Document Type : Research articles


1 Neurosciences Research Center, Tabriz University of Medical sciences, Tabriz, Iran

2 Department of Pharmacology and Toxicology, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran


Background: Spinal Cord Injury (SCI) is one of the leading causes of severe neurological deficits worldwide. The pathophysiology of SCI includes a primary injury followed by a cascade of secondary biochemical and cellular changes. Current pharmacological options are limited for significant recovery from SCI. The ?-lactam antibiotic ceftriaxone (CEF) and N-acetylcysteine (NAC) have shown to induce neuroprotection in animal models of neurodegenerative disorders.
Objectives: This study aimed to evaluate the effects of CEF, NAC, and their combination on the functional recovery and histological damage in experimental SCI.
Methods: Rats were randomly divided into four groups (n = 7): Saline, CEF, NAC, and CEF + NAC. Then, SCI was performed on rats under general anesthesia using the Neurosciences Research Center (NSRC) impactor. Locomotor recovery following SCI was monitored using the locomotor rating scale of Basso, Beattie, and Bresnahan (BBB). At the end of the study, all rats were sacrificed, and spinal cord cross-sections were stained with hematoxylin and eosin for histopathological evaluation.
Results: The CEF and NAC administration, either alone or in combination (CEF + NAC), significantly improved locomotor recovery following SCI in rats when compared to the saline group. The histological analysis showed that the severity of histopathological lesion in the spinal cord of rats was significantly lower in the CEF, NAC, and CEF + NAC groups than in the saline group.
Conclusions: Treatment with CEF and NAC, either separately or in combination, promotes locomotor recovery following SCI, which is associated with the effective reduction of the histopathological lesion.


