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Tocilizumab’s effect on cognitive deficits induced by intracerebroventricular administration of streptozotocin in Alzheimer’s model

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Abstract

Neuroinflammation plays pivotal roles in the pathogenesis of Alzheimer’s disease (AD). IL-6 is pleiotropic cytokine which plays significant pathological role in inflammatory diseases and causes prolonged inflammation. Additionally, IL-6 activates microglia cells and enhances the accumulation of amyloid-β peptides. Moreover, IL-6 signal transduction is mediated by membrane-bound and soluble IL-6 receptors. Tocilizumab which is a humanized anti-human IL-6 receptor (IL-6R) monoclonal antibody binds to both of these receptors and inhibits IL-6 signaling by this route. The objective was to investigate tocilizumab’s potential effects in the treatment of AD. Male Sprague–Dawley rats were divided into three groups: sham (control), streptozotocin (STZ), and tocilizumab-STZ. We used a single dose of intracerebroventricular (ICV) tocilizumab, beginning 1 h prior to injection of STZ for 3 weeks. The rats in STZ and tocilizumab-STZ groups were given ICV-STZ (3 mg/kg). Behavioral parameters were evaluated on days 17–20 and the rats were sacrificed on day-21 to examine histopathological changes. STZ injection caused significant decrease in the mean escape latency in passive avoidance and also declined the performance improvement in Morris water maze tests. Tocilizumab-STZ group significantly improved learning and spatial memory functions by increasing RLT in the passive avoidance and by shortening escape latency in reaching the platform in the Morris water maze. Histopathological changes were examined using hematoxylin and eosin and immunohistochemical (IHC) stainings. IHC analysis revealed that while protein expressions of amyloid-ß (3.5 ± 0.2) and IL-6 (2.9 ± 0.4) showed intense immune-positivity in STZ group, amyloid-ß (1.3 ± 0.1) and IL-6 (1.5 ± 0.2) immunoreactivities were substantially decreased in tocilizumab treatment group. We conclude that tocilizumab treatment attenuated significantly STZ-induced cognitive impairment and histopathological changes. Further studies would be desirable to investigate clinically relevant protective effects of tocilizumab in AD.

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References

  1. Shi JQ, Shen W, Chen J, Wang BR, Zhong LL, Zhu YW (2011) Anti-TNF-α reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res 1368:239–247

    Article  CAS  PubMed  Google Scholar 

  2. Isik AT, Çelik T, Ulusoy G et al (2009) Curcumin ameliorates impaired insulin/IGF signaling and memory deficit in a streptozotocin-treated rat model. AGE 31:39–49

    Article  CAS  PubMed  Google Scholar 

  3. Weiss EM, Kohler CG, Vonbank J, Stadelmann E, Kemmler G, Hinterhuber H (2008) Impairment in emotion recognition abilities in patients with mild cognitive impairment, early and moderate Alzheimer’s disease compared with healthy comparison subjects. Am J Geriatr Psychiatry 16:974–980

    Article  PubMed  Google Scholar 

  4. Heneka MT, O’Banion MK, Terwel D, Kummer MP (2010) Neuroinflammatory processes in Alzheimer’s disease. J Neural Transm 117:919–947

    Article  CAS  PubMed  Google Scholar 

  5. Zhang YY, Fan YC, Wang M, Wang D, Li XH (2013) Atorvastatin attenuates the production of IL-1β, IL-6, and TNF-α in the hippocampus of an amyloid β1-42-induced rat model of Alzheimer’s disease. Clin Interv Aging 8:103–110

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Tanaka T, Narazaki M, Kishimoto T (2012) Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 52:199–219

    Article  CAS  PubMed  Google Scholar 

  7. Tanaka T, Narazaki M, Ogata A, Kishimoto T (2014) A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy. Semin Immunol 26:88–96

    Article  CAS  PubMed  Google Scholar 

  8. Guptarak J, Wanchoo S, Durham-Lee J, Wu Y, Zivadinovic D, Paulucci-Holthauzen A (2013) Inhibition of IL-6 signaling: a novel therapeutic approach to treating spinal cord injury pain. Pain 154:1115–1128

