{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T07:05:15Z","timestamp":1775113515773,"version":"3.50.1"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,4,24]],"date-time":"2019-04-24T00:00:00Z","timestamp":1556064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007802","name":"Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007802","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Histamine is an immune modulator, neuroprotective, and remyelinating agent, beneficially acting on skeletal muscles and promoting anti\u2010inflammatory features in amyotrophic lateral sclerosis (ALS) microglia. Drugs potentiating the endogenous release of histamine are in trial for neurological diseases, with a role not systematically investigated in ALS. Here, we examine histamine pathway associations in ALS patients and the efficacy of a histamine\u2010mediated therapeutic strategy in ALS mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We adopted an integrative multi\u2010omics approach combining gene expression profiles, copy number variants, and single nucleotide polymorphisms of ALS patients. We treated superoxide dismutase 1 (SOD1)\u2010G93A mice that recapitulate key ALS features, with the brain\u2010permeable histamine precursor histidine in the symptomatic phase of the disease and analysed the rescue from disease pathological signs. We examined the action of histamine in cultured SOD1\u2010G93A motor neuron\u2010like cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 13 histamine\u2010related genes deregulated in the spinal cord of two ALS patient subgroups, among which genes involved in histamine metabolism, receptors, transport, and secretion. Some histamine\u2010related genes overlapped with genomic regions disrupted by DNA copy number and with ALS\u2010linked pathogenic variants. Histidine treatment in SOD1\u2010G93A mice proved broad efficacy in ameliorating ALS features, among which most importantly lifespan, motor performance, microgliosis, muscle atrophy, and motor neurons survival <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our gene set\/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine\u2010related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets. We disclose a novel important role for histamine in the characterization of the multi\u2010gene network responsible for ALS and, furthermore, in the drug development process.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12422","type":"journal-article","created":{"date-parts":[[2019,4,25]],"date-time":"2019-04-25T02:01:01Z","timestamp":1556157661000},"page":"872-893","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Histaminergic transmission slows progression of amyotrophic lateral sclerosis"],"prefix":"10.1002","volume":"10","author":[{"given":"Savina","family":"Apolloni","sequence":"first","affiliation":[{"name":"IRCCS Fondazione Santa Lucia  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanna","family":"Amadio","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Santa Lucia  Rome 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