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Injury to the spinal cord triggers a signaling cascade that results in activation of the inflammatory cascade, apoptosis, and Zn(II) ion homeostasis. Trehalose (Tre), a nonreducing disaccharide, and <jats:sc>l<\/jats:sc>-carnosine (Car), (\u03b2-alanyl-<jats:sc>l<\/jats:sc>-histidine), one of the endogenous histidine dipeptides have been recognized to suppress early inflammatory effects, oxidative stress and to possess neuroprotective effects. We report on the effects of the conjugation of Tre with Car (Tre\u2013car) in reducing inflammation in in vitro and in vivo models. The in vitro study was performed using rat pheochromocytoma cells (PC12 cell line). After 24\u00a0h, Tre\u2013car, Car, Tre, and Tre\u2009+\u2009Car mixture treatments, cells were collected and used to investigate Zn<jats:sup>2+<\/jats:sup> homeostasis. The in vivo model of SCI was induced by extradural compression of the spinal cord at the T6\u2013T8 levels. After treatments with Tre, Car and Tre\u2013Car conjugate 1 and 6\u00a0h after SCI, spinal cord tissue was collected for analysis. In vitro results demonstrated the ionophore effect and chelating features of <jats:sc>l<\/jats:sc>-carnosine and its conjugate. In vivo, the Tre\u2013car conjugate treatment counteracted the activation of the early inflammatory cascade, oxidative stress and apoptosis after SCI. The Tre\u2013car conjugate stimulated neurotrophic factors release, and influenced Zn<jats:sup><jats:bold>2+<\/jats:bold><\/jats:sup> homeostasis. We demonstrated that Tre\u2013car, Tre and Car treatments improved tissue recovery after SCI. Tre\u2013car decreased proinflammatory, oxidative stress mediators release, upregulated neurotrophic factors and restored Zn<jats:sup>2+<\/jats:sup> homeostasis, suggesting that Tre\u2013car may represent a promising therapeutic agent for counteracting the consequences of SCI.<\/jats:p>","DOI":"10.1007\/s10571-022-01273-w","type":"journal-article","created":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T06:02:47Z","timestamp":1663567367000},"page":"1637-1659","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Trehalose\u2013Carnosine Prevents the Effects of Spinal Cord Injury Through Regulating Acute Inflammation and Zinc(II) Ion Homeostasis"],"prefix":"10.1007","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4316-2291","authenticated-orcid":false,"given":"Irene","family":"Paterniti","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9642-6844","authenticated-orcid":false,"given":"Alessia","family":"Filippone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3186-6355","authenticated-orcid":false,"given":"Irina","family":"Naletova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6694-2151","authenticated-orcid":false,"given":"Valentina","family":"Greco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8557-9386","authenticated-orcid":false,"given":"Sebastiano","family":"Sciuto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2663-6387","authenticated-orcid":false,"given":"Emanuela","family":"Esposito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6131-3690","authenticated-orcid":false,"given":"Salvatore","family":"Cuzzocrea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5367-0823","authenticated-orcid":false,"given":"Enrico","family":"Rizzarelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,9,19]]},"reference":[{"key":"1273_CR1","first-page":"1","volume":"1","author":"F Abbaszadeh","year":"2020","unstructured":"Abbaszadeh F, Fakhri S, Khan H (2020) Targeting apoptosis and autophagy following spinal cord injury: therapeutic approaches to polyphenols and candidate phytochemicals. 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