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In the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), recent evidence supports a link between NPY and ALS disease processes. The goal of this study was to determine the therapeutic potential and role of NPY in ALS, harnessing the brain\u2010targeted intranasal delivery of the peptide, previously utilised to correct motor and cognitive phenotypes in other neurological conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To confirm the association with clinical disease characteristics, NPY expression was quantified in post\u2010mortem motor cortex tissue of ALS patients and age\u2010matched controls. The effect of NPY on ALS cortical pathophysiology was investigated using slice electrophysiology and multi\u2010electrode array recordings of SOD1<jats:sup>G93A<\/jats:sup> cortical cultures in vitro. The impact of NPY on ALS disease trajectory was investigated by treating SOD1<jats:sup>G93A<\/jats:sup> mice intranasally with NPY and selective NPY receptor agonists and antagonists from pre\u2010symptomatic and symptomatic phases of disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the human post\u2010mortem ALS motor cortex, we observe a significant increase in NPY expression, which is not present in the somatosensory cortex. In vitro, we demonstrate that NPY can ameliorate ALS hyperexcitability, while brain\u2010targeted nasal delivery of NPY and a selective NPY Y1 receptor antagonist modified survival and motor deficits specifically within the symptomatic phase of the disease in the ALS SOD1<jats:sup>G93A<\/jats:sup> mouse.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Taken together, these findings highlight the capacity for non\u2010invasive brain\u2010targeted interventions in ALS and support antagonism of NPY Y1Rs as a novel strategy to improve ALS motor function.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51885","type":"journal-article","created":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T04:46:36Z","timestamp":1693370796000},"page":"1985-1999","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Intranasal neuropeptide <scp>Y1<\/scp> receptor antagonism improves motor deficits in 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