Abstract
Purpose
Following tissue injury, melatonin is known to reduce detrimental effects of free radicals by stimulating antioxidant enzymes and also to inhibit posttraumatic polymorphonuclear infiltration. Beneficial effects after peripheral nerve injury have been suggested, but not studied in detail. Therefore, we aimed to elucidate the effects of melatonin on the recovery of the lesioned rat sciatic nerve by means of combined analysis.
Methods
A total number of 90 rats were randomly distributed into six groups: control (group 1), sham-operated (group 2), sciatic nerve cut (group 3), sciatic nerve cut + melatonin treatment (group 4), sciatic nerve crush (group 5), and sciatic nerve crush + melatonin treatment (group 6). Melatonin was administered intraperitoneally at a dose of 50 mg/kg/day for 6 weeks. Recovery of function was analyzed by assessment of the sciatic functional index based on walking track analysis, somatosensory evoked potentials, biochemical quantification of malondialdehyde, antioxidant enzymes levels, and ultrastructural analysis.
Results
Our data showed the beneficial effect of melatonin on sciatic nerve recovery. Rats treated with melatonin demonstrated better structural preservation of the myelin sheaths compared to the nontreated group. The biochemical analysis confirmed the beneficial effects of melatonin displaying lower lipid peroxidation and higher superoxide dismutase, catalase, and glutathione peroxidase activities in sciatic nerve samples in comparison to nontreated groups.
Conclusions
The beneficial effects of melatonin administration on the recovery of the cut and crush injured sciatic nerve may be attributed to its antioxidant properties. Based on these investigations, we think that our data would be helpful for clinicians who deal with peripheral nerve injuries.
Similar content being viewed by others
References
Agez L, Laurent V, Guerrero HY, Pevet P, Masson-Pevet M, Gauer F (2009) Endogenous melatonin provides an effective circadian message to both the suprachiasmatic nuclei and the pars tuberalis of the rat. J Pineal Res 46(1):95–105. doi:10.1111/j.1600-079X.2008.00636.x
Al Moutaery K, Arshaduddin M, Tariq M, Al Deeb S (1998) Functional recovery and vitamin E level following sciatic nerve crush injury in normal and diabetic rats. Int J Neurosci 96(3–4):245–254
Atik B, Erkutlu I, Tercan M, Buyukhatipoglu H, Bekerecioglu M, Pence S (2011) The effects of exogenous melatonin on peripheral nerve regeneration and collagen formation in rats. J Surg Res 166(2):330–336. doi:10.1016/j.jss.2009.06.002
Bain JR, Mackinnon SE, Hunter DA (1989) Functional evaluation of complete sciatic, peroneal, and posterior tibial nerve lesions in the rat. Plast Reconstr Surg 83(1):129–138
Baydas G, Reiter RJ, Nedzvetskii VS, Yasar A, Tuzcu M, Ozveren F, Canatan H (2003) Melatonin protects the central nervous system of rats against toluene-containing thinner intoxication by reducing reactive gliosis. Toxicol Lett 137(3):169–174
Bilici D, Akpinar E, Kiziltunc A (2002) Protective effect of melatonin in carrageenan-induced acute local inflammation. Pharmacol Res 46(2):133–139
Bubenik GA (2002) Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 47(10):2336–2348
Canu MH, Langlet C, Dupont E, Falempin M (2003) Effects of hypodynamia–hypokinesia on somatosensory evoked potentials in the rat. Brain Res 978(1–2):162–168
Cardinali DP, Rosner JM (1971) Metabolism of serotonin by the rat retina in vitro. J Neurochem 18(9):1769–1770
Carrillo-Vico A, Calvo JR, Abreu P, Lardone PJ, Garcia-Maurino S, Reiter RJ, Guerrero JM (2004) Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB J 18(3):537–539. doi:10.1096/fj.03-0694fje
