Melatonin Ameliorates Radiation-induced Sciatic Nerve Injury

Author(s): Dheyauldeen Shabeeb*, Ahmed Eleojo Musa, Mansoor Keshavarz, Gholamreza Hassanzadeh, Mohammed Reza Hadian, Azin Nowrouzi, Alireza Shirazi*, Masoud Najafi.

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 1 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Radiotherapy is a treatment method for cancer mostly utilized for about 60% of cancer patients. Peripheral neuropathy is one of the severe complications of radiotherapy. Two stages of neuropathy will occur following irradiation; electrophysiological and biochemical variations as the first stage, while the second stage involves fibrosis of soft tissues surrounding the exposed nerve. This novel study aimed to investigate the radioprotective effects of melatonin against ionizing radiation-induced sciatic nerve damage.

Methods: 60 rats were randomly assigned to four groups; C (Control), M (Melatonin), R (Radiation), MR (Radiation + Melatonin). Their right legs were exposed to 30 Gy single dose gamma rays. Melatonin (100 mg/kg) was administered 30 min before irradiation and once daily (5 mg/kg) till the day of rats’ sacrifice. Their exposed nerve tissues were evaluated for biochemical changes in addition to Electromyography (EMG) and Nerve Conduction Study (NCS).

Results: 4, 12 and 20 weeks post-irradiation, EMG and NCS examinations in R group showed reduced Compound Muscle Action Potential (CMAP) representing axonal degeneration when compared with C and M groups. Prolonged latency and a decrease in Conduction Velocity (CV) gave an indication of demyelinating neuropathy at 12 and 20 weeks. EMG and NCS results of R group showed partial nerve lesion. Biochemical assessments showed that irradiation of sciatic nerve led to increased MDA level, as well as decreased CAT and SOD activities. However, in all cases, treatment with melatonin can reverse these effects.

Conclusion: We conclude that melatonin can improve electrophysiological, oxidative stress and antioxidant defense features of irradiated rats’ sciatic nerves. We would also recommend the use of melatonin in an optimal and safe dose. It should be administered over a long period of time for effective protection of the peripheral nerve tissues, as well as improving the therapeutic ratio of radiotherapy.

Keywords: Radiation, melatonin, neuropathy, peripheral nerve, sciatic nerve, radiotherapy.

[1]
Halperin, E.C.; Brady, L.W.; Perez, C.A.; Wazer, D.E. Perez & Brady’s principles and practice of radiation oncology; Lippincott Williams & Wilkins, 2013.
[2]
Delanian, S.; Lefaix, J-L.; Pradat, P-F. Radiation-induced neuropathy in cancer survivors. Radiother. Oncol., 2012, 105(3), 273-282.
[http://dx.doi.org/10.1016/j.radonc.2012.10.012] [PMID: 23245644]
[3]
Gikas, P.D.; Hanna, S.A.; Aston, W.; Kalson, N.S.; Tirabosco, R.; Saifuddin, A.; Cannon, S.R. Post-radiation sciatic neuropathy: A case report and review of the literature. World J. Surg. Oncol., 2008, 6(1), 130.
[http://dx.doi.org/10.1186/1477-7819-6-130] [PMID: 19077234]
[4]
Gosk, J.; Rutowski, R.; Reichert, P.; Rabczyński, J. Radiation-induced brachial plexus neuropathy-aetiopathogenesis, risk factors, differential diagnostics, symptoms and treatment. Folia Neuropathol., 2007, 45(1), 26-30.
[PMID: 17357008]
[5]
Zhang, B.; Su, Y.; Ai, G.; Wang, Y.; Wang, T.; Wang, F. Involvement of peroxiredoxin I in protecting cells from radiation-induced death. J. Radiat. Res. (Tokyo), 2005, 46(3), 305-312.
[http://dx.doi.org/10.1269/jrr.46.305] [PMID: 16210786]
[6]
Mansour, H.H.; Hafez, H.F.; Fahmy, N.M.; Hanafi, N. Protective effect of N-acetylcysteine against radiation induced DNA damage and hepatic toxicity in rats. Biochem. Pharmacol., 2008, 75(3), 773-780.
