Skip to main content

Advertisement

SpringerLink
Log in

Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Mutations in the Cu2+/Zn2+ superoxide dismutase 1 (SOD1) gene underlie 14–23 % of familial and 1–7 % of sporadic cases of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by a specific loss of motor neurons in the brain and spinal cord. Neuroinflammation and oxidative stress are emerging as key players in the pathogenesis of ALS, thus justifying the interest in glial cells and particularly microglia, in addition to motor neurons, as novel therapeutic approaches against ALS. Recently, histamine was proven to participate in the pathogenesis of neuroinflammatory and neurodegenerative diseases, and particularly, microglia was shown to be sensitive to the histamine challenge mainly through histamine H1 receptors. Clemastine is a first-generation and CNS-penetrant H1 receptor antagonist considered as a safe antihistamine compound that was shown to possess immune suppressive properties. In order to investigate if clemastine might find promising application in the treatment of ALS, in this work, we tested its action in the SOD1G93A mouse model which is extensively used in ALS preclinical studies. We demonstrated that chronic clemastine administration in SOD1G93A mice reduces microgliosis, modulates microglia-related inflammatory genes, and enhances motor neuron survival. Moreover, in vitro, clemastine is able to modify several activation parameters of SOD1G93A microglia, and particularly CD68 and arginase-1 expression, as well as phospho-ERK1/2 and NADPH oxidase 2 levels. Being clemastine a drug already employed in clinical practice, our results strongly encourage its further exploitation as a candidate for preclinical trials and a new modulator of neuroinflammation in ALS.

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

Similar content being viewed by others

Abbreviations

ALS:

Amyotrophic lateral sclerosis

BDNF:

Brain-derived neurotrophic factor

BzATP:

2′-3′-O-(benzoyl-benzoyl) ATP

GFAP:

Glial fibrillary acidic protein

H1R:

Histamine 1 receptor

IL:

Interleukin

LPS:

Lipopolysaccharide

NOX2:

NADPH oxidase 2

p-ERK1/2:

Phospho-ERK1/2

PBS:

Phosphate-buffered saline

qRT-PCR:

Quantitative real-time PCR

ROS:

Reactive oxygen species

SOD1:

Superoxide dismutase 1

WT:

Wild type

References

  1. Poppe L, Rue L, Robberecht W, Van Den Bosch L (2014) Translating biological findings into new treatment strategies for amyotrophic lateral sclerosis (ALS). Exp Neurol. doi:10.1016/j.expneurol.2014.07.001

  2. Andersen PM, Al-Chalabi A (2011) Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol 7(11):603–615

    Article  CAS  PubMed  Google Scholar 

  3. Philips T, Robberecht W (2011) Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol 10(3):253–263

    Article  CAS  PubMed  Google Scholar 

  4. Rizzo F, Riboldi G, Salani S, Nizzardo M, Simone C, Corti S, Hedlund E (2014) Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis. Cell Mol Life Sci 71(6):999–1015

    Article  CAS  PubMed  Google Scholar 

  5. Philips T, Rothstein JD (2014) Glial cells in amyotrophic lateral sclerosis. Exp Neurol. doi:10.1016/j.expneurol.2014.05.015

  6. Passani MB, Blandina P (2011) Histamine receptors in the CNS as targets for therapeutic intervention. Trends Pharmacol Sci 32(4):242–249

    Article  CAS  PubMed  Google Scholar 

  7. Provensi G, Coccurello R, Umehara H, Munari L, Giacovazzo G, Galeotti N, Nosi D, Gaetani S, Romano A, Moles A, Blandina P, Passani MB (2014) Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake. Proc Natl Acad Sci U S A 111(31):11527–11532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Passani MB, Ballerini C (2012) Histamine and neuroinflammation: insights from murine experimental autoimmune encephalomyelitis. Front Syst Neurosci 6:32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Saligrama N, Noubade R, Case LK, del Rio R, Teuscher C (2012) Combinatorial roles for histamine H1-H2 and H3-H4 receptors in autoimmune inflammatory disease of the central nervous system. Eur J Immunol 42(6):1536–1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Katoh Y, Niimi M, Yamamoto Y, Kawamura T, Morimoto-Ishizuka T, Sawada M, Takemori H, Yamatodani A (2001) Histamine production by cultured microglial cells of the mouse. Neurosci Lett 305(3):181–184

