{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:19:08Z","timestamp":1790813948143,"version":"4.1.0"},"reference-count":60,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,8,6]],"date-time":"2022-08-06T00:00:00Z","timestamp":1659744000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition, primarily affecting girls for which no cure currently exists. Neuronal morphogenesis and plasticity impairments as well as metabolic dysfunctions occur in CDD patients. The present study explored the potential therapeutic value for CDD of FRAX486, a brain\u2010penetrant molecule that was reported to selectively inhibit group I p21\u2010activated kinases (PAKs), serine\/threonine kinases critically involved in the regulation of neuronal morphology and glucose homeostasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effects of treatment with FRAX486 on CDD\u2010related alterations were assessed in vitro (100\u2009nM for 48\u2009h) on primary hippocampal cultures from <jats:italic>Cdkl5<\/jats:italic>\u2010knockout male mice (<jats:italic>Cdkl5<\/jats:italic>\u2010KO) and in vivo (20\u2009mg\/Kg, s.c. for 5\u2009days) on <jats:italic>Cdkl5<\/jats:italic>\u2010KO heterozygous females (<jats:italic>Cdkl5<\/jats:italic>\u2010Het).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The in vitro treatment with FRAX486 completely rescued the abnormal neuronal maturation and the number of PSD95\u2010positive puncta in <jats:italic>Cdkl5<\/jats:italic>\u2010KO mouse neurons. In vivo, FRAX486 normalized the general health status, the hyperactive profile and the fear learning defects of fully symptomatic <jats:italic>Cdkl5<\/jats:italic>\u2010Het mice. Systemically, FRAX486 treatment normalized the levels of reactive oxidizing species in the whole blood and the fasting\u2010induced hypoglycemia displayed by <jats:italic>Cdkl5<\/jats:italic>\u2010Het mice. In the hippocampus of <jats:italic>Cdkl5<\/jats:italic>\u2010Het mice, treatment with FRAX486 rescued spine maturation and PSD95 expression and restored the abnormal PAKs phosphorylation at sites which are critical for their activation (P\u2010PAK\u2010Ser144\/141\/139) or for the control cytoskeleton remodeling (P\u2010PAK1\u2010Thr212).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Present results provide evidence that PAKs may represent innovative therapeutic targets for CDD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.13907","type":"journal-article","created":{"date-parts":[[2022,8,6]],"date-time":"2022-08-06T07:40:03Z","timestamp":1659771603000},"page":"1718-1732","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Treatment with <scp>FRAX486<\/scp> rescues neurobehavioral and metabolic alterations in a female mouse model of <scp>CDKL5<\/scp> deficiency disorder"],"prefix":"10.1111","volume":"28","author":[{"given":"Claudia","family":"Fuchs","sequence":"first","affiliation":[{"name":"Department of Biomedical and Neuromotor Science University of Bologna  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Cosentino","sequence":"additional","affiliation":[{"name":"Center for Behavioral Sciences and Mental Health Istituto Superiore di Sanit\u00e0  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Urbinati","sequence":"additional","affiliation":[{"name":"Center for Behavioral Sciences and Mental Health Istituto Superiore di Sanit\u00e0  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"Talamo","sequence":"additional","affiliation":[{"name":"Center for Behavioral Sciences and Mental Health Istituto Superiore di Sanit\u00e0  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Medici","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science University of Bologna  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"Quattrini","sequence":"additional","affiliation":[{"name":"Core Facilities, Istituto Superiore di Sanit\u00e0  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Mottolese","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science University of Bologna  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"Pietraforte","sequence":"additional","affiliation":[{"name":"Core Facilities, Istituto Superiore di Sanit\u00e0  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Fuso","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Ciani","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science University of Bologna  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6508-1206","authenticated-orcid":false,"given":"Bianca","family":"De Filippis","sequence":"additional","affiliation":[{"name":"Center for Behavioral Sciences and Mental Health Istituto Superiore di Sanit\u00e0  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,6]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2019.02.015"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn197"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37851"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1086\/375538"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22639"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091613"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20174075"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2566"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2015.05.010"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2011.01.007"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.10.018"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.72.121801.161742"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201003008"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.07.023"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00956-9"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200104123"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M105599200"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.9.3726-3736.2005"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.05.003"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2487"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.04.064"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13674-9"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3822"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0705003104"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1219383110"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1321109111"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00506.2013"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn4019"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2014.06.007"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/9726950"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw231"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.104791"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2020.0827"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-183X.2006.00249.x"},{"key":"e_1_2_9_36_1","first-page":"e4389","article-title":"Performing vaginal lavage, crystal violet staining, and vaginal cytological evaluation for mouse estrous cycle staging identification","volume":"67","author":"McLean AC","year":"2012","journal-title":"Journal of Visualized Experiments JoVE"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2011.301"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2012.05.048"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2015.00086"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2014.105"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1138389"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4660"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)52451-6"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2019.107746"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-2929-0_17"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"issue":"1","key":"e_1_2_9_47_1","first-page":"1","article-title":"Procedures for detecting outlying observations in samples","volume":"11","author":"Grubbs FE","year":"1969","journal-title":"Dent Tech"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2015.08.028"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M009316200"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-53665-6"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI153606"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx237"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2014.02.001"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1943"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa122"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-016-0230-6"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15300"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz208"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2007.03.002"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/8267234"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.08.009"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.13907","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cns.13907","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.13907","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T20:28:41Z","timestamp":1692649721000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cns.13907"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,6]]},"references-count":60,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["10.1111\/cns.13907"],"URL":"https:\/\/doi.org\/10.1111\/cns.13907","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,6]]},"assertion":[{"value":"2022-01-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}