Champier J, Claustrat B, Besancon R, Eymin C, Killer C, Jouvet A, Chamba G, Fevre-Montange M (1997) Evidence for tryptophan hydroxylase and hydroxy-indol-O-methyl-transferase mRNAs in human blood platelets. Life Sci 60(24):2191–2197
Chen KB, Lin AM, Chiu TH (2003) Oxidative injury to the locus coeruleus of rat brain: neuroprotection by melatonin. J Pineal Res 35(2):109–117
Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM (2000) Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res 28(4):193–202
Costantino G, Cuzzocrea S, Mazzon E, Caputi AP (1998) Protective effects of melatonin in zymosan-activated plasma-induced paw inflammation. Eur J Pharmacol 363(1):57–63
Cuzzocrea S, Zingarelli B, Gilad E, Hake P, Salzman AL, Szabo C (1997) Protective effect of melatonin in carrageenan-induced models of local inflammation: relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity. J Pineal Res 23(2):106–116
Dagum AB (1998) Peripheral nerve regeneration, repair, and grafting. J Hand Ther 11(2):111–117
de Medinaceli L, Freed WJ, Wyatt RJ (1982) An index of the functional condition of rat sciatic nerve based on measurements made from walking tracks. Exp Neurol 77(3):634–643
Desmedt JE, Cheron G (1980) Central somatosensory conduction in man: neural generators and interpeak latencies of the far-field components recorded from neck and right or left scalp and earlobes. Electroencephalogr Clin Neurophysiol 50(5–6):382–403
Drobnik J, Dabrowski R (1996) Melatonin suppresses the pinealectomy-induced elevation of collagen content in a wound. Cytobios 85(340):51–58
El-Abhar HS, Shaalan M, Barakat M, El-Denshary ES (2002) Effect of melatonin and nifedipine on some antioxidant enzymes and different energy fuels in the blood and brain of global ischemic rats. J Pineal Res 33(2):87–94
Esposito E, Cuzzocrea S (2010) Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol 8(3):228–242. doi:10.2174/157015910792246155
Esrefoglu M, Gul M, Parlakpinar H, Acet A (2005) Effects of melatonin and caffeic acid phenethyl ester on testicular injury induced by myocardial ischemia/reperfusion in rats. Fundam Clin Pharmacol 19(3):365–372. doi:10.1111/j.1472-8206.2005.00331.x
Fee DB, Swartz KR, Scheff N, Roberts K, Gabbita P, Scheff S (2010) Melatonin-analog, beta-methyl-6-chloromelatonin, supplementation in spinal cord injury. Brain Res 1340:81–85. doi:10.1016/j.brainres.2010.04.047
Fujimoto T, Nakamura T, Ikeda T, Takagi K (2000) Potent protective effects of melatonin on experimental spinal cord injury. Spine (Phila Pa 1976) 25(7):769–775
Garcia-Navarro A, Gonzalez-Puga C, Escames G, Lopez LC, Lopez A, Lopez-Cantarero M, Camacho E, Espinosa A, Gallo MA, Acuna-Castroviejo D (2007) Cellular mechanisms involved in the melatonin inhibition of HT-29 human colon cancer cell proliferation in culture. J Pineal Res 43(2):195–205. doi:10.1111/j.1600-079X.2007.00463.x
Gaudet AD, Popovich PG, Ramer MS (2011) Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation 8(1):110. doi:10.1186/1742-2094-8-110
Gramsbergen A, IJkema-Paassen J, Meek MF (2000) Sciatic nerve transection in the adult rat: abnormal EMG patterns during locomotion by aberrant innervation of hindleg muscles. Exp Neurol 161(1):183–193. doi:10.1006/exnr.1999.7233
Gupta YK, Gupta M, Kohli K (2003) Neuroprotective role of melatonin in oxidative stress vulnerable brain. Indian J Physiol Pharmacol 47(4):373–386
Hall ED, Braughler JM (1982) Effects of intravenous methylprednisolone on spinal cord lipid peroxidation and Na+ + K+)-ATPase activity. Dose–response analysis during 1st hour after contusion injury in the cat. J Neurosurg 57(2):247–253. doi:10.3171/jns.1982.57.2.0247