    Article  CAS  PubMed  Google Scholar 

  11. Vizuete ML, Merino M, Venero JL, Santiago M, Cano J, Machado A (2000) Histamine infusion induces a selective dopaminergic neuronal death along with an inflammatory reaction in rat substantia nigra. J Neurochem 75(2):540–552

    Article  CAS  PubMed  Google Scholar 

  12. Hiraga N, Adachi N, Liu K, Nagaro T, Arai T (2007) Suppression of inflammatory cell recruitment by histamine receptor stimulation in ischemic rat brains. Eur J Pharmacol 557(2–3):236–244

    Article  CAS  PubMed  Google Scholar 

  13. Ferreira R, Santos T, Goncalves J, Baltazar G, Ferreira L, Agasse F, Bernardino L (2012) Histamine modulates microglia function. J Neuroinflammation 9:90

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dong H, Zhang W, Zeng X, Hu G, Zhang H, He S, Zhang S (2014) Histamine induces upregulated expression of histamine receptors and increases release of inflammatory mediators from microglia. Mol Neurobiol 49(3):1487–1500

    Article  CAS  PubMed  Google Scholar 

  15. Zhu J, Qu C, Lu X, Zhang S (2014) Activation of microglia by histamine and substance P. Cell Physiol Biochem 34(3):768–780

    Article  CAS  PubMed  Google Scholar 

  16. Rocha SM, Pires J, Esteves M, Graca B, Bernardino L (2014) Histamine: a new immunomodulatory player in the neuron-glia crosstalk. Front Cell Neurosci 8:120

    Article  PubMed  PubMed Central  Google Scholar 

  17. Norenberg W, Hempel C, Urban N, Sobottka H, Illes P, Schaefer M (2011) Clemastine potentiates the human P2X7 receptor by sensitizing it to lower ATP concentrations. J Biol Chem 286(13):11067–11081

    Article  PubMed  PubMed Central  Google Scholar 

  18. Mei F, Fancy SP, Shen YA, Niu J, Zhao C, Presley B, Miao E, Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L, Franklin RJ, Green A, Hauser SL, Chan JR (2014) Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med 20(8):954–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Johansen P, Weiss A, Bunter A, Waeckerle-Men Y, Fettelschoss A, Odermatt B, Kundig TM (2011) Clemastine causes immune suppression through inhibition of extracellular signal-regulated kinase-dependent proinflammatory cytokines. J Allergy Clin Immunol 128(6):1286–1294

    Article  CAS  PubMed  Google Scholar 

  20. Pizzasegola C, Caron I, Daleno C, Ronchi A, Minoia C, Carri MT, Bendotti C (2009) Treatment with lithium carbonate does not improve disease progression in two different strains of SOD1 mutant mice. Amyotroph Lateral Scler 10(4):221–228

    Article  CAS  PubMed  Google Scholar 

  21. Apolloni S, Amadio S, Montilli C, Volonté C, D’Ambrosi N (2013) Ablation of P2X7 receptor exacerbates gliosis and motoneuron death in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. Hum Mol Genet 22(20):4102–4116

    Article  CAS  PubMed  Google Scholar 

  22. Gapeyev ABSJ, Lushnikov KV, Chemeris NK (2006) Anti-inflammatory effects of low-intensity millimeter wave radiation. Bioelectromagnetics. Springer, Dordrecht

    Google Scholar 

  23. Ludolph AC, Bendotti C, Blaugrund E, Chio A, Greensmith L, Loeffler JP, Mead R, Niessen HG, Petri S, Pradat PF, Robberecht W, Ruegg M, Schwalenstocker B, Stiller D, van den Berg L, Vieira F, von Horsten S (2010) Guidelines for preclinical animal research in ALS/MND: A consensus meeting. Amyotroph Lateral Scler 11(1–2):38–45

    Article  PubMed  Google Scholar 

  24. Weydt P, Hong SY, Kliot M, Moller T (2003) Assessing disease onset and progression in the SOD1 mouse model of ALS. Neuroreport 14(7):1051–1054