[http://dx.doi.org/10.1016/j.bcp.2007.09.018] [PMID: 18028880]
[7]
Gillette, E.; Mahler, P.; Powers, B.; Gillette, S.; Vujaskovic, Z. Late radiation injury to muscle and peripheral nerves. Int. J. Radiat. Oncol. Biol. Phys., 1995, 31(5), 1309-1318.
[http://dx.doi.org/10.1016/0360-3016(94)00422-H]
[8]
Mendes, D.G.; Nawalkar, R.R.; Eldar, S. Post-irradiation femoral neuropathy. A case report. J. Bone Joint Surg. Am., 1991, 73(1), 137-140.
[http://dx.doi.org/10.2106/00004623-199173010-00020] [PMID: 1985985]
[9]
Johansson, S.; Svensson, H.; Denekamp, J. Dose response and latency for radiation-induced fibrosis, edema, and neuropathy in breast cancer patients. Int. J. Radiat. Oncol. Biol. Phys., 2002, 52(5), 1207-1219.
[http://dx.doi.org/10.1016/S0360-3016(01)02743-2]
[10]
Johansson, S.; Svensson, H.; Denekamp, J. Timescale of evolution of late radiation injury after postoperative radiotherapy of breast cancer patients. Int. J. Radiat. Oncol. Biol. Phys., 2000, 48(3), 745-750.
[http://dx.doi.org/10.1016/S0360-3016(00)00674-X]
[11]
Gunderson, L.L.; Nelson, H.; Martenson, J.A.; Cha, S.; Haddock, M.; Devine, R.; Fieck, J.M.; Wolff, B.; Dozois, R.; O’Connell, M.J. Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation±5-FU. Int. J. Radiat. Oncol. Biol. Phys., 1997, 37(3), 601-614.
[12]
Birben, E.; Sahiner, U.M.; Sackesen, C.; Erzurum, S.; Kalayci, O. Oxidative stress and antioxidant defense. World Allergy Organ. J., 2012, 5(1), 9-19.
[http://dx.doi.org/10.1097/WOX.0b013e3182439613] [PMID: 23268465]
[13]
Chevion, S.; Or, R.; Berry, E.M. The antioxidant status of patients subjected to total body irradiation. Biochem. Mol. Biol. Int., 1999, 47(6), 1019-1027.
[PMID: 10410248]
[14]
Taysi, S.; Uslu, C.; Akcay, F.; Sutbeyaz, M.Y. Malondialdehyde and nitric oxide levels in the plasma of patients with advanced laryngeal cancer. Surg. Today, 2003, 33(9), 651-654.
[http://dx.doi.org/10.1007/s00595-002-2562-3] [PMID: 12928839]
[15]
Halliwell, B. Antioxidants in human health and disease. Annu. Rev. Nutr., 1996, 16(1), 33-50.
[http://dx.doi.org/10.1146/annurev.nu.16.070196.000341] [PMID: 8839918]
[16]
Victor, V.M.; McCreath, K.J.; Rocha, M. Recent progress in pharmacological research of antioxidants in pathological conditions: Cardiovascular health. Recent Patents Anti-Infect. Drug Disc., 2006, 1(1), 17-31.
[http://dx.doi.org/10.2174/157489106775244136] [PMID: 18221131]
[17]
Najafi, M.; Shirazi, A.; Motevaseli, E.; Geraily, G.; Norouzi, F.; Heidari, M.; Rezapoor, S. The melatonin immunomodulatory actions in radiotherapy. Biophys. Rev., 2017, 9(2), 139-148.
[http://dx.doi.org/10.1007/s12551-017-0256-8] [PMID: 28510090]
[18]
Najafi, M.; Shirazi, A.; Motevaseli, E.; Rezaeyan, A.H.; Salajegheh, A.; Rezapoor, S. Melatonin as an anti-inflammatory agent in radiotherapy. Inflammopharmacology, 2017, 25(4), 403-413.
[http://dx.doi.org/10.1007/s10787-017-0332-5] [PMID: 28255737]
[19]
Shirazi, A.; Ghobadi, G.; Ghazi-Khansari, M. A radiobiological review on melatonin: A novel radioprotector. J. Radiat. Res. (Tokyo), 2007, 48(4), 263-272.
[http://dx.doi.org/10.1269/jrr.06070] [PMID: 17641465]
[20]
Karbownik, M.; Reiter, R.J. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc. Soc. Exp. Biol. Med., 2000, 225(1), 9-22.