  1. Hayta E, Elden H. Acute spinal cord injury: A review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention. J Chem Neuroanat. 2018;87:25-31. doi: 10.1016/j.jchemneu.2017.08.001. [PubMed: 28803968].
  2. Hurlbert RJ, Hadley MN, Walters BC, Aarabi B, Dhall SS, Gelb DE, et al. Pharmacological therapy for acute spinal cord injury. Neurosurgery. 2015;76 Suppl 1:S71-83. doi: 10.1227/01.neu.0000462080.04196.f7. [PubMed: 25692371].
  3. Evaniew N, Belley-Côté EP, Fallah N, Noonan VK, Rivers CS, Dvorak MF. Methylprednisolone for the Treatment of Patients with Acute Spinal Cord Injuries: A Systematic Review and Meta-Analysis. Journal of neurotrauma. 2016;33(5):468-81. doi: 10.1089/neu.2015.4192. [PubMed: 26529320].
  4. Rosado IR, Lavor MS, Alves EG, Fukushima FB, Oliveira KM, Silva CM, et al. Effects of methylprednisolone, dantrolene, and their combination on experimental spinal cord injury. Int J Clin Exp Pathol. 2014;7(8):4617-26. [PubMed: 25197334]. [PubMed Central: PMC4152024].
  5. Rouanet C, Reges D, Rocha E, Gagliardi V, Silva GS. Traumatic spinal cord injury: current concepts and treatment update. Arq Neuropsiquiatr. 2017;75(6):387-93. doi: 10.1590/0004-282x20170048. [PubMed: 28658409].
  6. Wei J, Pan X, Pei Z, Wang W, Qiu W, Shi Z, et al. The beta-lactam antibiotic, ceftriaxone, provides neuroprotective potential via anti-excitotoxicity and anti-inflammation response in a rat model of traumatic brain injury. J Trauma Acute Care Surg. 2012;73(3):654-60. doi: 10.1097/TA.0b013e31825133c0. [PubMed: 22710775].
  7. Hsieh MH, Meng WY, Liao WC, Weng JC, Li HH, Su HL, et al. Ceftriaxone reverses deficits of behavior and neurogenesis in an MPTP-induced rat model of Parkinson's disease dementia. Brain Res Bull. 2017;132:129-38. doi: 10.1016/j.brainresbull.2017.05.015. [PubMed: 28576659].
  8. Cui C, Cui Y, Gao J, Sun L, Wang Y, Wang K, et al. Neuroprotective effect of ceftriaxone in a rat model of traumatic brain injury. Neurol Sci. 2014;35(5):695-700. doi: 10.1007/s10072-013-1585-4. [PubMed: 24277205].
  9. Kim SY, Jones TA. The effects of ceftriaxone on skill learning and motor functional outcome after ischemic cortical damage in rats. Restor Neurol Neurosci. 2013;31(1):87-97. doi: 10.3233/rnn-2012-120245. [PubMed: 23047495]. [PubMed Central: PMC4433287].
  10. Tajkey J, Biglari A, Habibi Asl B, Ramazani A, Mazloomzadeh S. Comparative Study on the Effects of Ceftriaxone and Monocytes on Recovery after Spinal Cord Injury in Rat. Adv Pharm Bull. 2015;5(2):189-94. doi: 10.15171/apb.2015.026. [PubMed: 26236656]. [PubMed Central: PMC4517078].
  11. Gunther M, Davidsson J, Plantman S, Norgren S, Mathiesen T, Risling M. Neuroprotective effects of N-acetylcysteine amide on experimental focal penetrating brain injury in rats. J Clin Neurosci. 2015;22(9):1477-83. doi: 10.1016/j.jocn.2015.03.025. [PubMed: 26100161].
  12. Olakowska E, Marcol W, Wlaszczuk A, Woszczycka-Korczynska I, Lewin-Kowalik J. The neuroprotective effect of N-acetylcysteine in spinal cord-injured rats. Adv Clin Exp Med. 2017;26(9):1329-34. doi: 10.17219/acem/65478. [PubMed: 29442452].
  13. Karalija A, Novikova LN, Kingham PJ, Wiberg M, Novikov LN. Neuroprotective effects of N-acetyl-cysteine and acetyl-L-carnitine after spinal cord injury in adult rats. PLoS One. 2012;7(7). e41086. doi: 10.1371/journal.pone.0041086. [PubMed: 22815926]. [PubMed Central: PMC3398872].
  14. Ghorbani M, Shahabi P, Ebrahimi-kalan A, Soltani-Zangbar H, Mahmoudi J, Bani S, et al. Induction of traumatic brain and spinal cord injury models in rat using a modified impactor device. Physiology and Pharmacology. 2018;22(4):228-39.
  15. Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma. 1995;12(1):1-21. doi: 10.1089/neu.1995.12.1. [PubMed: 7783230].
  16. Liu J, Zhang C, Liu Z, Zhang J, Xiang Z, Sun T. Honokiol downregulates Kruppel-like factor 4 expression, attenuates inflammation, and reduces histopathology after spinal cord injury in rats. Spine (Phila Pa 1976). 2015;40(6):363-8. doi: 10.1097/brs.0000000000000758. [PubMed: 25774462].
  17. Kwon BK, Tetzlaff W, Grauer JN, Beiner J, Vaccaro AR. Pathophysiology and pharmacologic treatment of acute spinal cord injury. Spine J. 2004;4(4):451-64. doi: 10.1016/j.spinee.2003.07.007. [PubMed: 15246307].
  18. Krzyzanowska W, Pomierny B, Bystrowska B, Pomierny-Chamiolo L, Filip M, Budziszewska B, et al. Ceftriaxone- and N-acetylcysteine-induced brain tolerance to ischemia: Influence on glutamate levels in focal cerebral ischemia. PLoS One. 2017;12(10). e0186243. doi: 10.1371/journal.pone.0186243. [PubMed: 29045497]. [PubMed Central: PMC5646803].
  19. Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005;433(7021):73-7. doi: 10.1038/nature03180. [PubMed: 15635412].
  20. Guerriero RM, Giza CC, Rotenberg A. Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep. 2015;15(5):27. doi: 10.1007/s11910-015-0545-1. [PubMed: 25796572]. [PubMed Central: PMC4640931].
  21. Ramos KM, Lewis MT, Morgan KN, Crysdale NY, Kroll JL, Taylor FR, et al. Spinal upregulation of glutamate transporter GLT-1 by ceftriaxone: therapeutic efficacy in a range of experimental nervous system disorders. Neuroscience. 2010;169(4):1888-900. doi: 10.1016/j.neuroscience.2010.06.014. [PubMed: 20547213].
  22. Azbill RD, Mu X, Bruce-Keller AJ, Mattson MP, Springer JE. Impaired mitochondrial function, oxidative stress and altered antioxidant enzyme activities following traumatic spinal cord injury. Brain Res. 1997;765(2):283-90. [PubMed: 9313901].
  23. Krzyzanowska W, Pomierny B, Budziszewska B, Filip M, Pera J. N-Acetylcysteine and Ceftriaxone as Preconditioning Strategies in Focal Brain Ischemia: Influence on Glutamate Transporters Expression. Neurotox Res. 2016;29(4):539-50. doi: 10.1007/s12640-016-9602-z. [PubMed: 26861954]. [PubMed Central: PMC4820483].
  24. Karalija A, Novikova LN, Kingham PJ, Wiberg M, Novikov LN. The effects of N-acetyl-cysteine and acetyl-L-carnitine on neural survival, neuroinflammation and regeneration following spinal cord injury. Neuroscience. 2014;269:143-51. doi: 10.1016/j.neuroscience.2014.03.042. [PubMed: 24680856].
  25. Cakir O, Erdem K, Oruc A, Kilinc N, Eren N. Neuroprotective effect of N-acetylcysteine and hypothermia on the spinal cord ischemia-reperfusion injury. Cardiovasc Surg. 2003;11(5):375-9. doi: 10.1016/s0967-2109(03)00077-2. [PubMed: 12958548].
  26. Patel SP, Sullivan PG, Pandya JD, Goldstein GA, VanRooyen JL, Yonutas HM, et al. N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma. Exp Neurol. 2014;257:95-105. doi: 10.1016/j.expneurol.2014.04.026. [PubMed: 24805071]. [PubMed Central: PMC4114148].
  27. Gurcay AG, Gurcan O, Kazanci A, Bozkurt I, Senturk S, Bodur E, et al. Comparative Biochemical and Motor Function Analysis of Alpha Lipoic Acid and N-Acetyl Cysteine Treatment on Rats with Experimental Spinal Cord Injury. Turk Neurosurg. 2016;26(1):119-26. doi: 10.5137/1019-5149.jtn.14594-15.0. [PubMed: 26768878].