Molecular Neurobiology

, Volume 53, Issue 1, pp 518–531 | Cite as

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

  • Savina Apolloni
  • Paola Fabbrizio
  • Chiara Parisi
  • Susanna Amadio
  • Cinzia Volonté
Article

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.

Keywords

Histamine H1 receptor Microglia Motor neuron P2X7 M1/M2 phenotype 

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

Notes

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.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Savina Apolloni
    • 1
    • 2
  • Paola Fabbrizio
    • 2
  • Chiara Parisi
    • 1
  • Susanna Amadio
    • 2
  • Cinzia Volonté
    • 1
    • 2
  1. 1.Cellular Biology and Neurobiology InstituteCNRRomeItaly
  2. 2.Division Experimental NeuroscienceSanta Lucia Foundation, IRCCS,RomeItaly

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