Molecular Biology Reports

, Volume 43, Issue 10, pp 1157–1163 | Cite as

Minocycline ameliorates d-galactose-induced memory deficits and loss of Arc/Arg3.1 expression

  • Xu LiEmail author
  • Fen LuEmail author
  • Wei Li
  • Jun Xu
  • Xiao-Jing Sun
  • Ling-Zhi Qin
  • Qian-Lin Zhang
  • Yong Yao
  • Qing-Kai Yu
  • Xin-Liang Liang
Original Article


Dysfunction of learning and memory is widely found in many neurological diseases. Understanding how to preserve the normal function of learning and memory will be extremely beneficial for the treatment of these diseases. However, the possible protective effect of minocycline in memory impairment is unknown. We used the well-established d-galactose rat amnesia model and two behavioral tasks, the Morris water maze and the step-down task, for memory evaluation. Western blot and PCR were used to examine the protein and mRNA levels of Arc/Arg3.1. We report that minocycline supplementation ameliorates both the spatial and fear memory deficits caused by d-galactose. We also found that Arc/Arg3.1, c-fos, and brain-derived neurotrophic factor levels are decreased in the d-galactose animal model, and that minocycline reverses the protein and mRNA levels of Arc in the hippocampus, suggesting the potential role of Arc/Arg3.1 in minocycline’s neuroprotective mechanism. Our study strongly suggests that minocycline can be used as a novel treatment for memory impairment in neurological diseases.


Memory deficits Arc d-Galactose 



This study was supported by grants from Key Scientific and Technological Projects of Henan Province (No. 122102310072 and No. 122102310155), Scientific and Technological Projects of Zhengzhou (No. 121PPTGG492-4 and No.  121PPTGG492-5).

Compliance with ethical standards

Conflict of interest

The authors have declared that they have no conflict of interest.


