Ceftriaxone improves senile neurocognition damages induced by D-galactose in mice

Document Type: Original Article


1 Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

2 Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

3 Department of Anatomy, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

4 Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran

5 Research Center for Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran


Objective(s): Ceftriaxone (Cef), a beta-lactam antibiotic, is accompanied by antioxidant and anti-inflammatory properties. It has been shown that Cef has beneficial effects on Alzheimer’s disease. In the current investigation, the effect of Cef in a mice model of aging was investigated.
Materials and Methods: Forty male mice were equally aliquoted into four groups as follows: Control (as healthy normal animals), D-galactose (DG) group (treated with 500 mg/kg/day DG for 6 weeks), DG + Cef group (treated with DG plus Cef 200 mg/kg/day for 6 weeks), and Cef group (treated with Cef 200 mg/kg/day for 6 weeks). A battery of behavioral tests was done to evaluate age-related neurocognitive changes. The activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), as well as the level of malondialdehyde (MDA) in the brain, were measured by biochemical methods. Also, to determine the brain damage, histopathological alterations in the hippocampus were measured using hematoxylin and eosin (H&E) staining.
Results: Our results indicate that neurobehavioral dysfunctions of DG can be prevented by co-administration of Cef. We also found that Cef increases the activity of SOD, GPx, and CAT as well as decreasing the level of MDA in the brain of aged mice.
Conclusion: Based on our findings, Cef declines neurocognitive dysfunctions in the DG-induced model of aging, possibly through its antioxidative properties.