Hardeland R, Reiter RJ, Poeggeler B, Tan DX (1993) The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances. Neurosci Biobehav Rev 17(3):347–357
Huebner EA, Strittmatter SM (2009) Axon regeneration in the peripheral and central nervous systems. Results Probl Cell Differ 48:339–351. doi:10.1007/400_2009_19
Jou IM, Chang PJ, Wu HH, Wang PJ, Chu KS, Lin RM, Tsai YC (2004) A long-term analysis of the spinal somatosensory evoked potential of rats with sciatic constriction injury. Acta Anaesthesiol Taiwan 42(2):69–76
Kanda F, Jinnai K, Tada K, Fujita T (1989) Somatosensory evoked potentials in rats with acute uremia. Jpn J Med 28(6):687–691
Kaptanoglu E, Tuncel M, Palaoglu S, Konan A, Demirpence E, Kilinc K (2000) Comparison of the effects of melatonin and methylprednisolone in experimental spinal cord injury. J Neurosurg 93(1 Suppl):77–84
Kawakami Y, Suzuki H, Dong WK (1989) Assessment of peripheral nerve crush injury with cortical somatosensory evoked potentials in the cat. Exp Neurol 103(2):146–153
Khalil Z, Khodr B (2001) A role for free radicals and nitric oxide in delayed recovery in aged rats with chronic constriction nerve injury. Free Radic Biol Med 31(4):430–439
Konat GW, Wiggins RC (1985) Effect of reactive oxygen species on myelin membrane proteins. J Neurochem 45(4):1113–1118
Kondoh T, Uneyama H, Nishino H, Torii K (2002) Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats. Life Sci 72(4–5):583–590
Kotler M, Rodriguez C, Sainz RM, Antolin I, Menendez-Pelaez A (1998) Melatonin increases gene expression for antioxidant enzymes in rat brain cortex. J Pineal Res 24(2):83–89
Lee YM, Chen HR, Hsiao G, Sheu JR, Wang JJ, Yen MH (2002) Protective effects of melatonin on myocardial ischemia/reperfusion injury in vivo. J Pineal Res 33(2):72–80
Leon J, Acuna-Castroviejo D, Escames G, Tan DX, Reiter RJ (2005) Melatonin mitigates mitochondrial malfunction. J Pineal Res 38(1):1–9. doi:10.1111/j.1600-079X.2004.00181.x
Liu C, Fukuhara C, Wessel JH 3rd, Iuvone PM, Tosini G (2004) Localization of Aa-nat mRNA in the rat retina by fluorescence in situ hybridization and laser capture microdissection. Cell Tissue Res 315(2):197–201. doi:10.1007/s00441-003-0822-1
Love S (1999) Oxidative stress in brain ischemia. Brain Pathol 9(1):119–131
Maldonado MD, Murillo-Cabezas F, Calvo JR, Lardone PJ, Tan DX, Guerrero JM, Reiter RJ (2007) Melatonin as pharmacologic support in burn patients: a proposed solution to thermal injury-related lymphocytopenia and oxidative damage. Crit Care Med 35(4):1177–1185. doi:10.1097/01.CCM.0000259380.52437.E9
Maldonado MD, Murillo-Cabezas F, Terron MP, Flores LJ, Tan DX, Manchester LC, Reiter RJ (2007) The potential of melatonin in reducing morbidity–mortality after craniocerebral trauma. J Pineal Res 42(1):1–11. doi:10.1111/j.1600-079X.2006.00376.x
Maldonado MD, Siu AW, Sanchez-Hidalgo M, Acuna-Castroviejo D, Escames G (2006) Melatonin and lipid uptake by murine fibroblasts: clinical implications. Neuro Endocrinol Lett 27(5):601–608
Menendez-Pelaez A, Poeggeler B, Reiter RJ, Barlow-Walden L, Pablos MI, Tan DX (1993) Nuclear localization of melatonin in different mammalian tissues: immunocytochemical and radioimmunoassay evidence. J Cell Biochem 53(4):373–382. doi:10.1002/jcb.240530415
Mennenga K, Ueck M, Reiter RJ (1991) Immunohistological localization of melatonin in the pineal gland and retina of the rat. J Pineal Res 10(3):159–164
Morera AL, Abreu P (2006) Seasonality of psychopathology and circannual melatonin rhythm. J Pineal Res 41(3):279–283. doi:10.1111/j.1600-079X.2006.00365.x