  1. 1.
    Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL (2001) A default mode of brain function. Proc Natl Acad Sci USA 98(2):676–682. doi: 10.1073/pnas.98.2.676 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298(5594):789–791. doi: 10.1126/science.1074069 CrossRefPubMedGoogle Scholar
  3. 3.
    Won SJ, Kim JH, Yoo BH, Sohn M, Kauppinen TM, Park MS, Kwon HJ, Liu J, Suh SW (2012) Prevention of hypoglycemia-induced neuronal death by minocycline. J Neuroinflammation 9:225. doi: 10.1186/1742-2094-9-225 PubMedPubMedCentralGoogle Scholar
  4. 4.
    Lin S, Wei X, Xu Y, Yan C, Dodel R, Zhang Y, Liu J, Klaunig JE, Farlow M, Du Y (2003) Minocycline blocks 6-hydroxydopamine-induced neurotoxicity and free radical production in rat cerebellar granule neurons. Life Sci 72(14):1635–1641CrossRefPubMedGoogle Scholar
  5. 5.
    Li SY, Xia LX, Zhao YL, Yang L, Chen YL, Wang JT, Luo AL (2013) Minocycline mitigates isoflurane-induced cognitive impairment in aged rats. Brain Res 1496:84–93. doi: 10.1016/j.brainres.2012.12.025 CrossRefPubMedGoogle Scholar
  6. 6.
    Cui X, Zuo P, Zhang Q, Li X, Hu Y, Long J, Packer L, Liu J (2006) Chronic systemic d-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid. J Neurosci Res 84(3):647–654. doi: 10.1002/jnr.20899 CrossRefPubMedGoogle Scholar
  7. 7.
    Yao ZH, Zhang JJ, Xie XF (2012) Enriched environment prevents cognitive impairment and tau hyperphosphorylation after chronic cerebral hypoperfusion. Curr Neurovasc Res 9(3):176–184CrossRefPubMedGoogle Scholar
  8. 8.
    Wang X, Wang ZH, Wu YY, Tang H, Tan L, Wang X, Gao XY, Xiong YS, Liu D, Wang JZ, Zhu LQ (2013) Melatonin attenuates scopolamine-induced memory/synaptic disorder by rescuing EPACs/miR-124/Egr1 pathway. Mol Neurobiol 47(1):373–381. doi: 10.1007/s12035-012-8355-9 CrossRefPubMedGoogle Scholar
  9. 9.
    Wang S, Zhu L, Shi H, Zheng H, Tian Q, Wang Q, Liu R, Wang JZ (2007) Inhibition of melatonin biosynthesis induces neurofilament hyperphosphorylation with activation of cyclin-dependent kinase 5. Neurochem Res 32(8):1329–1335. doi: 10.1007/s11064-007-9308-y CrossRefPubMedGoogle Scholar
  10. 10.
    Nie C, Nie H, Zhao Y, Wu J, Zhang X (2016) Betaine reverses the memory impairments in a chronic cerebral hypoperfusion rat model. Neurosci Lett 615:9–14. doi: 10.1016/j.neulet.2015.11.019 CrossRefPubMedGoogle Scholar
  11. 11.
    Zhan PY, Peng CX, Zhang LH (2014) Berberine rescues d-galactose-induced synaptic/memory impairment by regulating the levels of Arc. Pharmacol Biochem Behav 117:47–51. doi: 10.1016/j.pbb.2013.12.006 CrossRefPubMedGoogle Scholar
  12. 12.
    Yi ZJ, Fu YR, Li M, Gao KS, Zhang XG (2009) Effect of LTA isolated from bifidobacteria on d-galactose-induced aging. Exp Gerontol 44(12):760–765. doi: 10.1016/j.exger.2009.08.011 CrossRefPubMedGoogle Scholar
  13. 13.
    Woo JY, Gu W, Kim KA, Jang SE, Han MJ, Kim DH (2014) Lactobacillus pentosus var. plantarum C29 ameliorates memory impairment and inflammaging in a d-galactose-induced accelerated aging mouse model. Anaerobe 27:22–26. doi: 10.1016/j.anaerobe.2014.03.003 CrossRefPubMedGoogle Scholar
  14. 14.
    Messaoudi E, Kanhema T, Soule J, Tiron A, Dagyte G, da Silva B, Bramham CR (2007) Sustained Arc/Arg3.1 synthesis controls long-term potentiation consolidation through regulation of local actin polymerization in the dentate gyrus in vivo. J Neurosci 27(39):10445–10455. doi: 10.1523/JNEUROSCI.2883-07.2007 CrossRefPubMedGoogle Scholar
  15. 15.
    Huff NC, Frank M, Wright-Hardesty K, Sprunger D, Matus-Amat P, Higgins E, Rudy JW (2006) Amygdala regulation of immediate-early gene expression in the hippocampus induced by contextual fear conditioning. J Neurosci 26(5):1616–1623. doi: 10.1523/JNEUROSCI.4964-05.2006 CrossRefPubMedGoogle Scholar
  16. 16.
    Monti B, Berteotti C, Contestabile A (2006) Subchronic rolipram delivery activates hippocampal CREB and arc, enhances retention and slows down extinction of conditioned fear. Neuropsychopharmacology 31(2):278–286. doi: 10.1038/sj.npp.1300813 CrossRefPubMedGoogle Scholar
  17. 17.
    Waltereit R, Dammermann B, Wulff P, Scafidi J, Staubli U, Kauselmann G, Bundman M, Kuhl D (2001) Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation. J Neurosci 21(15):5484–5493PubMedGoogle Scholar
  18. 18.
    Zhao Y, Xiao M, He W, Cai Z (2015) Minocycline upregulates cyclic AMP response element binding protein and brain-derived neurotrophic factor in the hippocampus of cerebral ischemia rats and improves behavioral deficits. Neuropsychiatr dis treat 11:507–516. doi: 10.2147/NDT.S73836 PubMedPubMedCentralGoogle Scholar
  19. 19.