[http://dx.doi.org/10.1046/j.1525-1373.2000.22502.x] [PMID: 10998194]
[21]
Ohrnell, L.O.; Brånemark, R.; Nyman, J.; Nilsson, P.; Thomsen, P. Effects of irradiation on the biomechanics of osseointegration. An experimental in vivo study in rats. Scand. J. Plast. Reconstr. Surg. Hand Surg., 1997, 31(4), 281-293.
[http://dx.doi.org/10.3109/02844319709008974] [PMID: 9444704]
[22]
Daglioglu, E.; Serdar Dike, M.; Kilinc, K.; Erdogan, D.; Take, G.; Ergungor, F.; Okay, O.; Biyikli, Z. Neuroprotective effect of melatonin on experimental peripheral nerve injury: An electron microscopic and biochemical study. Cent. Eur. Neurosurg., 2009, 70(3), 109-114.
[http://dx.doi.org/10.1055/s-0029-1220712] [PMID: 19701868]
[23]
Atik, B.; Erkutlu, I.; Tercan, M.; Buyukhatipoglu, H.; Bekerecioglu, M.; Pence, S. The effects of exogenous melatonin on peripheral nerve regeneration and collagen formation in rats. J. Surg. Res., 2011, 166(2), 330-336.
[http://dx.doi.org/10.1016/j.jss.2009.06.002] [PMID: 20006352]
[24]
Shirazi, A.; Haddadi, G.; Minaee, B.; Sepehrizadeh, Z.; Mahdavi, S.; Jaberi, E.; Haddadi, M. Evaluation of melatonin for modulation of apoptosis-related genes in irradiated cervical spinal cord. Int. J. Low Radiat., 2010, 7(6), 436-445.
[http://dx.doi.org/10.1504/IJLR.2010.037665]
[25]
Reiter, R.J.; Tan, D-X.; Herman, T.S.; Thomas, C.R. Melatonin as a radioprotective agent: a review. Int. J. Radiat. Oncol. Biol. Phys., 2004, 59(3), 639-653.
[26]
Slominski, A.; Tobin, D.J.; Zmijewski, M.A.; Wortsman, J.; Paus, R. Melatonin in the skin: Synthesis, metabolism and functions. Trends Endocrinol. Metab., 2008, 19(1), 17-24.
[http://dx.doi.org/10.1016/j.tem.2007.10.007] [PMID: 18155917]
[27]
Fischer, T.W.; Slominski, A.; Zmijewski, M.A.; Reiter, R.J.; Paus, R. Melatonin as a major skin protectant: From free radical scavenging to DNA damage repair. Exp. Dermatol., 2008, 17(9), 713-730.
[http://dx.doi.org/10.1111/j.1600-0625.2008.00767.x] [PMID: 18643846]
[28]
Reiter, R.J.; Tan, D.X.; Manchester, L.C.; Qi, W. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: A review of the evidence. Cell Biochem. Biophys., 2001, 34(2), 237-256.
[http://dx.doi.org/10.1385/CBB:34:2:237] [PMID: 11898866]
[29]
Korte, N.; Schenk, H.C.; Grothe, C.; Tipold, A.; Haastert-Talini, K. Evaluation of periodic electrodiagnostic measurements to monitor motor recovery after different peripheral nerve lesions in the rat. Muscle Nerve, 2011, 44(1), 63-73.
[http://dx.doi.org/10.1002/mus.22023] [PMID: 21674522]
[30]
Siconolfi, L.B.; Seeds, N.W. Mice lacking tPA, uPA, or plasminogen genes showed delayed functional recovery after sciatic nerve crush. J. Neurosci., 2001, 21(12), 4348-4355.
[http://dx.doi.org/10.1523/JNEUROSCI.21-12-04348.2001] [PMID: 11404420]
[31]
Agthong, S.; Kaewsema, A.; Charoensub, T. Curcumin ameliorates functional and structural abnormalities in cisplatin-induced neuropathy. Exp. Neurobiol., 2015, 24(2), 139-145.
[http://dx.doi.org/10.5607/en.2015.24.2.139] [PMID: 26113793]
[32]
Esterbauer, H. Cheeseman, K.H. Methods in enzymology; Elsevier 1990, 186, 407-421.
[33]
Reboul, F.L. Radiotherapy and chemotherapy in locally advanced non-small cell lung cancer: Preclinical and early clinical data. Hematol. Oncol. Clin. North Am., 2004, 18(1), 41-53.