1. Shin KR, Kim MY, and Kim YH, Study on the lived experience of aging. Nurs Health Sci 2003; 5: 245-252.
2. Crivello NA, Rosenberg IH, Dallal GE, Bielinski D, and Joseph JA, Age-related changes in neutral sphingomyelin-specific phospholipase C activity in striatum, hippocampus, and frontal cortex: implication for sensitivity to stress and inflammation. Neurochem Int 2005; 47: 573-579.
3. Taghipour Z, Kaviani E, Kaeidi A, Shamsizadeh A, Hassanshahi J, and Fatemi I, Atorvastatin attenuates D-galactose-induced hepatorenal toxicity in mice: an experimental study with histopathological evaluations. Physiol Pharmacol 2019; 23: 36-43.
4. Harman D, Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956; 11: 298-300.
5. Fatemi I, Heydari S, Kaeidi A, Shamsizadeh A, Hakimizadeh E, Khaluoi A, et al. Metformin ameliorates the age-related changes of d-galactose administration in ovariectomized mice. Fundam Clin Pharmacol 2018; 32: 392-399.
6. Fatemi I, Khaluoi A, Kaeidi A, Shamsizadeh A, Heydari S, and Allahtavakoli MA, Protective effect of metformin on D-galactose-induced aging model in mice. Iran J Basic Med Sci 2018; 21: 19-25.
7. Nelson SJ, Boies EG, and Shackelford PG, Ceftriaxone in the treatment of infections caused by Staphylococcus aureus in children. Pediatr Infect Dis 1985; 4: 27-31.
8. Amin B, Hajhashemi V, Abnous K, and Hosseinzadeh H, Ceftriaxone, a beta-lactam antibiotic, modulates apoptosis pathways and oxidative stress in a rat model of neuropathic pain. Biomed Res Int 2014; 2014: 937568.
9. Kaur B and Prakash A, Ceftriaxone attenuates glutamate-mediated neuro-inflammation and restores BDNF in MPTP model of Parkinson’s disease in rats. Pathophysiology 2017; 24: 71-79.
10. Chu K, Lee ST, Sinn DI, Ko SY, Kim EH, Kim JM, et al. Pharmacological induction of ischemic tolerance by glutamate transporter-1 (EAAT2) upregulation. Stroke 2007; 38: 177-182.
11. Nizzardo M, Nardini M, Ronchi D, Salani S, Donadoni C, Fortunato F, et al. Beta-lactam antibiotic offers neuroprotection in a spinal muscular atrophy model by multiple mechanisms. Exp Neurol 2011; 229: 214-225.
12. Sari Y, Prieto AL, Barton SJ, Miller BR, and Rebec GV, Ceftriaxone-induced up-regulation of cortical and striatal GLT1 in the R6/2 model of Huntington’s disease. J Biomed Sci 2010; 17: 62-67.
13. 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: 73-77.
14. Yang J, Li MX, Luo Y, Chen T, Liu J, Fang P, et al. Chronic ceftriaxone treatment rescues hippocampal memory deficit in AQP4 knockout mice via activation of GLT-1. Neuropharmacology 2013; 75: 213-222.
15. Leung TC, Lui CN, Chen LW, Yung WH, Chan YS, and Yung KK, Ceftriaxone ameliorates motor deficits and protects dopaminergic neurons in 6-hydroxydopamine-lesioned rats. ACS Chem Neurosci 2012; 3: 22-30.
16. Zumkehr J, Rodriguez-Ortiz CJ, Cheng D, Kieu Z, Wai T, Hawkins C, et al. Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer’s disease. Neurobiol Aging 2015; 36: 2260-2271.
17. Kaviani E, Rahmani M, Kaeidi A, Shamsizadeh A, Allahtavakoli M, Mozafari N, et al. Protective effect of atorvastatin on d-galactose-induced aging model in mice. Behav Brain Res 2017; 334: 55-60.
18. Hakimizadeh E, Oryan S, Hajizadeh Moghaddam A, Shamsizadeh A, Roohbakhsh A. Endocannabinoid system and TRPV1 receptors in the dorsal hippocampus of the rats modulate anxiety-like behaviors. Iran J Basic Med Sci 2012; 15: 795-802.
19. Baeta-Corral R, Castro-Fuentes R, Gimenez-Llort L. Sexual dimorphism in the behavioral responses and the immunoendocrine status in d-galactose-induced aging. J Gerontol A Biol Sci Med Sci 2018; 73: 1147-1157.
20. Fatemi I, Shamsizadeh A, Ayoobi F, Taghipour Z, Sanati MH, Roohbakhsh A, et al. Role of orexin-A in experimental autoimmune encephalomyelitis. J Neuroimmunol 2016; 291: 101-109.
21. du Jardin KG, Jensen JB, Sanchez C, and Pehrson AL, Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism. Eur Neuropsychopharmacol 2014; 24: 160-171.
22. Haghani M, Shabani M, Javan M, Motamedi F, and Janahmadi M, CB1 cannabinoid receptor activation rescues amyloid beta-induced alterations in behaviour and intrinsic electrophysiological properties of rat hippocampal CA1 pyramidal neurones. Cell Physiol Biochem 2012; 29: 391-406.
23. Zheng Z and Yenari MA, Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol Res 2004; 26: 884-892.
24. Hadadianpour Z, Fatehi F, Ayoobi F, Kaeidi A, Shamsizadeh A, and Fatemi I, The effect of orexin-A on motor and cognitive functions in a rat model of Parkinson’s disease. Neurol Res 2017; 39: 845-851.
25. Fatemi I, Delrobaee F, Bahmani M, Shamsizadeh A, and Allahtavakoli M, The effect of the anti-diabetic drug metformin on behavioral manifestations associated with ovariectomy in mice. Neurosci Lett 2019; 690: 95-98.
26. Delrobaei F, Fatemi I, Shamsizadeh A, and Allahtavakoli M, Ascorbic acid attenuates cognitive impairment and brain oxidative stress in ovariectomized mice. Pharmacol Rep 2018; 71: 133-138.
