Journal of Molecular Neuroscience

, Volume 62, Issue 1, pp 123–129 | Cite as

Regulation of Human Brain Microvascular Endothelial Cell Adhesion and Barrier Functions by Memantine

  • Fei WangEmail author
  • Zhirong Zou
  • Yi Gong
  • Dong Yuan
  • Xun Chen
  • Tao Sun


Vascular risk factors have been linked to cognitive decline and dementia in the elderly. Microvascular inflammation, especially of the endothelium, may contribute to the progression of neurodegenerative events in Alzheimer’s disease (AD). Memantine, an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is a licensed drug used for the treatment of moderate to severe AD. However, little information is available regarding its anti-inflammatory effects on the endothelium. In this study, we investigated the effects of memantine on human brain microvascular endothelial dysfunction induced by the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Our results show that memantine prevents the attachment of monocyte THP-1 cells to human brain microvascular endothelial cells (HBMVEs). An in vitro BBB model experiment displayed that memantine could rescue TNF-α-induced disruption of the in vitro BBB model. In addition, memantine also interferes with monocyte transmigration across the BBB model. Our results indicate that TNF-α significantly increased the expression of cell adhesion molecules, such as ICAM-1, VCAM-1, and E-selectin, which was prevented by pretreatment with memantine. Mechanistically, memantine reversed activation of the transcription factor NF-κB by preventing the phosphorylation and degradation of its inhibitor IκBα. Our data is the first to describe a novel anti-inflammatory mechanism driven by the endothelial cell-mediated neuroprotective effects of memantine.


Alzheimer’s disease (AD) Memantine Blood-brain barrier (BBB) Endothelial cells NF-κB 



This work was supported by the National Natural Science Foundation of China (No. 81260182, 81560206) and Natural Science Foundation of Yunnan Province (No. FB2016121).

Supplementary material

12031_2017_917_Fig6_ESM.gif (3.7 mb)
Supplementary Figure 1

Memantine inhibits the adhesion of monocytes to human brain microvascular endothelial cells (HBMVEs). Human brain microvascular endothelial cells (HBMVEs) were pretreated with 10 μM or 20 μM memantine for 24 h, followed by incubation with TNF-α (5 ng/ml) for another 24 h. Quantitative data for THP-1 cells attached to HBMVEs was shown (#, P < 0.01 vs. untreated control group; *, P < 0.01 vs. TNF-α treated group). (GIF 3754 kb)

12031_2017_917_MOESM1_ESM.tif (2.9 mb)
High resolution image (TIFF 2964 kb)