    Article  PubMed  Google Scholar 

  25. Thau N, Jungnickel J, Knippenberg S, Ratzka A, Dengler R, Petri S, Grothe C (2012) Prolonged survival and milder impairment of motor function in the SOD1 ALS mouse model devoid of fibroblast growth factor 2. Neurobiol Dis 47(2):248–257

    Article  CAS  PubMed  Google Scholar 

  26. Apolloni S, Parisi C, Pesaresi MG, Rossi S, Carri MT, Cozzolino M, Volonté C, D’Ambrosi N (2013) The NADPH oxidase pathway is dysregulated by the P2X7 receptor in the SOD1-G93A microglia model of amyotrophic lateral sclerosis. J Immunol 190(10):5187–5195

    Article  CAS  PubMed  Google Scholar 

  27. Nikodemova M, Small AL, Smith SM, Mitchell GS, Watters JJ (2014) Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats. Neurobiol Dis 69:43–53

    Article  CAS  PubMed  Google Scholar 

  28. Chhor V, Le Charpentier T, Lebon S, Ore MV, Celador IL, Josserand J, Degos V, Jacotot E, Hagberg H, Savman K, Mallard C, Gressens P, Fleiss B (2013) Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behav Immun 32:70–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. De Simone R, Niturad CE, De Nuccio C, Ajmone-Cat MA, Visentin S, Minghetti L (2010) TGF-beta and LPS modulate ADP-induced migration of microglial cells through P2Y1 and P2Y12 receptor expression. J Neurochem 115(2):450–459

    Article  PubMed  Google Scholar 

  30. Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9(12):1512–1519

    Article  CAS  PubMed  Google Scholar 

  31. Fiala M, Chattopadhay M, La Cava A, Tse E, Liu G, Lourenco E, Eskin A, Liu PT, Magpantay L, Tse S, Mahanian M, Weitzman R, Tong J, Nguyen C, Cho T, Koo P, Sayre J, Martinez-Maza O, Rosenthal MJ, Wiedau-Pazos M (2010) IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patients. J Neuroinflammation 7:76

    Article  PubMed  PubMed Central  Google Scholar 

  32. Graves MC, Fiala M, Dinglasan LA, Liu NQ, Sayre J, Chiappelli F, van Kooten C, Vinters HV (2004) Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells. Amyotroph Lateral Scler Other Motor Neuron Disord 5(4):213–219

    Article  CAS  PubMed  Google Scholar 

  33. Mizwicki MT, Fiala M, Magpantay L, Aziz N, Sayre J, Liu G, Siani A, Chan D, Martinez-Maza O, Chattopadhyay M, La Cava A (2012) Tocilizumab attenuates inflammation in ALS patients through inhibition of IL6 receptor signaling. Am J Neurodegener Dis 1(3):305–315

    PubMed  PubMed Central  Google Scholar 

  34. Skaper SD, Facci L, Giusti P (2013) Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator. Mol Neurobiol 48(2):340–352

    Article  CAS  PubMed  Google Scholar 

  35. Skaper SD, Giusti P, Facci L (2014) Microglia and mast cells: two tracks on the road to neuroinflammation. FASEB J 26(8):3103–3117

    Article  Google Scholar 

  36. Haas HL, Sergeeva OA, Selbach O (2008) Histamine in the nervous system. Physiol Rev 88(3):1183–1241

    Article  CAS  PubMed  Google Scholar 

  37. Henkel JS, Beers DR, Zhao W, Appel SH (2009) Microglia in ALS: the good, the bad, and the resting. J Neuroimmune Pharmacol 4(4):389–398

    Article  PubMed  Google Scholar 

  38. Beers DR, Zhao W, Liao B, Kano O, Wang J, Huang A, Appel SH, Henkel JS (2011) Neuroinflammation modulates distinct regional and temporal clinical responses in ALS mice. Brain Behav Immun 25(5):1025–1035

    Article  CAS  PubMed  Google Scholar 

  39. Zhao W, Beers DR, Appel SH (2013) Immune-mediated mechanisms in the pathoprogression of amyotrophic lateral sclerosis. J Neuroimmune Pharmacol 8(4):888–899

