{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:06:52Z","timestamp":1790633212911,"version":"4.1.0"},"reference-count":72,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,9,9]],"date-time":"2019-09-09T00:00:00Z","timestamp":1567987200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>The specific mechanisms underlying cyclin\u2010dependent kinase 5 (Cdk5)\u2010mediated neuropathic pain at the spinal cord level remain elusive. The aim of the present study was to explore the role of crosstalk between Cdk5\/p35 and extracellular signal\u2010regulated kinase 1\/2 (ERK1\/2) signalling in mediating spinal astrocyte activity via the PPAR\u03b3 pathway in a rat model of chronic constriction injury (CCI). Here, we quantified pain behaviour after CCI; detected the localization of p35, Cdk5, phosphorylated ERK1\/2 (pERK1\/2), phosphorylated peroxisome proliferator\u2010activated receptor \u03b3 (pPPAR\u03b3), neuronal nuclei (a neuronal marker), glial fibrillary acidic protein (GFAP, an activated astrocyte marker) and ionized calcium binding adaptor molecule 1 (a microglial marker) in the dorsal horn using immunofluorescence; measured the protein levels of Cdk5, p35, pERK1\/2, pPPAR\u03b3 and GFAP using western blot analysis; and gauged the enzyme activity of Cdk5\/p35 kinase using a Cdk5\/p35 kinase activity assay kit. Tumour necrosis factor\u2010\u03b1, interleukin (IL)\u20101\u03b2 and IL\u20106 levels were measured using enzyme\u2010linked immunosorbent assay (ELISA). Ligation of the right sciatic nerve induced mechanical allodynia; thermal hyperalgesia; and the time\u2010dependent upregulation of p35, pERK1\/2 and GFAP and downregulation of pPPAR\u03b3. p35 colocalized with Cdk5, pERK1\/2, pPPAR\u03b3, neurons and astrocytes but not microglia. Meanwhile, intrathecal injection of the Cdk5 inhibitor roscovitine, the mitogen\u2010activated ERK kinase (MEK) inhibitor U0126 and the PPAR\u03b3 agonist pioglitazone prevented or reversed behavioural allodynia, increased pPPAR\u03b3 expression, inhibited astrocyte activation and alleviated proinflammatory cytokine (tumour necrosis factor\u2010\u03b1, IL\u20101\u03b2, and IL\u20106) release from activated astrocytes. Furthermore, crosstalk between the Cdk5\/p35 and ERK1\/2 pathways was observed with CCI. Blockade of either Cdk5\/p35 or ERK1\/2 inhibited Cdk5 activity. These findings indicate that spinal crosstalk between the Cdk5\/p35 and ERK1\/2 pathways mediates astrocyte activity via the PPAR\u03b3 pathway in CCI rats and that targeting this crosstalk could be an effective strategy to attenuate CCI and astrocyte\u2010derived neuroinflammation.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14827-fig-0010-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14827","type":"journal-article","created":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T18:48:24Z","timestamp":1563389304000},"page":"166-184","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Crosstalk between Cdk5\/p35 and ERK1\/2 signalling mediates spinal astrocyte activity via the PPAR\u03b3 pathway in a rat model of chronic constriction injury"],"prefix":"10.1111","volume":"151","author":[{"given":"Yu","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Anesthesiology The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Cardiovascular Institute Nanning Guangxi P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7198-7506","authenticated-orcid":false,"given":"Yubo","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,9]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/530274"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13887"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(88)90209-6"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2004.10.018"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-013-2807-4"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(94)90144-9"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09291"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2008.02.002"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001021"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2006.10.002"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1016525716209"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.2174\/1876386300902010011"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nurt.2010.05.016"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2015.01.018"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.j.pain.0000460333.79127.be"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2014.09.019"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2010.07.031"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2015.04.008"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(88)90026-7"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20485"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12985"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2017.01.006"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-016-9833-2"},{"key":"e_1_2_7_25_1","first-page":"1233","article-title":"Role of the glia in neuropathic pain caused by peripheral nerve injury","volume":"64","author":"Inoue K.","year":"2012","journal-title":"Brain Nerve"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep22007"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2008.12.011"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2013.06.022"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81950"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.2741\/2802"},{"key":"e_1_2_7_31_1","first-page":"191","article-title":"CDK5 is a novel regulatory protein in PPARgamma ligand\u2010induced antiproliferation","volume":"28","author":"Kim E.","year":"2006","journal-title":"Int. J. Oncol."},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1080\/00207454.2017.1375913"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2014.04.008"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1159\/000485008"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7742(09)85013-7"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.08207FP"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2013.01.072"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e12-02-0125"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2003.08.064"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynpai.2018.07.003"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejp.860"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.5.6.2578"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510405103"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00129.2009"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M308518200"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.514"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2012.04.035"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00065"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109324200"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1745-7254.2005.00123.x"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(95)00164-6"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-019-01278-z"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.c1079"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(01)00343-4"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2009.04.002"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-7-49"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(00)00003-6"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-018-0836-4"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26526"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2006.08.008"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-014-1713-9"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2008.09.074"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13620"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0b013e31826f0a4a"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2012.03.025"},{"key":"e_1_2_7_66_1","article-title":"The BDNF\/TrkB signaling pathway is involved in heat hyperalgesia mediated by Cdk5 in rats","volume":"9","author":"Zhang H. H.","year":"2014","journal-title":"PLoS ONE"},{"key":"e_1_2_7_67_1","article-title":"ERK MAP kinase activation in spinal cord regulates phosphorylation of Cdk5 at serine 159 and contributes to peripheral inflammation induced pain\/hypersensitivity","volume":"9","author":"Zhang X.","year":"2014","journal-title":"PLoS ONE"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-017-2513-1"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.28790"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1177\/1744806918796057"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E06-09-0851"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.1177\/1744806917697979"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(83)90201-4"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjnc.14827","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.14827","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jnc.14827","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.14827","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T10:30:04Z","timestamp":1718015404000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.14827"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,9]]},"references-count":72,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,10]]}},"alternative-id":["10.1111\/jnc.14827"],"URL":"https:\/\/doi.org\/10.1111\/jnc.14827","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,9]]},"assertion":[{"value":"2019-04-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}