  1. Andjelkovic AV, Pachter JS (1998) Central nervous system endothelium in neuroinflammatory, neuroinfectious, and neurodegenerative disease. J Neurosci Res 51:423–430CrossRefPubMedGoogle Scholar
  2. Bevilacqua MP, Gimbrone MA Jr (1987) Inducible endothelial functions in inflammation and coagulation. Semin Thromb Hemost 13:425–433CrossRefPubMedGoogle Scholar
  3. Chen SL, Tao PL, Chu CH, Chen SH, Wu HE, Tseng LF et al (2012) Low-dose memantine through its anti-inflammation and neurotrophic effects in rats. J NeuroImmune Pharmacol 7:444–453CrossRefPubMedGoogle Scholar
  4. Chengye Z, Daixing Z, Qiang Z, Shusheng L (2013) PGC-1-related coactivator (PRC) negatively regulates endothelial adhesion of monocytes via inhibition of NF κB activity. Biochem Biophys Res Commun 439:121–125CrossRefPubMedGoogle Scholar
  5. Cho GS, Lee JC, Ju C, Kim C, Kim WK (2013) N-Methyl-D-aspartate receptor antagonists memantine and MK-801 attenuate the cerebral infarct accelerated by intracorpus callosum injection of lipopolysaccharides. Neurosci Lett 538:9–14CrossRefPubMedGoogle Scholar
  6. Cristante E, McArthur S, Mauro C, Maggioli E, Romero IA, Wylezinska-Arridge M et al (2013) Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications. Proc Natl Acad Sci U S A 110:832–841CrossRefPubMedGoogle Scholar
  7. Frijns CJ, Kappelle LJ (2002) Inflammatory cell adhesion molecules in ischemic cerebrovascular disease. Stroke 33:2115–2122CrossRefPubMedGoogle Scholar
  8. Fukami K, Yamagishi S, Okuda S (2014) Role of AGEs-RAGE system in cardiovascular disease. Curr Pharm 20:2395–2402CrossRefGoogle Scholar
  9. Grammas P, Ovase R (2001) Inflammatory factors are elevated in brain microvessels in Alzheimer’s disease. Neurobiol Aging 22:837–842CrossRefPubMedGoogle Scholar
  10. Granger DN, Senchenkova E (2010) Inflammation and the microcirculation. In: integrated systems physiology: from molecule to function, vol. 2. Morgan & Claypool Life Sciences Publishers, San Rafael, pp 21–87Google Scholar
  11. Hayden MS, West AP, Ghosh S (2006) NF-kappaB and the immune response. Oncogene 25:758–780CrossRefGoogle Scholar
  12. Larochelle C, Alvarez JI, Prat A (2011) How do immune cells overcome the blood-brain barrier in multiple sclerosis? FEBS Lett 585:3770–3780CrossRefPubMedGoogle Scholar
  13. Lee ST, Chu K, Jung KH, Kim J, Kim EH, Kim SJ et al (2006) Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement. J Cereb Blood Flow Metab 26:536–544CrossRefPubMedGoogle Scholar
  14. Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11:519–531CrossRefPubMedGoogle Scholar
  15. Miguel-Hidalgo JJ, Paul IA, Wanzo V, Banerjee PK (2012) Memantine prevents cognitive impairment and reduces Bcl-2 and caspase 8 immunoreactivity in rats injected with amyloid beta1-40. Eur J Pharmacol 692:38–45CrossRefPubMedGoogle Scholar
  16. Mount C, Downton C (2006) Alzheimer disease: progress or profit? Nat Med 12:780–784CrossRefPubMedGoogle Scholar
  17. Murta V, Farías MI, Pitossi FJ, Ferrari CC (2015) Chronic systemic IL-1β exacerbates central neuroinflammation independently of the blood-brain barrier integrity. J Neuroimmunol 278:30–43CrossRefPubMedGoogle Scholar
  18. Parsons CG, Danysz W, Quack G (1999) Memantine is a clinically well tolerated N-methyl-d aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology 38:735–767CrossRefPubMedGoogle Scholar
  19. Perez-de-Puig I, Miró-Mur F, Ferrer-Ferrer M, Gelpi E, Pedragosa J, Justicia C et al (2015) Neutrophil recruitment to the brain in mouse and human ischemic stroke. Acta Neuropathol 129:239–257CrossRefPubMedGoogle Scholar
  20. Rao RM, Yang L, Garcia-Cardena G, Luscinskas FW (2007) Endothelial-dependent mechanisms of monocyte recruitment to the vascular wall. Circ Res 101:234–247CrossRefPubMedGoogle Scholar
  21. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ (2003) Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 348:1333–1341CrossRefPubMedGoogle Scholar
  22. Salvador E, Shityakov S, Forster C (2014) Glucocorticoids and endothelial cell barrier function. Cell Tissue Res 355:597–605CrossRefPubMedGoogle Scholar
  23. Schweingruber N, Reichardt SD, Lühder F, Reichardt HM (2012) Mechanisms of glucocorticoids in the control of neuroinflammation. J Neuroendocrinol 24:174–182CrossRefPubMedGoogle Scholar
  24. Serra G, Demontis F, Serra F, De Chiara L, Spoto A, Girardi P, Vidotto G, Serra G (2014) Memantine: new prospective in bipolar disorder treatment. World J Psychiatry 4:80–90CrossRefPubMedPubMedCentralGoogle Scholar
  25. Srinivasan M, Lahiri DK (2015) Significance of NF-κB as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer’s disease and multiple sclerosis. Expert Opin Ther Targets 19:471–487CrossRefPubMedGoogle Scholar
  26. Sulkowski G, Dąbrowska-Bouta B, Chalimoniuk M, Strużyńska L (2013) Effects of antagonists of glutamate receptors on pro-inflammatory cytokines in the brain cortex of rats subjected to experimental autoimmune encephalomyelitis. J Neuroimmunol 261:67–76CrossRefPubMedGoogle Scholar
  27. Verma S, Kumar M, Gurjav U, Lum S, Nerurkar VR (2010) Reversal of West Nile virus-induced blood-brain barrier disruption and tight junction proteins degradation by matrix metalloproteinases inhibitor. Virology 397:130–138CrossRefPubMedGoogle Scholar
  28. Woehrl B, Klein M, Rupprecht T, Schmetzer H, Angele B, Häcker H et al (2010) CXCL16 contributes to neutrophil recruitment to cerebrospinal fluid in pneumococcal meningitis. J Infect Dis 202:1389–1396CrossRefPubMedGoogle Scholar
  29. Wu HM, Tzeng NS, Qian L, Wei SJ, Hu X, Chen SH et al (2009a) Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation. Eur Secur 34:2344–2357Google Scholar
  30. Zuliani G, Cavalieri M, Galvani M et al (2008) Markers of endothelial dysfunction in older subjects with late onset Alzheimer’s disease or vascular dementia. J Neurol Sci 272:164–170CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Fei Wang
    • 1
    Email author
  • Zhirong Zou
    • 2
  • Yi Gong
    • 1
  • Dong Yuan
    • 1
  • Xun Chen
    • 1
  • Tao Sun
    • 1
  1. 1.Second Department of NeurosurgeryThe First Affiliated Hospital of Kunming Medical UniversityKunmingChina
  2. 2.Department of Anatomy, Histology and EmbryologyKunming Medical UniversityKunmingChina

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