    Article  PubMed  PubMed Central  Google Scholar 

  40. Apolloni S, Amadio S, Parisi C, Matteucci A, Potenza RL, Armida M, Popoli P, D’Ambrosi N, Volonté C (2014) Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis. Dis Model Mech 7(9):1101–1109

    Article  PubMed  PubMed Central  Google Scholar 

  41. Weisman GA, Camden JM, Peterson TS, Ajit D, Woods LT, Erb L (2012) P2 receptors for extracellular nucleotides in the central nervous system: role of P2X7 and P2Y(2) receptor interactions in neuroinflammation. Mol Neurobiol 46(1):96–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Marden JJ, Harraz MM, Williams AJ, Nelson K, Luo M, Paulson H, Engelhardt JF (2007) Redox modifier genes in amyotrophic lateral sclerosis in mice. J Clin Invest 117(10):2913–2919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Trumbull KA, McAllister D, Gandelman MM, Fung WY, Lew T, Brennan L, Lopez N, Morre J, Kalyanaraman B, Beckman JS (2012) Diapocynin and apocynin administration fails to significantly extend survival in G93A SOD1 ALS mice. Neurobiol Dis 45(1):137–144

    Article  CAS  PubMed  Google Scholar 

  44. Parone PA, Da Cruz S, Han JS, McAlonis-Downes M, Vetto AP, Lee SK, Tseng E, Cleveland DW (2013) Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis. J Neurosci 33(11):4657–4671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Huang G, Lee X, Bian Y, Shao Z, Sheng G, Pepinsky RB, Mi S (2013) Death receptor 6 (DR6) antagonist antibody is neuroprotective in the mouse SOD1G93A model of amyotrophic lateral sclerosis. Cell Death Dis 4:e841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rouaux C, Panteleeva I, Rene F, Gonzalez de Aguilar JL, Echaniz-Laguna A, Dupuis L, Menger Y, Boutillier AL, Loeffler JP (2007) Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model. J Neurosci 27(21):5535–5545

    Article  CAS  PubMed  Google Scholar 

  47. D’Ambrosi N, Finocchi P, Apolloni S, Cozzolino M, Ferri A, Padovano V, Pietrini G, Carri MT, Volonté C (2009) The proinflammatory action of microglial P2 receptors is enhanced in SOD1 models for amyotrophic lateral sclerosis. J Immunol 183(7):4648–4656

    Article  PubMed  Google Scholar 

  48. Pantano F, Berti P, Guida FM, Perrone G, Vincenzi B, Amato MM, Righi D, Dell’aquila E, Graziano F, Catalano V, Caricato M, Rizzo S, Muda AO, Russo A, Tonini G, Santini D (2013) The role of macrophages polarization in predicting prognosis of radically resected gastric cancer patients. J Cell Mol Med 17(11):1415–1421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Amadio S, Parisi C, Montilli C, Carrubba AS, Apolloni S, Volonté C (2014) P2Y(12) receptor on the verge of a neuroinflammatory breakdown. Mediat Inflamm 2014:975849

Download references

Acknowledgments

This work was supported by the Progetto Ministero della Salute RC FSL-C: “Studio molecolare e funzionale dei recettori purinergici P2 nel sistema nervoso e nelle patologie neurodegenerative e neuroinfiammatorie” and by the Italian Ministry of Education, University and Research “Flagship Project Nanomax.” We thank Dr. Roberto Coccurello and Dr. Nadia D’Ambrosi for critical reading of the manuscript.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Cellular Biology and Neurobiology Institute, CNR, Via del Fosso di Fiorano, 65, 00143, Rome, Italy

    Savina Apolloni, Chiara Parisi & Cinzia Volonté

  2. Division Experimental Neuroscience, Santa Lucia Foundation, IRCCS,, Via del Fosso di Fiorano, 65, Rome, 00143, Italy

    Savina Apolloni, Paola Fabbrizio, Susanna Amadio & Cinzia Volonté

Authors
  1. Savina Apolloni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Fabbrizio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chiara Parisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susanna Amadio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cinzia Volonté
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cinzia Volonté.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Apolloni, S., Fabbrizio, P., Parisi, C. et al. Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis. Mol Neurobiol 53, 518–531 (2016). https://doi.org/10.1007/s12035-014-9019-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-9019-8

Keywords

Search

Navigation