[http://dx.doi.org/10.1016/S0889-8588(03)00138-2] [PMID: 15005280]
[34]
Rose, T.; Garcia, E.; Bachand, F.; Kim, D.; Petrik, D.; Halperin, R.; Crook, J. QOL Comparison of acute side effects from a high dose rate vs. low dose rate prostate brachytherapy boost combined with external beam radiotherapy. Brachytherapy, 2015, 14, S36.
[http://dx.doi.org/10.1016/j.brachy.2015.02.245]
[35]
Savard, J.; Ivers, H.; Savard, M.H.; Morin, C.M. Cancer treatments and their side effects are associated with aggravation of insomnia: Results of a longitudinal study. Cancer, 2015, 121(10), 1703-1711.
[http://dx.doi.org/10.1002/cncr.29244] [PMID: 25677509]
[36]
Johansson, S.; Svensson, H.; Larsson, L-G.; Denekamp, J. Brachial plexopathy after postoperative radiotherapy of breast cancer patients-a long-term follow-up. Acta Oncol., 2000, 39(3), 373-382.
[http://dx.doi.org/10.1080/028418600750013140] [PMID: 10987234]
[37]
Killer, H.E.; Hess, K. Natural history of radiation-induced brachial plexopathy compared with surgically treated patients. J. Neurol., 1990, 237(4), 247-250.
[http://dx.doi.org/10.1007/BF00314628] [PMID: 2391547]
[38]
Calvo, W.; Forteza-Vila, J. Glycogen changes in bone marrow nerves after whole-body X-irradiation. Acta Neuropathol., 1972, 20(1), 78-83.
[http://dx.doi.org/10.1007/BF00687904] [PMID: 5020595]
[39]
Match, R.M. Radiation-induced brachial plexus paralysis. Arch. Surg., 1975, 110(4), 384-386.
[http://dx.doi.org/10.1001/archsurg.1975.01360100026005] [PMID: 1147755]
[40]
Mondrup, K.; Olsen, N.K.; Pfeiffer, P.; Rose, C. Clinical and electrodiagnostic findings in breast cancer patients with radiation-induced brachial plexus neuropathy. Acta Neurol. Scand., 1990, 81(2), 153-158.
[http://dx.doi.org/10.1111/j.1600-0404.1990.tb00952.x] [PMID: 2327236]
[41]
Pierce, S.M.; Recht, A.; Lingos, T.I.; Abner, A.; Vicini, F.; Silver, B.; Herzog, A.; Harris, J.R. Long-term radiation complications following conservative surgery (CS) and radiation therapy (RT) in patients with early stage breast cancer. Int. J. Radiat. Oncol. Biol. Phys., 1992, 23(5), 915-923.
[42]
Kinsella, T.J.; Deluca, A.M.; Barnes, M.; Anderson, W.; Terrill, R.; Sindelar, W.F. Threshold dose for peripheral neuropathy following intraoperative radiotherapy (IORT) in a large animal model. Int. J. Radiat. Oncol. Biol. Phys., 1991, 20(4), 697-701.
[43]
Vujaskovic, Z.; Gillette, S.M.; Powers, B.E.; LaRue, S.M.; Gillette, E.L.; Borak, T.B.; Scott, R.J.; Colacchio, T.A. Intraoperative radiation (IORT) injury to sciatic nerve in a large animal model. Radiother. Oncol., 1994, 30(2), 133-139.
[http://dx.doi.org/10.1016/0167-8140(94)90042-6] [PMID: 8184110]
[44]
Scaravilli, F.; Love, S.; Myers, R. X-irradiation impairs regeneration of peripheral nerve across a gap. J. Neurocytol., 1986, 15(4), 439-449.
[http://dx.doi.org/10.1007/BF01611727] [PMID: 3746354]
[45]
Stearns, M.P. The effect of irradiation on nerve grafting. Clin. Otolaryngol. Allied Sci., 1982, 7(3), 161-164.
[http://dx.doi.org/10.1111/j.1365-2273.1982.tb01577.x] [PMID: 7105448]
[46]
Brandt, K.; Evans, G.R.; Gürlek, A.; Savel, T.; Lohman, R.; Nabawi, A.; Williams, J.; Patrick, C.W.; Ang, K.K.; Lembo, T.; Tinkey, P.; Cromeens, D. The effects of preoperative irradiation on peripheral nerve regeneration. Ann. Plast. Surg., 1998, 40(3), 277-282.
