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Within this framework, the locus coeruleus (LC), the principal source of noradrenaline (NA) in the central nervous system, emerges as a plausible regulatory hub within a distributed monoaminergic network.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main body<\/jats:title>\n                    <jats:p>\n                      LC-derived NA shapes microglial and astrocytic reactivity, oxidative stress, mitochondrial function, oligodendrocyte differentiation, and blood-brain barrier stability through adrenergic receptor signaling. Neuropathological studies show LC neuron loss, astrogliosis, and altered NA levels in MS and related animal models. Post-mortem findings suggest that neuromelanin-bound metals and redox-active trace elements selectively accumulate in LC neurons, potentially triggering mitochondrial dysfunction, barrier disruption, and chronic glial activation. In animal models, pharmacological or genetic reductions in NA worsen inflammation, demyelination, and axonal damage, while increasing NA improves disease outcomes and restores glial and cytokine profiles. Early clinical studies of \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      -adrenergic agonists and NA-modulating drugs suggest benefits across specific symptom domains, including relapse activity, fatigue, mood, bladder function, and selected cognitive measures, but remain limited by small cohorts and insufficient stratification of patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Together, these findings support LC-NA dysfunction as a targetable aspect of MS pathobiology and justify biomarker-driven trials that combine noradrenergic interventions with molecular indicators of glial activity, myelin integrity, and stress-related signaling.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-026-03981-2","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:23:41Z","timestamp":1787725421000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The locus coeruleus at the crossroads of inflammation and neurodegeneration in multiple sclerosis"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4632-9784","authenticated-orcid":false,"given":"Intakhar","family":"Ahmad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6279-179X","authenticated-orcid":false,"given":"Rebecca","family":"Alemani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2815-2885","authenticated-orcid":false,"given":"Douglas L.","family":"Feinstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"issue":"4","key":"3981_CR1","doi-asserted-by":"publisher","first-page":"342","DOI":"10.2174\/1570159X12666140828220938","volume":"12","author":"D Braun","year":"2014","unstructured":"Braun D, Madrigal JL, Feinstein DL. 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