27. Haybar H, Goudarzi M, Mehrzadi S, Aminzadeh A, Khodayar MJ, Kalantar M, et al. Effect of gemfibrozil on cardiotoxicity induced by doxorubicin in male experimental rats. Biomed Pharmacother 2019; 109: 530-535.
28.Nakatomi H, Kuriu T, Okabe S, Yamamoto S-i, Hatano O, Kawahara N, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002; 110: 429-441.
29. Goudarzi M, Mombeini MA, Fatemi I, Aminzadeh A, Kalantari H, Nesari A, et al. Neuroprotective effects of Ellagic acid against acrylamide-induced neurotoxicity in rats. Neurol Res 2019; 41: 419-428.
30. Banji OJ, Banji D, and Ch K, Curcumin and hesperidin improve cognition by suppressing mitochondrial dysfunction and apoptosis induced by D-galactose in rat brain. Food Chem Toxicol 2014; 74: 51-59.
31. Prakash A and Kumar A, Pioglitazone alleviates the mitochondrial apoptotic pathway and mito-oxidative damage in the d-galactose-induced mouse model. Clin Exp Pharmacol Physiol 2013; 40: 644-651.
32. Hsieh HM, Wu WM, and Hu ML, Soy isoflavones attenuate oxidative stress and improve parameters related to aging and Alzheimer’s disease in C57BL/6J mice treated with D-galactose. Food Chem Toxicol 2009; 47: 625-632.
33. Shan Q, Lu J, Zheng Y, Li J, Zhou Z, Hu B, et al. Purple sweet potato color ameliorates cognition deficits and attenuates oxidative damage and inflammation in aging mouse brain induced by d-galactose. J Biomed Biotechnol 2009; 2009: 564737.
34. Barnes CA, Nadel L, and Honig WK, Spatial memory deficit in senescent rats. Can J Psychol 1980; 34: 29-39.
35. Hsu CY, Hung CS, Chang HM, Liao WC, Ho SC, and Ho YJ, Ceftriaxone prevents and reverses behavioral and neuronal deficits in an MPTP-induced animal model of Parkinson’s disease dementia. Neuropharmacology 2015; 91: 43-56.
36. Rossetti ZL and Carboni S, Noradrenaline and dopamine elevations in the rat prefrontal cortex in spatial working memory. J Neurosci 2005; 25: 2322-2329.
37. Kim SY and Jones TA, The effects of ceftriaxone on skill learning and motor functional outcome after ischemic cortical damage in rats. Restor Neurol Neurosci 2013; 31: 87-97.
38. Ho SC, Hsu CC, Pawlak CR, Tikhonova MA, Lai TJ, Amstislavskaya TG, et al. Effects of ceftriaxone on the behavioral and neuronal changes in an MPTP-induced Parkinson’s disease rat model. Behav Brain Res 2014; 268: 177-184.
39. Rybka J, Kupczyk D, Kedziora-Kornatowska K, Pawluk H, Czuczejko J, Szewczyk-Golec K, et al. Age-related changes in an antioxidant defense system in elderly patients with essential hypertension compared with healthy controls. Redox Rep 2011; 16: 71-77.
40. Cui X, Zuo P, Zhang Q, Li X, Hu Y, Long J, et al. Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid. J Neurosci Res 2006; 84: 647-654.
41. Lewerenz J, Albrecht P, Tien ML, Henke N, Karumbayaram S, Kornblum HI, et al. Induction of Nrf2 and xCT are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro. J Neurochem 2009; 111: 332-343.
42. Gorrini C, Harris IS, and Mak TW, Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 2013; 12: 931-947.
43. Bisht R, Kaur B, Gupta H, and Prakash A, Ceftriaxone mediated rescue of nigral oxidative damage and motor deficits in MPTP model of Parkinson’s disease in rats. Neurotoxicology 2014; 44: 71-79.
44. Altas M, Meydan S, Aras M, Yilmaz N, Ulutas KT, Okuyan HM, et al. Effects of ceftriaxone on ischemia/reperfusion injury in rat brain. J Clin Neurosci 2013; 20: 457-461.
45. Wolitzky-Taylor KB, Castriotta N, Lenze EJ, Stanley MA, and Craske MG, Anxiety disorders in older adults: a comprehensive review. Depress Anxiety 2010; 27: 190-211.
46. Bouayed J, Rammal H, and Soulimani R, Oxidative stress and anxiety: relationship and cellular pathways. Oxid Med Cell Longev 2009; 2: 63-67.
47. Kang S, Li J, Bekker A, and Ye JH, Rescue of glutamate transport in the lateral habenula alleviates depression- and anxiety-like behaviors in ethanol-withdrawn rats. Neuropharmacology 2018; 129: 47-56.
48. Ingram DK, Age-related decline in physical activity: generalization to nonhumans. Med Sci Sports Exerc 2000; 32: 1623-1629.
49. Boguszewski P and Zagrodzka J, Emotional changes related to age in rats--a behavioral analysis. Behav Brain Res 2002; 133: 323-332.
50. Wei H, Li L, Song Q, Ai H, Chu J, and Li W, Behavioural study of the D-galactose induced aging model in C57BL/6J mice. Behav Brain Res 2005; 157: 245-251.
51. Chang L, Liu X, Liu J, Li H, Yang Y, Liu J, et al. D-galactose induces a mitochondrial complex I deficiency in mouse skeletal muscle: potential benefits of nutrient combination in ameliorating muscle impairment. J Med Food 2014; 17: 357-364.
52. Tikhonova MA, Ho SC, Akopyan AA, Kolosova NG, Weng JC, Meng WY, et al. Neuroprotective effects of ceftriaxone treatment on cognitive and neuronal deficits in a rat model of accelerated senescence. Behav Brain Res 2017; 330: 8-16.