[http://dx.doi.org/10.1097/00000637-199803000-00014] [PMID: 9523612]
[47]
Powell, S.; Cooke, J.; Parsons, C. Radiation-induced brachial plexus injury: Follow-up of two different fractionation schedules. Radiother. Oncol., 1990, 18(3), 213-220.
[http://dx.doi.org/10.1016/0167-8140(90)90057-4] [PMID: 2217869]
[48]
Bae, Y.S.; Oh, H.; Rhee, S.G.; Yoo, Y.D. Regulation of reactive oxygen species generation in cell signaling. Mol. Cells, 2011, 32(6), 491-509.
[http://dx.doi.org/10.1007/s10059-011-0276-3] [PMID: 22207195]
[49]
Allison, R.; Dicker, A. Minimizing morbidity in radiation oncology: A special issue from Future Oncology. Future Oncol., 2014, 10(15), 2303-2305.
[http://dx.doi.org/10.2217/fon.14.195] [PMID: 25525839]
[50]
Najafi, M.; Motevaseli, E.; Shirazi, A.; Geraily, G.; Rezaeyan, A.; Norouzi, F.; Rezapoor, S.; Abdollahi, H. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: Clinical implications. Int. J. Radiat. Biol., 2018, 94(4), 335-356.
[http://dx.doi.org/10.1080/09553002.2018.1440092] [PMID: 29504497]
[51]
Ghobadi, A.; Shirazi, A.; Najafi, M.; Kahkesh, M.H.; Rezapoor, S. Melatonin ameliorates radiation-induced oxidative stress at targeted and nontargeted lung tissue. J. Med. Phys., 2017, 42(4), 241-244.
[http://dx.doi.org/10.4103/jmp.JMP_60_17] [PMID: 29296038]
[52]
Martínez-Campa, C.; Menéndez-Menéndez, J.; Alonso-González, C.; González, A.; Álvarez-García, V.; Cos, S. What is known about melatonin, chemotherapy and altered gene expression in breast cancer. Oncol. Lett., 2017, 13(4), 2003-2014.
[http://dx.doi.org/10.3892/ol.2017.5712] [PMID: 28454355]
[53]
Erol, F.S.; Kaplan, M.; Tiftikci, M.; Yakar, H.; Ozercan, I.; Ilhan, N.; Topsakal, C. Comparison of the effects of octreotide and melatonin in preventing nerve injury in rats with experimental spinal cord injury. J. Clin. Neurosci., 2008, 15(7), 784-790.
[http://dx.doi.org/10.1016/j.jocn.2007.06.009] [PMID: 18407497]
[54]
Sinha, K.; Degaonkar, M.N.; Jagannathan, N.R.; Gupta, Y.K. Effect of melatonin on ischemia reperfusion injury induced by middle cerebral artery occlusion in rats. Eur. J. Pharmacol., 2001, 428(2), 185-192.
[http://dx.doi.org/10.1016/S0014-2999(01)01253-5] [PMID: 11675035]
[55]
Kondoh, T.; Uneyama, H.; Nishino, H.; Torii, K. Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats. Life Sci., 2002, 72(4-5), 583-590.
[http://dx.doi.org/10.1016/S0024-3205(02)02256-7] [PMID: 12467899]
[56]
Shabeeb, D.; Najafi, M.; Hasanzadeh, G.; Hadian, M.R.; Musa, A.E.; Shirazi, A. Electrophysiological measurements of diabetic peripheral neuropathy: A systematic review. Diabetes Metab. Syndr., 2018, 12(4), 591-600.
[http://dx.doi.org/10.1016/j.dsx.2018.03.026] [PMID: 29610062]
[57]
Shokouhi, G.; Tubbs, R.S.; Shoja, M.M.; Hadidchi, S.; Ghorbanihaghjo, A.; Roshangar, L.; Farahani, R.M.; Mesgari, M.; Oakes, W.J. Neuroprotective effects of high-dose vs low-dose melatonin after blunt sciatic nerve injury. Childs Nerv. Syst., 2008, 24(1), 111-117.
