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We have previously shown that JNK inhibition by a specific cell-permeable peptide significantly reduces infarct size and neuronal death in an <jats:italic>in vivo<\/jats:italic> model of cerebral ischemia. However, systemic inhibition of JNK may have detrimental side effects, owing to blockade of its physiological function. Here we designed a new inhibitor peptide (growth arrest and DNA damage-inducible 45<jats:italic>\u03b2<\/jats:italic> (GADD45<jats:italic>\u03b2<\/jats:italic>-I)) targeting mitogen-activated protein kinase kinase 7 (MKK7), an upstream activator of JNK, which exclusively mediates JNK\u2019s pathological activation. GADD45<jats:italic>\u03b2<\/jats:italic>-I was engineered by optimizing the domain of the GADD45<jats:italic>\u03b2<\/jats:italic>, able to bind to MKK7, and by linking it to the TAT peptide sequence, to allow penetration of biological membranes. Our data clearly indicate that GADD45<jats:italic>\u03b2<\/jats:italic>-I significantly reduces neuronal death in excitotoxicity induced by either <jats:italic>N<\/jats:italic>-methyl-<jats:sc>D<\/jats:sc>-aspartate exposure or by oxygen\u2013glucose deprivation <jats:italic>in vitro<\/jats:italic>. Moreover, GADD45<jats:italic>\u03b2<\/jats:italic>-I exerted neuroprotection <jats:italic>in vivo<\/jats:italic> in two models of ischemia, obtained by electrocoagulation and by thromboembolic occlusion of the middle cerebral artery (MCAo). Indeed, GADD45<jats:italic>\u03b2<\/jats:italic>-I reduced the infarct size when injected 30\u2009min before the lesion in both models. The peptide was also effective when administrated 6\u2009h after lesion, as demonstrated in the electrocoagulation model. The neuroprotective effect of GADD45<jats:italic>\u03b2<\/jats:italic>-I is long lasting; in fact, 1 week after MCAo the infarct volume was still reduced by 49%. Targeting MKK7 could represent a new therapeutic strategy for the treatment of ischemia and other pathologies involving MKK7\/JNK activation. Moreover, this new inhibitor can be useful to further dissect the physiological and pathological role of the JNK pathway in the brain.<\/jats:p>","DOI":"10.1038\/cddis.2015.226","type":"journal-article","created":{"date-parts":[[2015,8,13]],"date-time":"2015-08-13T15:48:47Z","timestamp":1439480927000},"page":"e1854-e1854","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Exploring the role of MKK7 in excitotoxicity and cerebral ischemia: a novel pharmacological strategy against brain injury"],"prefix":"10.1038","volume":"6","author":[{"given":"A","family":"Vercelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Biggi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Sclip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I E","family":"Repetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Cimini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Falleroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Tomasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Monti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Tonna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Morelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V","family":"Grande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Stravalaci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Biasini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O","family":"Marin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Bianco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"di Marino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Borsello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,8,13]]},"reference":[{"key":"BFcddis2015226_CR1","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/nrd1958","volume":"5","author":"SA Lipton","year":"2006","unstructured":"Lipton SA . 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