{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T20:58:18Z","timestamp":1782334698191,"version":"3.54.5"},"reference-count":126,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T00:00:00Z","timestamp":1470182400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,11,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\"><jats:list-item><jats:p>Impaired uptake of glutamate builds up the extracellular level of this excitatory transmitter to trigger rhythmic neuronal bursting and delayed cell death in the brainstem motor nucleus hypoglossus.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>This process is the expression of the excitotoxicity that underlies motoneuron degeneration in diseases such as amyotrophic lateral sclerosis affecting bulbar motoneurons.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>In a model of motoneuron excitotoxicity produced by pharmacological block of glutamate uptake<jats:italic>in vitro<\/jats:italic>, rhythmic bursting is suppressed by activation of neuronal nicotinic receptors with their conventional agonist nicotine. Emergence of bursting is facilitated by nicotinic receptor antagonists.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Following excitotoxicity, nicotinic receptor activity decreases mitochondrial energy dysfunction, endoplasmic reticulum stress and production of toxic radicals. Globally, these phenomena synergize to provide motoneuron protection.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Nicotinic receptors may represent a novel target to contrast pathological overactivity of brainstem motoneurons and therefore to prevent their metabolic distress and death.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Excitotoxicity is thought to be one of the early processes in the onset of amyotrophic lateral sclerosis (ALS) because high levels of glutamate have been detected in the cerebrospinal fluid of such patients due to dysfunctional uptake of this transmitter that gradually damages brainstem and spinal motoneurons. To explore potential mechanisms to arrest ALS onset, we used an established<jats:italic>in vitro<\/jats:italic>model of rat brainstem slice preparation in which excitotoxicity is induced by the glutamate uptake blocker<jats:sc>dl<\/jats:sc>\u2010threo\u2010\u03b2\u2010benzyloxyaspartate (TBOA). Because certain brain neurons may be neuroprotected via activation of nicotinic acetylcholine receptors (nAChRs) by nicotine, we investigated if nicotine could arrest excitotoxic damage to highly ALS\u2010vulnerable hypoglossal motoneurons (HMs). On 50% of patch\u2010clamped HMs, TBOA induced intense network bursts that were inhibited by 1\u201310\u00a0\u03bc<jats:sc>m<\/jats:sc>nicotine, whereas nAChR antagonists facilitated burst emergence in non\u2010burster cells. Furthermore, nicotine inhibited excitatory transmission and enhanced synaptic inhibition. Strong neuroprotection by nicotine prevented the HM loss observed after 4\u00a0h of TBOA exposure. This neuroprotective action was due to suppression of downstream effectors of neurotoxicity such as increased intracellular levels of reactive oxygen species, impaired energy metabolism and upregulated genes involved in endoplasmic reticulum (ER) stress. In addition, HMs surviving TBOA toxicity often expressed UDP\u2010glucose glycoprotein glucosyltransferase, a key element in repair of misfolded proteins: this phenomenon was absent after nicotine application, indicative of ER stress prevention. Our results suggest nAChRs to be potential targets for inhibiting excitotoxic damage of motoneurons at an early stage of the neurodegenerative process.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp272591","type":"journal-article","created":{"date-parts":[[2016,7,4]],"date-time":"2016-07-04T08:56:47Z","timestamp":1467622607000},"page":"6777-6798","source":"Crossref","is-referenced-by-count":16,"title":["Nicotinic receptor activation contrasts pathophysiological bursting and neurodegeneration evoked by glutamate uptake block on rat hypoglossal motoneurons"],"prefix":"10.1113","volume":"594","author":[{"given":"Silvia","family":"Corsini","sequence":"first","affiliation":[{"name":"Department of Neuroscience International School for Advanced Studies (SISSA) Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Tortora","sequence":"additional","affiliation":[{"name":"Department of Neuroscience International School for Advanced Studies (SISSA) Trieste 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