    Article  CAS  PubMed  Google Scholar 

  9. Fridman JS, Scherle PA, Collins R et al (2010) Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol 184:5298–5307

    Article  CAS  PubMed  Google Scholar 

  10. Wu GI, Chai N, Kim I, Klein AS, Jordan SC (2013) Monoclonal anti-interleukin-6 receptor antibody attenuates donor-specific antibody responses in a mouse model of allosensitization. Transpl Immunol 28:138–143

    Article  CAS  PubMed  Google Scholar 

  11. Mayer G, Nitsch R, Hoyer S (1990) Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats. Brain Res 532:91–100

    Article  Google Scholar 

  12. Blokland A, Jolles J (2014) Spatial learning deficit and reduced hippocampal ChAT activity in rats after an i.c.v. injection of streptozotocin. Pharmacol Biochem Behav 44:491–494

    Article  Google Scholar 

  13. Rodrigues L, Dutra MF, Ilha J, Biasibetti R, Quincozes-Santos A, Leite MC (2010) Treadmill training restores spatial cognitive deficits and neurochemical alterations in the hippocampus of rats submitted to an intracerebroventricular administration of streptozotocin. J Neural Transm 117:1295–1305

    Article  CAS  PubMed  Google Scholar 

  14. Chu S, Gu J, Feng L, Liu J, Zhang M, Jia X (2014) Ginsenoside Rg5 improves cognitive dysfunction and beta-amyloid deposition in STZ-induced memory impaired rats via attenuating neuroinflammatory responses. Int Immunopharmacol 19:317–326

    Article  CAS  PubMed  Google Scholar 

  15. Sharma M, Gupta YK (2001) Effect of chronic treatment of melatonin on learning, memory and oxidative deficiencies induced by intracerebroventricular streptozotocin in rats. Pharmacol Biochem Behav 70:325–331

    Article  CAS  PubMed  Google Scholar 

  16. Saxena G, Bharti S, Kamat PK, Sharma S, Nath C (2010) Melatonin alleviates memory deficits and neuronal degeneration induced by intracerebroventricular administration of streptozotocin in rats. Pharmacol Biochem Behav 94:397–403

    Article  CAS  PubMed  Google Scholar 

  17. Nakahara N, Iga Y, Mizobe F, Kawanishi G (1998) Effects of intracerebroventricular injection of AF64A on learning behaviors in rats. Jpn J Pharmacol 48:121–130

    Article  Google Scholar 

  18. Elcioglu HK, Kabasakal L, Alan S, Şalva E, Tufan T, Karan MA (2013) Thalidomide attenuates learning and memory deficits induced by intracerebroventricular administration of streptozotocin in rats. Biotech Histochem 88:145–152

    Article  CAS  PubMed  Google Scholar 

  19. Morris R (1984) Development of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60

    Article  CAS  PubMed  Google Scholar 

  20. Provias J, Jeynes B (2010) Immunohistochemical detection of receptor-associated protein in normal human brain and Alzheimer’s disease. Pathol Res Int 2010:173496. doi:10.4061/2010/173496

    Article  Google Scholar 

  21. Ogata A, Hirano T, Hishitani Y, Tanaka T (2012) Safety and efficacy of tocilizumab for the treatment of rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord 5:27–42

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kaly L, Rosner I (2012) Tocilizumab-a novel therapy for non-organ-specific autoimmune diseases. Best Pract Res Clin Rheumatol 26:157–165

    Article  CAS  PubMed  Google Scholar 

  23. Deng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong CX (2009) Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: implication for Alzheimer’s disease. Am J Pathol 175:2089–2098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Grunblatt E, Salkovic-Petrisic M, Osmanovic J, Riederer P, Hoyer S (2007) Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem 101:757–770

    Article  PubMed  Google Scholar 

  25. Ejaz Ahmed M, Khan MM, Javed H et al (2013) Amelioration of cognitive impairment and neurodegeneration by catechin hydrate in rat model of streptozotocin-induced experimental dementia of Alzheimer’s type. Neurochem Int 62:492–501

