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Minocycline Protects Against Lipopolysaccharide-Induced Cognitive Impairment and Oxidative Stress: Possible Role of the CREB-BDNF Signaling Pathway

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Abstract

The oxidative stress-induced dysregulation of the cyclic AMP response element-binding protein- brain-derived neurotrophic factor (CREB-BDNF) cascade has been linked to cognitive impairment in several studies. This study aimed to investigate the effect of minocycline on the levels of oxidative stress markers, CREB, and BDNF in lipopolysaccharide (LPS)-induced cognitive impairment. Fifty adult male Sprague Dawley rats were divided randomly into five groups. Group 1 was an untreated control group. Groups 2, 3, 4 and 5 were treated concurrently with LPS (5 mg/kg, i.p) once on day 5 and normal saline (0.7 ml/rat, i.p) or minocycline (25 and 50 mg/kg, i.p) or memantine (10 mg/kg, i.p) once daily from day 1 until day 14, respectively. From day 15 to day 22 of the experiment, Morris Water Maze (MWM) was used to evaluate learning and reference memory in rats. The levels of protein carbonyl (PCO), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) were determined by enzyme-linked immunosorbent assay (ELISA). CREB and BDNF expression and density were measured by immunohistochemistry and western blot analysis, respectively. LPS administration significantly increased escape latency to the hidden platform with decreased travelled distance, swimming speed, target crossings and time spent in the target quadrant. Besides, the hippocampal tissue of LPS rats showed increased levels of PCO and MDA, decreased levels of CAT and SOD, and reduced expression and density of BDNF and CREB. Treatment with minocycline reversed these effects in a dose-dependent manner, comparable to the effects of memantine. Both doses of minocycline treatment protect against LPS-induced cognitive impairment by reducing oxidative stress and upregulating the CREB-BDNF signalling pathway in the rat hippocampus.

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References

  1. Cásedas G, Bennett AC, González-Burgos E, Gómez-Serranillos MP, López V, Smith C (2019) Polyphenol-associated oxidative stress and inflammation in a model of LPS-induced inflammation in glial cells: do we know enough for responsible compounding? Inflammopharmacology 27(1):189–197. https://doi.org/10.1007/s10787-018-0549-y

    Article  CAS  PubMed  Google Scholar 

  2. Banks WA, Gray AM, Erickson MA, Salameh TS, Damodarasamy M, Sheibani N et al (2015) Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. J Neuroinflammation 12(1):1–15. https://doi.org/10.1186/s12974-015-0434-1

    Article  CAS  Google Scholar 

  3. Zhao J, Bi W, **ao S, Lan X, Cheng X, Zhang J et al (2019) Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep 9(1):1–12. https://doi.org/10.1038/s41598-019-42286-8

    Article  CAS  Google Scholar 

  4. Thingore C, Kshirsagar V, Juvekar A (2021) Amelioration of oxidative stress and neuroinflammation in lipopolysaccharide-induced memory impairment using Rosmarinic acid in mice. Metab Brain Dis 36(2):299–313

    Article  CAS  PubMed  Google Scholar 

  5. Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y (2020) Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol Neurodegener 15(1):1–37

    Article  Google Scholar 

  6. Bitner RS (2012) Cyclic AMP response element-binding protein (CREB) phosphorylation: a mechanistic marker in the development of memory enhancing Alzheimer’s disease therapeutics. Biochem Pharmacol 83(6):705–714. https://doi.org/10.1016/j.bcp.2011.11.009

    Article  CAS  Google Scholar 

  7. Nam SM, Choi JH, Yoo DY, Kim W, Jung HY, Kim JW et al (2014) Effects of curcumin (Curcuma longa) on learning and spatial memory as well as cell proliferation and neuroblast differentiation in adult and aged mice by upregulating brain-derived neurotrophic factor and CREB signaling. J Med Food 17(6):641–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang B, Zhao J, Yu M, Meng X, Cui X, Zhao Y et al (2014) Disturbance of intracellular calcium homeostasis and CaMKII/CREB signaling is associated with learning and memory impairments induced by chronic aluminum exposure. Neurotox Res 26(1):52–63

