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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)518-531
Number of pages14
JournalMolecular Neurobiology
Volume53
Issue number1
DOIs
Publication statusPublished - 2015

Keywords

  • Histamine H1 receptor
  • M1/M2 phenotype
  • Microglia
  • Motor neuron
  • P2X7

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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