    Article  CAS  PubMed  Google Scholar 

  26. Gutierres JM, Carvalho FB, Schetinger MR, Marisco P, Agostinho P, Rodrigues M (2014) Anthocyanins restore behavioral and biochemical changes caused by streptozotocin-induced sporadic dementia of Alzheimer’s type. Life Sci 96:7–17

    Article  CAS  PubMed  Google Scholar 

  27. Massoud F, Gauthier S (2010) Update on the pharmacological treatment of Alzheimer’s disease. Curr Neuropharmacol 8:69–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rajasekar N, Dwivedi S, Tota SK et al (2013) Neuroprotective effect of curcumin on okadaic acid induced memory impairment in mice. Eur J Pharmacol 715:381–394

    Article  CAS  PubMed  Google Scholar 

  29. Bın Z, Zhı-Gang W, Jıe D, Nıng L, Da-Mıng W, Lıang-Caı D (2014) Chronic lipopolysaccharide exposure induces cognitive dysfunction without affecting BDNF expression in the rat hippocampus. Exp Ther Med 7:750–754

    Google Scholar 

  30. Reale M, Iarlori C, Gambi F et al (2004) Treatment with an acetylcholinesterase inhibitor in Alzheimer patients modulates the expression and production of the pro-inflammatory and anti-inflammatory cytokines. J Neuroimmunol 148:162–171

    Article  CAS  PubMed  Google Scholar 

  31. Elcioglu HK, Kabasakal L, Tufan F et al (2015) Effects of systemic thalidomide and intracerebroventricular etanercept and infliximab in a streptozotocin-induced dementia model in rats. Acta Histochem 117:176–181

    Article  PubMed  Google Scholar 

  32. Hartman J, Frishman WH (2014) Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy. Cardiol Rev 22:147–151

    Article  PubMed  Google Scholar 

  33. Atzeni F, Ventura D, Batticciotto A, Boccassini L, Sarzi-Puttini P (2012) Interleukin 6 blockade: tocilizumab in psoriatic arthritis. J Rheumatol 89(Suppl):97–99

    CAS  Google Scholar 

  34. Mizwicki MT, Fiala M, Magpantay L et al (2012) Tocilizumab attenuates inflammation in ALS patients through inhibition of IL6 receptor signaling. Am J Neurodegener Dis 1:305–315

    PubMed  PubMed Central  Google Scholar 

  35. Yokota S, Tanaka T, Kishimoto T (2012) Efficacy, safety and tolerability of tocilizumab in patients with systemic juvenile idiopathic arthritis. Ther Adv Musculoskelet Dis 4:387–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fabiola A, Benucci M, Salli S, Bongiovanni S, Boccassini L, Sarzi-Puttini P (2013) Different effects of biological drugs in rheumatoid arthritis. Autoimmun Rev 12:575–579

    Article  Google Scholar 

  37. Dolatabadi HRD, Reisi P, Alaei H, Malekabadi HA, Pilehvarian AA (2012) Folic acid and coenzyme Q10 ameliorate cognitive dysfunction in the rats with intracerebroventricular injection of streptozotocin. Iranian J Basic Med Sci 15:719–724

    CAS  Google Scholar 

  38. Hsu LJ, Mallory M, Xia Y et al (1998) Expression pattern of synucleins (non-A beta component of Alzheimer’s disease amyloid precursor protein/alpha-synuclein) during murine brain development. J Neurochem 71:338–344

    Article  CAS  PubMed  Google Scholar 

  39. Nguven JT, Yamani A, Kiso Y (2006) Views on amyloid hypothesis and secretase inhibitors for treating Alzheimer’s disease: progress and problems. Curr Pharm Res 12:4295–4312

    Article  Google Scholar 

Download references

Acknowledgments

This research work was supported by the Marmara University Scientific Research Community (Project No: SAG-C-YLP-120613-0241).

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Correspondence to H. Kübra Elcioğlu or Sarfraz Ahmad.

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Elcioğlu, H.K., Aslan, E., Ahmad, S. et al. Tocilizumab’s effect on cognitive deficits induced by intracerebroventricular administration of streptozotocin in Alzheimer’s model. Mol Cell Biochem 420, 21–28 (2016). https://doi.org/10.1007/s11010-016-2762-6

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  • DOI: https://doi.org/10.1007/s11010-016-2762-6

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