[http://dx.doi.org/10.1007/s00381-007-0366-x] [PMID: 17503055]
[58]
Wadd, N.J.; Lucraft, H.H. Brachial plexus neuropathy following mantle radiotherapy. Clin. Oncol. (R. Coll. Radiol.), 1998, 10(6), 399-400.
[http://dx.doi.org/10.1016/S0936-6555(98)80040-X] [PMID: 9890543]
[59]
Brennan, M.J. Breast cancer recurrence in a patient with a previous history of radiation injury of the brachial plexus: A case report. Arch. Phys. Med. Rehabil., 1995, 76(10), 974-976.
[http://dx.doi.org/10.1016/S0003-9993(95)80077-8] [PMID: 7487441]
[60]
Churn, M.; Clough, V.; Slater, A. Early onset of bilateral brachial plexopathy during mantle radiotherapy for Hodgkin’s disease. Clin. Oncol. (R. Coll. Radiol.), 2000, 12(5), 289-291.
[PMID: 11315711]
[61]
Shabeeb, D.; Najafi, M.; Keshavarz, M.; Musa, A.E.; Hassanzadeh, G.; Hadian, M.R.; Shirazi, A. Recent finding in repair of the peripheral nerve lesions using pharmacological agents: Common methods for evaluating the repair process. Cent. Nerv. Syst. Agents Med. Chem., 2018, 18(3), 161-172.
[62]
Farhood, B.; Goradel, N.H.; Mortezaee, K.; Khanlarkhani, N.; Salehi, E.; Nashtaei, M.S.; Shabeeb, D.; Musa, A.E.; Fallah, H.; Najafi, M. Intercellular communications-redox interactions in radiation toxicity; potential targets for radiation mitigation. J. Cell Commun. Signal., 2019, 13(1), 3-16.
[http://dx.doi.org/10.1007/s12079-018-0473-3] [PMID: 29911259]
[63]
Romero, F.J.; Monsalve, E.; Hermenegildo, C.; Puertas, F.J.; Higueras, V.; Nies, E.; Segura-Aguilar, J.; Romá, J. Oxygen toxicity in the nervous tissue: Comparison of the antioxidant defense of rat brain and sciatic nerve. Neurochem. Res., 1991, 16(2), 157-161.
[http://dx.doi.org/10.1007/BF00965704] [PMID: 1908956]
[64]
Subramanian, P.; Mirunalini, S.; Pandi-Perumal, S.R.; Trakht, I.; Cardinali, D.P. Melatonin treatment improves the antioxidant status and decreases lipid content in brain and liver of rats. Eur. J. Pharmacol., 2007, 571(2-3), 116-119.
[http://dx.doi.org/10.1016/j.ejphar.2007.06.011] [PMID: 17720153]
[65]
Reiter, R.J. Oxidative damage in the central nervous system: Protection by melatonin. Prog. Neurobiol., 1998, 56(3), 359-384.
[http://dx.doi.org/10.1016/S0301-0082(98)00052-5] [PMID: 9770244]
[66]
Fujimoto, T.; Nakamura, T.; Ikeda, T.; Takagi, K. Potent protective effects of melatonin on experimental spinal cord injury. Spine, 2000, 25(7), 769-775.
[http://dx.doi.org/10.1097/00007632-200004010-00003] [PMID: 10751286]
[67]
Reiter, R.J. Melatonin: Lowering the high price of free radicals. News Physiol. Sci., 2000, 15(5), 246-250.
[http://dx.doi.org/10.1152/physiologyonline.2000.15.5.246] [PMID: 11390919]
[68]
Salie, R.; Harper, I.; Cillie, C.; Genade, S.; Huisamen, B.; Moolman, J.; Lochner, A. Melatonin protects against ischaemic-reperfusion myocardial damage. J. Mol. Cell. Cardiol., 2001, 33(2), 343-357.
[http://dx.doi.org/10.1006/jmcc.2000.1306] [PMID: 11162138]
[69]
Cuzzocrea, S.; Reiter, R.J. Pharmacological actions of melatonin in acute and chronic inflammation. Curr. Top. Med. Chem., 2002, 2(2), 153-165.
[http://dx.doi.org/10.2174/1568026023394425] [PMID: 11899098]


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 17
ISSUE: 1
Year: 2020
Page: [21 - 30]
Pages: 10
DOI: 10.2174/1570180816666190617160434
Price: $65

Article Metrics

PDF: 14
HTML: 2