    Article  CAS  PubMed  Google Scholar 

  9. Xu Y, Zhang C, Wu F, Xu X, Wang G, Lin M et al (2016) Piperine potentiates the effects of trans-resveratrol on stress-induced depressive-like behavior: involvement of monoaminergic system and cAMP-dependent pathway. Metab Brain Dis 31(4):837–848. https://doi.org/10.1007/s11011-016-9809-y

    Article  CAS  PubMed  Google Scholar 

  10. Yamashita K, Wiessner C, Lindholm D, Thoenen H, Hossmann KA (1997) Post-occlusion treatment with BDNF reduces infarct size in a model of permanent occlusion of the middle cerebral artery in rat. Metab Brain Dis 12(4):271–280. https://doi.org/10.1007/BF02674671

    Article  CAS  PubMed  Google Scholar 

  11. Motaghinejad M, Farokhi N, Motevalian M, Safari S (2020) Molecular, histological and behavioral evidences for neuroprotective effects of minocycline against nicotine-induced neurodegeneration and cognition impairment: Possible role of CREB-BDNF signaling pathway. Behav Brain Res 386:112597. https://doi.org/10.1016/j.bbr.2020.112597

    Article  CAS  PubMed  Google Scholar 

  12. Motaghinejad M, Mashayekh R, Motevalian M, Safari S (2021) The possible role of CREB-BDNF signaling pathway in neuroprotective effects of minocycline against alcohol-induced neurodegeneration: molecular and behavioral evidences. Fundam Clin Pharmacol 35(1):113–130

    Article  CAS  PubMed  Google Scholar 

  13. Romero-Miguel D, Lamanna-Rama N, Casquero-Veiga M, Gómez-Rangel V, Desco M, Soto-Montenegro ML (2021) Minocycline in neurodegenerative and psychiatric diseases: an update. Eur J Neurol 28(3):1056–1081

    Article  PubMed  Google Scholar 

  14. Plane JM et al (2021) Prospects for minocycline neuroprotection. Arch Neurol 67(12):1442–1448

    Google Scholar 

  15. Beheshti Nasr SM, Moghimi A, Mohammad-Zadeh M, Shamsizadeh A, Noorbakhsh SM (2013) The effect of minocycline on seizures induced by amygdala kindling in rats. Seizure. 22(8):670–674. https://doi.org/10.1016/j.seizure.2013.05.005

    Article  PubMed  Google Scholar 

  16. Hemmati F, Dargahi L, Nasoohi S, Omidbakhsh R (2013) Neurorestorative effect of FTY720 in a rat model of Alzheimer’s. Behav Brain Res 252:415–421

    Article  CAS  PubMed  Google Scholar 

  17. Subhramanyam CS, Wang C, Hu Q, Dheen ST (2019) Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin Cell Dev Biol 94(May):112–120

    Article  CAS  PubMed  Google Scholar 

  18. Zakaria R, Wan Yaacob WMH, Othman Z, Long I, Ahmad AH, Al-Rahbi B (2017) Lipopolysaccharide-induced memory impairment in rats: a model of Alzheimer’s disease. Physiol Res 66(4):553

    Article  CAS  PubMed  Google Scholar 

  19. Ciesielska A, Matyjek M, Kwiatkowska K (2021) TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cell Mol Life Sci 78(4):1233–1261. https://doi.org/10.1007/s00018-020-03656-y

    Article  CAS  PubMed  Google Scholar 

  20. Ali AM, Kunugi H (2021) The effects of royal jelly acid, 10-hydroxy-trans-2-decenoic acid, on neuroinflammation and oxidative stress in astrocytes stimulated with lipopolysaccharide and hydrogen peroxide. Immuno 1(3):212–222

    Article  Google Scholar 

  21. Yaseen E, Qaid A, Long I, Azman KF, Ahmad AH, Othman Z et al (2021) Quantitative description of publications (1986–2020) related to Alzheimer disease and oxidative stress: a bibliometric study. J Biomed Boitechnol 12(1):955–968

    Google Scholar 

  22. Yaacob WMHW, Long I, Zakaria R, Othman Z (2018) Tualang honey and its methanolic fraction improve LPS-induced learning and memory impairment in male rats: comparison with memantine. Curr Nutr Food Sci 16(3):333–342

