura K, Ohbayashi M, Sano M, et al. The recovery of blood-nerve barrier in crush nerve injury--a quantitative analysis utilizing immunohistochemistry. Brain Res. 2004; 1001(1-2): 13–21.
  49. Pan HC, Yang DY, Ho SP, et al. Escalated regeneration in sciatic nerve crush injury by the combined therapy of human amniotic fluid mesenchymal stem cells and fermented soybean extracts, Natto. J Biomed Sci. 2009; 16: 75.
  50. Patil CS, Singh VP, Kulkarni SK. Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats. Pharmacol Rep. 2006; 58(3): 373–380.
  51. Pettegrew JW, Levine J, McClure RJ. Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression. Mol Psychiatry. 2000; 5(6): 616–632.
  52. Ragy MM. Effect of exposure and withdrawal of 900-MHz-electromagnetic waves on brain, kidney and liver oxidative stress and some biochemical parameters in male rats. Electromagn Biol Med. 2015; 34(4): 279–284.
  53. Ramli D, Aziz I, Mohamad M, et al. The changes in rats with sciatic nerve crush injury supplemented with evening primrose oil: behavioural, morphologic, and morphometric analysis. Evid Based Complement Alternat Med. 2017; 2017: 3476407.
  54. Roglio I, Bianchi R, Gotti S, et al. Neuroprotective effects of dihydroprogesteroone in an experimental model of nerve crush injury. Neuroscience. 2008; 155: 673–685.
  55. Rump TJ, Abdul Muneer PM, Szlachetka AM, et al. Acetyl-L-carnitine protects neuronal function from alcohol-induced oxidative damage in the brain. Free Radic Biol Med. 2010; 49(10): 1494–1504.
  56. Senoglu M, Nacitarhan V, Kurutas EB, et al. Intraperitoneal Alpha-Lipoic Acid to prevent neural damage after crush injury to the rat sciatic nerve. J Brachial Plex Peripher Nerve Inj. 2009; 4: 22.
  57. Smith D, Tweed C, Fernyhough P, et al. Nuclear factor-kappaB activation in axons and Schwann cells in experimental sciatic nerve injury and its role in modulating axon regeneration: studies with etanercept. J Neuropathol Exp Neurol. 2009; 68(6): 691–700.
  58. Song C, Yang Z, Zhong M, et al. Sericin protects against diabetes-induced injuries in sciatic nerve and related nerve cells. Neural Regen Res. 2013; 8(6): 506–513.
  59. Stevens A, Wilson IG. The haematoxylin and eosin. In: Bancroft JD, Turner DR. Theory and practice of histological techniques. 4th ed. Churchill Livingstone, New York 1996: 99–112.
  60. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988; 34(3): 497–500.
  61. Tamaddonfard E, Farshid AA, Ahmadian E, et al. Crocin enhanced functional recovery after sciatic nerve crush injury in rats. Iran J Basic Med Sci. 2013; 16(1): 83–90.
  62. Tkalec M, Stambuk A, Srut M, et al. Oxidative and genotoxic effects of 900 MHz electromagnetic fields in the earthworm Eisenia fetida. Ecotoxicol Environ Saf. 2013; 90: 7–12.
  63. Tomassoni D, Di Cesare Mannelli L, Bramanti V, et al. Treatment with acetyl-L-carnitine exerts a neuroprotective effect in the sciatic nerve following loose ligation: a functional and microanatomical study. Neural Regen Res. 2018; 13(4): 692–698.
  64. Uthayathas S, Karuppagounder SS, Thrash BM, et al. Versatile effects of sildenafil: recent pharmacological applications. Pharmacol Rep. 2007; 59(2): 150–163.
  65. Vakharia KT, Lindsay RW, Knox C, et al. The effects of potential neuroprotective agents on rat facial function recovery following facial nerve injury. Otolaryngol Head Neck Surg. 2011; 144(1): 53–59.
  66. Wang Y, Shan Q, Meng Y, et al. Mrpl10 and Tbp are suitable reference genes for peripheral nerve crush injury. Int J Mol Sci. 2017; 18(2).
  67. Wilson ADH, Hart A, Wiberg M, et al. Acetyl-l-carnitine increases nerve regeneration and target organ reinnervation - a morphological study. J Plast Reconstr Aesthet Surg. 2010; 63(7): 1186–1195.
  68. Wilson ADH, Hart A, Brannstrom T, et al. Primary sensory neuronal rescue with systemic acetyl-L-carnitine following peripheral axotomy. A dose-response analysis. Br J Plast Surg. 2003; 56(8): 732–739.
  69. Xia Z, Tian X, Kong W, et al. Effects of L-carnitine on liver injury in rats and its impact on blood lipids. Int J Clin Exp Med. 2018; 11(9): 9768–9773.
  70. Yanardag R, Ozsoy-Sacan O, Ozdil S, et al. Combined effects of vitamin C, vitamin E, and sodium selenate supplementation on absolute ethanol-induced injury in various organs of rats. Int J Toxicol. 2007; 26(6): 513–523.
  71. Yildirim AE, Dalgic A, Divanlioglu D, et al. Biochemical and histopathological effects of catechin on experimental peripheral nerve injuries. Turk Neurosurg. 2015; 25(3): 453–460.
  72. Yuan W, Feng X. Immune cell distribution and immunoglobulin levels change following sciatic nerve injury in a rat model. Iran J Basic Med Sci. 2016; 19(7): 794–799.
  73. Yüce S, Cemal Gökçe E, Işkdemir A, et al. An experimental comparison of the effects of propolis, curcumin, and methylprednisolone on crush injuries of the sciatic nerve. Ann Plast Surg. 2015; 74(6): 684–692.
  74. Zhang Z, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009; 8(5): 491–500.
  75. Zhang Q, Nguyen P, Xu Q, et al. Neural progenitor-like cells induced from human gingiva-derived mesenchymal stem cells regulate myelination of schwann cells in rat sciatic nerve regeneration. Stem Cells Transl Med. 2017; 6(2): 458–470.
  76. Zochodne DW. The challenges and beauty of peripheral nerve regrowth. J Peripher Nerv Syst. 2012; 17(1): 1–18.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By  "Via Medica sp. z o.o." sp.k., Świętokrzyska 73, 80–180 Gdańsk, Poland

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl