Skip to main content

Advertisement

SpringerLink
Log in

Melatonin-pretreated adipose-derived mesenchymal stem cells efficeintly improved learning, memory, and cognition in an animal model of Alzheimer's disease

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Currently, mesenchymal stem cells (MSCs) based therapy has extensive attraction for Alzheimer’s disease (AD). However, low survival rate of MSCs after transplantation is a huge challenging. The current study aimed to improve adipose-derived MSCs (AD-MSCs)-based therapy by their pre-treatment with melatonin (MT) ‘a well-known antioxidant’ in an animal model of AD. In this study, after isolating rat AD-MSCs from the epididymal white adipose tissues, the cells were pretreated with 5μM of MT for 24 hours. Forty male Wistar rats were randomly allocated to control, sham, amyloid-beta (Aβ) peptide, AD-MSCs and MT-pretreated ADMSCs groups. The novel object recognition, passive avoidance test, Morris water maze and open field test were performed two months following the cell transplantation. The rats were sacrificed 69 days following cell therapy. The brain tissues were removed for histopathological analysis and also immunohistochemistry was performed for two Aβ1-42 and Iba1 proteins. It has been revealed that both AD-MSCs and MT-AD-MSCs migrated to brain tissues after intravenous transplantation. However, MT-ADMSCs significantly improved learning, memory and cognition compared with AD-MSCs (P<0.05). Furthermore, clearance of Aβ deposition and reduction of microglial cells were significantly increased in the MT-ADMSCs compared with AD-MSCs. Although stem cell therapy has been introduced as a promising strategy in neurodegenerative diseases, however, its therapeutic properties are limited. It is suggested that pretreatment of MSCs with melatonin partly would increase the cells efficiency and consequently could decrease AD complication including memory and cognition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Ager RR, Davis JL, Agazaryan A, Benavente F, Poon WW, LaFerla FM, Blurton-Jones M (2015) Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer's disease and neuronal loss. Hippocampus 25:813–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amstrup A, Sikjaer T, Mosekilde L, Rejnmark L (2013) Melatonin and the skeleton. Osteoporos Int 24:2919–2927

    Article  CAS  PubMed  Google Scholar 

  • Asadbegi M, Yaghmaei P, Salehi I, Komaki A, Ebrahim-Habibi A (2017) Investigation of thymol effect on learning and memory impairment induced by intrahippocampal injection of amyloid beta peptide in high fat diet-fed rats. Metab Brain Dis 32:827–839

    Article  CAS  PubMed  Google Scholar 

  • Bali P, Lahiri DK, Banik A, Nehru B, Anand A (2017) Potential for stem cells therapy in Alzheimer’s disease: do neurotrophic factors play critical role? Curr Alzheimer Res 14:208–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campos AC, Fogaca MV, Aguiar DC, Guimaraes FS (2013) Animal models of anxiety disorders and stress. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999) 35(Suppl 2):S101–S111. https://doi.org/10.1590/1516-4446-2013-1139

    Article  Google Scholar 

  • Cardinali DP, Esquifino AI, Srinivasan V, Pandi-Perumal SR (2008) Melatonin and the immune system in aging. Neuroimmunomodulation 15:272–278

    Article  CAS  PubMed  Google Scholar 

  • Carpentieri A, Areco V, de Barboza GD, Rivoira MA, Guizzardi S, de Talamoni NT (2016) Melatonin: Basic and Clinical Aspects. In: Melatonin, Neuroprotective Agents and Antidepressant Therapy. Springer, pp 55–64

  • Cetin F, Yazihan N, Dincer S, Akbulut G (2013) The effect of intracerebroventricular injection of beta amyloid peptide (1-42) on caspase-3 activity, lipid peroxidation, nitric oxide and NOS expression in young adult and aged rat brain. Turk Neurosurg 23:144–150

    PubMed  Google Scholar 

  • Chen HH et al (2014a) Additional benefit of combined therapy with melatonin and apoptotic adipose-derived mesenchymal stem cell against sepsis-induced kidney injury. J Pineal Res 57:16–32

    Article  CAS  PubMed  Google Scholar 

  • Chen YT et al (2014b) Melatonin treatment further improves adipose-derived mesenchymal stem cell therapy for acute interstitial cystitis in rat. J Pineal Res 57:248–261

    Article  CAS  PubMed  Google Scholar 

  • Choi SS, Lee S-R, Kim SU, Lee HJ (2014) Alzheimer's disease and stem cell therapy. Exp Neurobiol 23:45–52

    Article  PubMed  PubMed Central  Google Scholar 

  • Eftekharzadeh M et al (2015) The effect of intrathecal delivery of bone marrow stromal cells on hippocampal neurons in rat model of Alzheimer’s disease Iranian journal of basic medical sciences, vol 18, p 520

    Google Scholar 

  • Espino J, Pariente JA, Rodríguez AB (2012) Oxidative stress and immunosenescence: therapeutic effects of melatonin Oxidative medicine and cellular longevity 2012

    Google Scholar 

  • Esteban-Zubero E et al (2016) Potential benefits of melatonin in organ transplantation: a review. J Endocrinol 229:R129–R146

    Article  CAS  PubMed  Google Scholar 

  • Etaee F, Asadbegi M, Taslimi Z, Shahidi S, Sarihi A, Asl SS, Komaki A (2017) The effects of methamphetamine and buprenorphine, and their interaction on anxiety-like behavior and locomotion in male rats. Neurosci Lett 655:172–178

    Article  CAS  PubMed  Google Scholar 

  • Gholami M, Saki G, Hemadi M, Khodadadi A, Mohammadi-asl J (2014) Melatonin improves spermatogonial stem cells transplantation efficiency in azoospermic mice. Iran J Basic Med Sci 17(93)

  • Haider KH, Ashraf M (2012) Preconditioning approach in stem cell therapy for the treatment of infarcted heart. In: Prog Mol Biol Transl Sci, vol 111. Elsevier, pp 323-356

  • Hasanein P, Shahidi S (2011) Effects of Hypericum perforatum extract on diabetes-induced learning and memory impairment in rats. Phytother Res 25:544–549

    Article  CAS  PubMed  Google Scholar 

  • Jahnke G, Marr M, Myers C, Wilson R, Travlos G, Price C (1999) Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Toxicological Sciences: an Official Journal of the Society of Toxicology 50:271–279

    Article  CAS  Google Scholar 

  • Kan I, Barhum Y, Melamed E, Offen D (2011) Mesenchymal stem cells stimulate endogenous neurogenesis in the subventricular zone of adult mice. Stem Cell Rev Rep 7:404–412

    Article  PubMed  Google Scholar 

  • Khatibi S, Taban ZF, Halabian R, Roushandeh AM (2017) Combined preconditioning with hypoxia and Hydrogen Peroxide Improved efficiency of Mesenchymal Stem Cell in cell culture. Entomol Appl Sci Lett 3:89–96

    Google Scholar 

  • Kim S, Chang K-A, Park H-G, Ra JC, Kim H-S, Suh Y-H (2012) The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer’s disease mice. PLoS One 7:e45757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JA et al (2015) Neural stem cell transplantation at critical period improves learning and memory through restoring synaptic impairment in Alzheimer's disease mouse model. Cell Death Dis 6:e1789. https://doi.org/10.1038/cddis.2015.138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Komaki A, Khalili A, Salehi I, Shahidi S, Sarihi A (2014) Effects of exposure to an extremely low frequency electromagnetic field on hippocampal long-term potentiation in rat. Brain Res 1564:1–8

    Article  CAS  PubMed  Google Scholar 

  • Kommaddi RP et al (2018) Abeta mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease. J Neurosci 38:1085–1099. https://doi.org/10.1523/jneurosci.2127-17.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koyama H, Nakade O, Takada Y, Kaku T, Lau KHW (2002) Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. J Bone Miner Res 17:1219–1229

    Article  CAS  PubMed  Google Scholar 

  • Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Js B (2010) Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses. Stem Cells 28:329–343

    CAS  PubMed  Google Scholar 

  • Lee SJ, Jung YH, Oh SY, Yun SP, Han HJ (2014) Melatonin enhances the human mesenchymal stem cells motility via melatonin receptor 2 coupling with Gαq in skin wound healing. J Pineal Res 57:393–407

    Article  CAS  PubMed  Google Scholar 

  • Lemmens MA, Sierksma AS, Rutten BP, Dennissen F, Steinbusch HW, Lucassen PJ, Schmitz C (2011) Age-related changes of neuron numbers in the frontal cortex of a transgenic mouse model of Alzheimer’s disease. Brain Struct Funct 216:227

    Article  PubMed  PubMed Central  Google Scholar 

  • Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185

    CAS  PubMed  Google Scholar 

  • Liu XB, Wang JA, Ogle ME, Wei L (2009) Prolyl hydroxylase inhibitor dimethyloxalylglycine enhances mesenchymal stem cell survival. J Cell Biochem 106:903–911

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML (2016) MT1 and MT2 melatonin receptors: a therapeutic perspective. Annu Rev Pharmacol Toxicol 56:361–383

    Article  CAS  PubMed  Google Scholar 

  • Luchetti F et al (2010) Melatonin signaling and cell protection function. FASEB J 24:3603–3624

    Article  CAS  PubMed  Google Scholar 

  • Malin DH et al (2001) Hippocampal injections of amyloid beta-peptide 1-40 impair subsequent one-trial/day reward learning. Neurobiol Learn Mem 76:125–137. https://doi.org/10.1006/nlme.2000.3991

    Article  CAS  PubMed  Google Scholar 

  • Mandrekar-Colucci S, Landreth GE (2010) Microglia and inflammation in Alzheimer's disease. CNS Neurol Disord Drug Targets 9:156–167

    Article  CAS  PubMed  Google Scholar 

  • Mortezaee K et al (2016) Melatonin pretreatment enhances the homing of bone marrow-derived mesenchymal stem cells following transplantation in a rat model of liver fibrosis. Iran Biomed J 20:207

    PubMed  PubMed Central  Google Scholar 

  • Munoz JR, Stoutenger BR, Robinson AP, Spees JL, Prockop DJ (2005) Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc Natl Acad Sci 102:18171–18176

    Article  CAS  PubMed  Google Scholar 

  • Ohsawa K, Imai Y, Sasaki Y, Kohsaka S (2004) Microglia/macrophage-specific protein Iba1 binds to fimbrin and enhances its actin-bundling activity. J Neurochem 88:844–856

    Article  CAS  PubMed  Google Scholar 

  • Paul CA, Beltz B, Berger-Sweeney J (2007) Testing spatial and nonspatial learning using a morris water maze. CSH protocols 2007:pdb.prot4801. https://doi.org/10.1101/pdb.prot4801

    Article  PubMed  Google Scholar 

  • Rafat A, Roushandeh AM, Alizadeh A, Hashemi-Firouzi N, Golipoor Z (2018) Comparison of the melatonin preconditioning efficacy between bone marrow and adipose-derived mesenchymal stem cells. Cell Journal (Yakhteh) 20:450

    Google Scholar 

  • Rockenstein E et al (2015) Neuro-peptide treatment with Cerebrolysin improves the survival of neural stem cell grafts in an APP transgenic model of Alzheimer disease. Stem Cell Res 15:54–67

    Article  CAS  PubMed  Google Scholar 

  • Roushandeh AM, Bahadori M, Roudkenar MH (2017) Mesenchymal stem cell-based therapy as a new horizon for kidney injuries. Arch Med Res 48:133–146

    Article  CAS  PubMed  Google Scholar 

  • Ruzicka J, Kulijewicz-Nawrot M, Rodrigez-Arellano JJ, Jendelova P, Sykova E (2016) Mesenchymal stem cells preserve working memory in the 3xTg-AD mouse model of Alzheimer’s disease. Int J Mol Sci 17:152

    Article  CAS  PubMed Central  Google Scholar 

  • Sánchez-Barceló E, Mediavilla M, Tan D, Reiter R (2010) Clinical uses of melatonin: evaluation of human trials. Curr Med Chem 17:2070–2095

    Article  PubMed  Google Scholar 

  • Sarlus H, Heneka MT (2017) Microglia in Alzheimer’s disease. J Clin Invest 127:3240–3249

    Article  PubMed  PubMed Central  Google Scholar 

  • Shi Z et al (2012) Evaluation of an Abeta(1-40)-induced cognitive deficit in rat using a reward-directed instrumental learning task. Behav Brain Res 234:323–333. https://doi.org/10.1016/j.bbr.2012.07.006

    Article  CAS  PubMed  Google Scholar 

  • Shi Z et al (2015) Tong Luo Jiu Nao ameliorates Abeta1-40-induced cognitive impairment on adaptive behavior learning by modulating ERK/CaMKII/CREB signaling in the hippocampus. BMC Complement Altern Med 15:55. https://doi.org/10.1186/s12906-015-0584-9

    Article  PubMed  PubMed Central  Google Scholar 

  • Son JH, Cho YC, Sung IY, Kim IR, Park BS, Kim YD (2014) Melatonin promotes osteoblast differentiation and mineralization of MC3T3-E1 cells under hypoxic conditions through activation of PKD/p38 pathways. J Pineal Res 57:385–392

    Article  CAS  PubMed  Google Scholar 

  • Tan SS, Han X, Sivakumaran P, Lim SY, Morrison WA (2016) Melatonin Protects Human Adipose-Derived Stem Cells from Oxidative Stress and Cell Death. Arch Plast Surg 43:237–241. https://doi.org/10.5999/aps.2016.43.3.237

    Article  PubMed  PubMed Central  Google Scholar 

  • Tang YL, Tang Y, Zhang YC, Qian K, Shen L, Phillips MI (2005) Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. J Am Coll Cardiol 46:1339–1350

    Article  CAS  PubMed  Google Scholar 

  • Tang Y et al (2014) Melatonin pretreatment improves the survival and function of transplanted mesenchymal stem cells after focal cerebral ischemia. Cell Transplant 23:1279–1291

    Article  PubMed  Google Scholar 

  • Tong LM, Fong H, Huang Y (2015) Stem cell therapy for Alzheimer’s disease and related disorders: current status and future perspectives. Exp Mol Med 47:e151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van LP (1977) Ketamine and xylazine for surgical anesthesia in rats. J Am Vet Med Assoc 171:842–844

    Google Scholar 

  • Yan K et al (2013) Bone marrow-derived mesenchymal stem cells maintain the resting phenotype of microglia and inhibit microglial activation. PLoS One 8:e84116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan Y, Ma T, Gong K, Ao Q, Zhang X, Gong Y (2014) Adipose-derived mesenchymal stem cell transplantation promotes adult neurogenesis in the brains of Alzheimer's disease mice. Neural Regen Res 9:798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yip HK et al (2013) Melatonin treatment improves adipose-derived mesenchymal stem cell therapy for acute lung ischemia–reperfusion injury. J Pineal Res 54:207–221

    Article  CAS  PubMed  Google Scholar 

  • Yu SP, Wei Z, Wei L (2013) Preconditioning strategy in stem cell transplantation therapy. Transl Stroke Res 4:76–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang HM, Zhang Y (2014) Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res 57:131–146

    Article  CAS  PubMed  Google Scholar 

  • Zhang L et al (2010) Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARγ expression and enhancing Runx2 expression. J Pineal Res 49:364–372

    Article  CAS  PubMed  Google Scholar 

  • Zhao L et al (2017) Acupuncture improves cerebral microenvironment in mice with Alzheimer’s disease treated with hippocampal neural stem cells. Mol Neurobiol 54:5120–5130

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Guilan University of Medical Sciences granted this study (No., 96120508).

Author information

Authors and Affiliations

  1. Cellular and Molecular Research Center, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran

    Ebrahim Nasiri, Rouhollah Gazor & Zoleikha Golipoor

  2. Department of Tissue Engineering and Applied Cell Sciences, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran

    Akram Alizadeh

  3. Medical Biotechnology Department, Paramedicine Faculty, Guilan University of Medical Sciences, Rasht, Iran

    Amaneh Mohammadi Roushandeh

  4. Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran

    Nasrin Hashemi-Firouzi & Zoleikha Golipoor

Authors
  1. Ebrahim Nasiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akram Alizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amaneh Mohammadi Roushandeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rouhollah Gazor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nasrin Hashemi-Firouzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zoleikha Golipoor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zoleikha Golipoor.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nasiri, E., Alizadeh, A., Roushandeh, A.M. et al. Melatonin-pretreated adipose-derived mesenchymal stem cells efficeintly improved learning, memory, and cognition in an animal model of Alzheimer's disease. Metab Brain Dis 34, 1131–1143 (2019). https://doi.org/10.1007/s11011-019-00421-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-019-00421-4

Keywords

Search

Navigation