    Article  Google Scholar 

  23. Amraie E, Pouraboli I, Rajaei Z (2020) Neuroprotective effects of Levisticum officinale on LPS-induced spatial learning and memory impairments through neurotrophic, anti-inflammatory, and antioxidant properties. Food Funct 11(7):6608–6621. https://doi.org/10.1039/d0fo01030h

    Article  CAS  PubMed  Google Scholar 

  24. Noworyta-Sokolowska K, Górska A, Golembiowska K (2013) LPS-induced oxidative stress and inflammatory reaction in the rat striatum. Pharmacol Reports 65(4):863–869

    Article  CAS  Google Scholar 

  25. Sharma N, Nehru B (2015) Characterization of the lipopolysaccharide induced model of Parkinson’s disease: role of oxidative stress and neuroinflammation. Neurochem Int 87:92–105. https://doi.org/10.1016/j.neuint.2015.06.004

    Article  CAS  PubMed  Google Scholar 

  26. Wan Yaacob WMH, Long I, Zakaria R, Othman Z (2021) Tualang honey and its methanolic fraction ameliorate lipopolysaccharide-induced oxidative stress, amyloid deposition and neuronal loss of the rat hippocampus. Adv Tradit Med. 21(1):121–129. https://doi.org/10.1007/s13596-020-00449-3

    Article  CAS  Google Scholar 

  27. Hou Y, **e G, Liu X, Li G, Jia C, Xu J et al (2016) Minocycline protects against lipopolysaccharide-induced cognitive impairment in mice. Psychopharmacology 233(5):905–916. https://doi.org/10.1007/s00213-015-4169-6

    Article  CAS  PubMed  Google Scholar 

  28. Fan LW, Pang Y, Lin S, Tien LT, Ma T, Rhodes PG et al (2005) Minocycline reduces lipopolysaccharide-induced neurological dysfunction and brain injury in the neonatal rat. J Neurosci Res 82(1):71–82

    Article  CAS  PubMed  Google Scholar 

  29. Stolp HB, Ek CJ, Johansson PA, Dziegielewska KM, Potter AM, Habgood MD et al (2007) Effect of minocycline on inflammation-induced damage to the blood–brain barrier and white matter during development. Eur J Neurosci 26(12):3465–3474. https://doi.org/10.1111/j.1460-9568.2007.05973.x

    Article  CAS  PubMed  Google Scholar 

  30. Keilhoff G, Schild L, Fansa H (2008) Minocycline protects Schwann cells from ischemia-like injury and promotes axonal outgrowth in bioartificial nerve grafts lacking Wallerian degeneration. Exp Neurol 212(1):189–200

    Article  CAS  PubMed  Google Scholar 

  31. Cankaya S, Cankaya B, Kilic U, Kilic E, Yulug B (2019) The therapeutic role of minocycline in Parkinson’s disease. Drugs Context 8:1–14

    Article  Google Scholar 

  32. Morren JA, Galvez-Jimenez N (2012) Current and prospective disease-modifying therapies for amyotrophic lateral sclerosis. Expert Opin Investig Drugs 21(3):297–320

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The research funding for this work came from Universiti Sains Malaysia (RUI 1001/PPSK/8012269).

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Authors and Affiliations

  1. School of Health Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia

    Entesar Yaseen Abdo Qaid, Zuraidah Abdullah & Idris Long

  2. Department of Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia

    Rahimah Zakaria

  3. Histology Department, Faculty of Medicine and Health Sciences, Taiz University, Taiz, Yemen

    Entesar Yaseen Abdo Qaid

Authors
  1. Entesar Yaseen Abdo Qaid
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  3. Rahimah Zakaria
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Correspondence to Idris Long.

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Qaid, E.Y.A., Abdullah, Z., Zakaria, R. et al. Minocycline Protects Against Lipopolysaccharide-Induced Cognitive Impairment and Oxidative Stress: Possible Role of the CREB-BDNF Signaling Pathway. Neurochem Res 48, 1480–1490 (2023). https://doi.org/10.1007/s11064-022-03842-3

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  • DOI: https://doi.org/10.1007/s11064-022-03842-3

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