Naik AK, Tandan SK, Dudhgaonkar SP, Jadhav SH, Kataria M, Prakash VR, Kumar D (2006) Role of oxidative stress in pathophysiology of peripheral neuropathy and modulation by N-acetyl-l-cysteine in rats. Eur J Pain 10(7):573–579. doi:10.1016/j.ejpain.2005.08.006
Nam E, Lee SM, Koh SE, Joo WS, Maeng S, Im HI, Kim YS (2005) Melatonin protects against neuronal damage induced by 3-nitropropionic acid in rat striatum. Brain Res 1046(1–2):90–96. doi:10.1016/j.brainres.2005.03.053
Odaci E, Kaplan S (2009) Chapter 16: melatonin and nerve regeneration. Int Rev Neurobiol 87:317–335. doi:10.1016/S0074-7742(09)87016-5
Okatani Y, Wakatsuki A, Reiter RJ, Enzan H, Miyahara Y (2003) Protective effect of melatonin against mitochondrial injury induced by ischemia and reperfusion of rat liver. Eur J Pharmacol 469(1–3):145–152
Panjwani NA, Harding JJ (1978) Isolation and hydroxylysine glycoside content of some cyanogen bromide-cleaved fragments of collagen from bovine corneal stroma. Biochem J 171(3):687–695
Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F (1994) Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci 55(15):PL271–PL276
Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC (1993) Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis. J Pineal Res 14(4):151–168
Radak Z, Zhao Z, Goto S, Koltai E (2011) Age-associated neurodegeneration and oxidative damage to lipids, proteins and DNA. Mol Aspects Med 32(4–6):305–315. doi:10.1016/j.mam.2011.10.010
Reiter RJ (1996) Functional diversity of the pineal hormone melatonin: its role as an antioxidant. Exp Clin Endocrinol Diabetes 104(1):10–16. doi:10.1055/s-0029-1211415
Reiter RJ (2000) Melatonin: lowering the high price of free radicals. News Physiol Sci 15:246–250
Reiter RJ, Acuna-Castroviejo D, Tan DX, Burkhardt S (2001) Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Ann N Y Acad Sci 939:200–215
Reiter RJ, Tan DX, Gitto E, Sainz RM, Mayo JC, Leon J, Manchester LC, Vijayalaxmi KE, Kilic U (2004) Pharmacological utility of melatonin in reducing oxidative cellular and molecular damage. Pol J Pharmacol 56(2):159–170
Reiter RJ, Tan DX, Jou MJ, Korkmaz A, Manchester LC, Paredes SD (2008) Biogenic amines in the reduction of oxidative stress: melatonin and its metabolites. Neuro Endocrinol Lett 29(4):391–398
Reiter RJ, Tan DX, Poeggeler B, Menendez-Pelaez A, Chen LD, Saarela S (1994) Melatonin as a free radical scavenger: implications for aging and age-related diseases. Ann N Y Acad Sci 719:1–12
Rogerio F, de Souza QL, Teixeira SA, Oliveira AL, de Nucci G, Langone F (2002) Neuroprotective action of melatonin on neonatal rat motoneurons after sciatic nerve transection. Brain Res 926(1–2):33–41
Romero FJ, Monsalve E, Hermenegildo C, Puertas FJ, Higueras V, Nies E, Segura-Aguilar J, Roma J (1991) Oxygen toxicity in the nervous tissue: comparison of the antioxidant defense of rat brain and sciatic nerve. Neurochem Res 16(2):157–161
Roth J, Shtokman J, Shamir MH, Nissan M, Shchetinkov L, Trejo LL, Rochkind S (2011) Regeneration of the transected rat sciatic nerve after suturing or adhesion with cyanoacrylate glue. J Neurosurg 114(1):245–252. doi:10.3171/2010.7.JNS091266
Salie R, Harper I, Cillie C, Genade S, Huisamen B, Moolman J, Lochner A (2001) Melatonin protects against ischaemic–reperfusion myocardial damage. J Mol Cell Cardiol 33(2):343–357. doi:10.1006/jmcc.2000.1306
Sanchez-Hidalgo M, Lu Z, Tan DX, Maldonado MD, Reiter RJ, Gregerman RI (2007) Melatonin inhibits fatty acid-induced triglyceride accumulation in ROS17/2.8 cells: implications for osteoblast differentiation and osteoporosis. Am J Physiol Regul Integr Comp Physiol 292(6):R2208–R2215. doi:10.1152/ajpregu.00013.2007
Sayan H, Ozacmak VH, Ozen OA, Coskun O, Arslan SO, Sezen SC, Aktas RG (2004) Beneficial effects of melatonin on reperfusion injury in rat sciatic nerve. J Pineal Res 37(3):143–148. doi:10.1111/j.1600-079X.2004.00145.x
Shamir MH, Rochkind S, Sandbank J, Alon M (2001) Double-blind randomized study evaluating regeneration of the rat transected sciatic nerve after suturing and postoperative low-power laser treatment. J Reconstr Microsurg 17(2):133–137. doi:10.1055/s-2001-12702, discussion 138
Shokouhi G, Tubbs RS, Shoja MM, Hadidchi S, Ghorbanihaghjo A, Roshangar L, Farahani RM, Mesgari M, Oakes WJ (2008) Neuroprotective effects of high-dose vs low-dose melatonin after blunt sciatic nerve injury. Childs Nerv Syst 24(1):111–117. doi:10.1007/s00381-007-0366-x
Skaper SD, Floreani M, Ceccon M, Facci L, Giusti P (1999) Excitotoxicity, oxidative stress, and the neuroprotective potential of melatonin. Ann N Y Acad Sci 890:107–118
Slominski A, Fischer TW, Zmijewski MA, Wortsman J, Semak I, Zbytek B, Slominski RM, Tobin DJ (2005) On the role of melatonin in skin physiology and pathology. Endocrine 27(2):137–148. doi:10.1385/ENDO:27:2:137
Soybir G, Topuzlu C, Odabas O, Dolay K, Bilir A, Koksoy F (2003) The effects of melatonin on angiogenesis and wound healing. Surg Today 33(12):896–901. doi:10.1007/s00595-003-2621-3
Subramanian P, Mirunalini S, Pandi-Perumal SR, Trakht I, Cardinali DP (2007) Melatonin treatment improves the antioxidant status and decreases lipid content in brain and liver of rats. Eur J Pharmacol 571(2–3):116–119. doi:10.1016/j.ejphar.2007.06.011
Szczepanik M (2007) Melatonin and its influence on immune system. J Physiol Pharmacol 58(Suppl 6):115–124
Taupin P (2008) Adult neurogenesis, neuroinflammation and therapeutic potential of adult neural stem cells. Int J Med Sci 5(3):127–132
Tomas-Zapico C, Coto-Montes A (2005) A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J Pineal Res 39(2):99–104. doi:10.1111/j.1600-079X.2005.00248.x
Urbanchek MS, Chung KC, Asato H, Washington LN, Kuzon WM Jr (1999) Rat walking tracks do not reflect maximal muscle force capacity. J Reconstr Microsurg 15(2):143–149. doi:10.1055/s-2007-1000085
Ustundag B, Kazez A, Demirbag M, Canatan H, Halifeoglu I, Ozercan IH (2000) Protective effect of melatonin on antioxidative system in experimental ischemia–reperfusion of rat small intestine. Cell Physiol Biochem 10(4):229–236
Wasowicz W, Neve J, Peretz A (1993) Optimized steps in fluorometric determination of thiobarbituric acid-reactive substances in serum: importance of extraction pH and influence of sample preservation and storage. Clin Chem 39(12):2522–2526
Weichselbaum R, Patel M, Das Gupta TK (1975) Influence of the pineal on wound healing. Nature 254(5498):349
Zencirci SG, Bilgin MD, Yaraneri H (2010) Electrophysiological and theoretical analysis of melatonin in peripheral nerve crush injury. J Neurosci Methods 191(2):277–282. doi:10.1016/j.jneumeth.2010.07.008
Acknowledgments
This study is a part of a MSc thesis and supported by Scientific Research Projects Coordination Unit of Akdeniz University (grant number: 2010.02.0122.015). The authors thank the staff of the Animal Care Laboratory for their technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kaya, Y., Sarıkcıoğlu, L., Aslan, M. et al. Comparison of the beneficial effect of melatonin on recovery after cut and crush sciatic nerve injury: a combined study using functional, electrophysiological, biochemical, and electron microscopic analyses. Childs Nerv Syst 29, 389–401 (2013). https://doi.org/10.1007/s00381-012-1936-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00381-012-1936-0