    Kovesdi E, Kamnaksh A, Wingo D, Ahmed F, Grunberg NE, Long JB, Kasper CE, Agoston DV (2012) Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury. Front Neurol 3:111. doi: 10.3389/fneur.2012.00111 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Bhatt LK, Addepalli V (2012) Potentiation of aspirin-induced cerebroprotection by minocycline: a therapeutic approach to attenuate exacerbation of transient focal cerebral ischaemia. Diab Vasc Dis Res 9(1):25–34. doi: 10.1177/1479164111427753 CrossRefPubMedGoogle Scholar
  21. 21.
    Mei XP, Chen L, Wang W, Wu D, Wang LY, Zhang T, Zhang H, Xu LX, Li YQ (2013) Combination of tramadol with minocycline exerted synergistic effects on a rat model of nerve injury-induced neuropathic pain. Neurosignals 21(3–4):184–196. doi: 10.1159/000338049 CrossRefPubMedGoogle Scholar
  22. 22.
    Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC (2012) Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer’s disease-like amyloid pathology. J Neuroinflammation 9:62. doi: 10.1186/1742-2094-9-62 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kalonia H, Mishra J, Kumar A (2012) Targeting neuro-inflammatory cytokines and oxidative stress by minocycline attenuates quinolinic-acid-induced Huntington’s disease-like symptoms in rats. Neurotox Res 22(4):310–320. doi: 10.1007/s12640-012-9315-x CrossRefPubMedGoogle Scholar
  24. 24.
    Thomas M, Le WD (2004) Minocycline: neuroprotective mechanisms in Parkinson’s disease. Curr Pharm Des 10(6):679–686CrossRefPubMedGoogle Scholar
  25. 25.
    Carri MT (2008) Minocycline for patients with ALS. Lancet Neurol 7(2):118–119; author reply 120–111. doi: 10.1016/S1474-4422(08)70005-X
  26. 26.
    Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R (2007) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 6(12):1045–1053. doi: 10.1016/S1474-4422(07)70270-3 CrossRefPubMedGoogle Scholar
  27. 27.
    Sonmez E, Kabatas S, Ozen O, Karabay G, Turkoglu S, Ogus E, Yilmaz C, Caner H, Altinors N (2013) Minocycline treatment inhibits lipid peroxidation, preserves spinal cord ultrastructure, and improves functional outcome after traumatic spinal cord injury in the rat. Spine (Phila Pa 1976) 38(15):1253–1259. doi: 10.1097/BRS.0b013e3182895587 CrossRefGoogle Scholar
  28. 28.
    Chen X, Ma X, Jiang Y, Pi R, Liu Y, Ma L (2011) The prospects of minocycline in multiple sclerosis. J Neuroimmunol 235(1–2):1–8. doi: 10.1016/j.jneuroim.2011.04.006 CrossRefPubMedGoogle Scholar
  29. 29.
    Borre Y, Sir V, de Kivit S, Westphal KG, Olivier B, Oosting RS (2012) Minocycline restores spatial but not fear memory in olfactory bulbectomized rats. Eur J Pharmacol 697(1–3):59–64. doi: 10.1016/j.ejphar.2012.09.005 CrossRefPubMedGoogle Scholar
  30. 30.
    Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim S, Suh YH (2007) Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models. Neuropsychopharmacology 32(11):2393–2404. doi: 10.1038/sj.npp.1301377 CrossRefPubMedGoogle Scholar
  31. 31.
    Fan R, Xu F, Previti ML, Davis J, Grande AM, Robinson JK, Van Nostrand WE (2007) Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci 27(12):3057–3063. doi: 10.1523/JNEUROSCI.4371-06.2007 CrossRefPubMedGoogle Scholar
  32. 32.
    Lu J, Wu DM, Zheng YL, Hu B, Zhang ZF, Ye Q, Liu CM, Shan Q, Wang YJ (2010) Ursolic acid attenuates d-galactose-induced inflammatory response in mouse prefrontal cortex through inhibiting AGEs/RAGE/NF-kappaB pathway activation. Cereb Cortex 20(11):2540–2548. doi: 10.1093/cercor/bhq002 CrossRefPubMedGoogle Scholar
  33. 33.
    Lei M, Su Y, Hua X, Ding J, Han Q, Hu G, Xiao M (2008) Chronic systemic injection of d-galactose impairs the septohippocampal cholinergic system in rats. Neuroreport 19(16):1611–1615. doi: 10.1097/WNR.0b013e3283136a1f CrossRefPubMedGoogle Scholar
  34. 34.
    Hunter CL, Bachman D, Granholm AC (2004) Minocycline prevents cholinergic loss in a mouse model of Down’s syndrome. Ann Neurol 56(5):675–688. doi: 10.1002/ana.20250 CrossRefPubMedGoogle Scholar
  35. 35.
    Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC (2004) Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. Eur J Neurosci 19(12):3305–3316. doi: 10.1111/j.0953-816X.2004.03439.x CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Xu Li
    • 1
    Email author
  • Fen Lu
    • 2
    Email author
  • Wei Li
    • 2
  • Jun Xu
    • 2
  • Xiao-Jing Sun
    • 2
  • Ling-Zhi Qin
    • 2
  • Qian-Lin Zhang
    • 2
  • Yong Yao
    • 2
  • Qing-Kai Yu
    • 1
  • Xin-Liang Liang
    • 2
  1. 1.Department of PathologyHenan Cancer Hospital (The Affiliated Cancer Hospital of Zhengzhou University)ZhengzhouChina
  2. 2.Department of NeurologyHenan Provincial People’s Hospital (The Affiliated People’s Hospital of Zhengzhou University)ZhengzhouChina

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