title: Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.
abstract: Mutations in the Cu(2+)/Zn(2+) 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 SOD1(G93A) mouse model which is extensively used in ALS preclinical studies. We demonstrated that chronic clemastine administration in SOD1(G93A) 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 SOD1(G93A) 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.
authors.affiliation: Cellular Biology and Neurobiology Institute, CNR, Via del Fosso di Fiorano, 65, 00143, Rome, Italy.|Division Experimental Neuroscience, Santa Lucia Foundation, IRCCS,, Via del Fosso di Fiorano, 65, Rome, 00143, Italy.
authors.forename: Savina
authors.initials: S
authors.lastname: Apolloni
authors.affiliation: Division Experimental Neuroscience, Santa Lucia Foundation, IRCCS,, Via del Fosso di Fiorano, 65, Rome, 00143, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fabbrizio
authors.affiliation: Cellular Biology and Neurobiology Institute, CNR, Via del Fosso di Fiorano, 65, 00143, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Parisi
authors.affiliation: Division Experimental Neuroscience, Santa Lucia Foundation, IRCCS,, Via del Fosso di Fiorano, 65, Rome, 00143, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Amadio
authors.affiliation: Cellular Biology and Neurobiology Institute, CNR, Via del Fosso di Fiorano, 65, 00143, Rome, Italy. cinzia.volonte@cnr.it.|Division Experimental Neuroscience, Santa Lucia Foundation, IRCCS,, Via del Fosso di Fiorano, 65, Rome, 00143, Italy. cinzia.volonte@cnr.it.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Volonté
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D002974:Clemastine / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D000066829:Neuroprotection / Q000187:drug effects* / Q000502:physiology; D010641:Phenotype; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D000893:Anti-Inflammatory Agents; D002974:Clemastine; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
keywords: Histamine H1 receptor; M1/M2 phenotype; Microglia; Motor neuron; P2X7