title: Treatment of stroke with a synthetic liver X receptor agonist, TO901317, promotes synaptic plasticity and axonal regeneration in mice.
abstract: In this study, we tested the hypothesis that TO901317 promotes synapse plasticity and axonal regeneration after stroke. Adult male C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo) and treated with or without TO901317 starting 24 h after MCAo daily for 14 days. Axonal damage and regeneration were evaluated by immunostaining. TO901317 significantly increased synaptophysin expression and axonal regeneration, as well as decreased the expressions of amyloid betaA4 precursor protein and Nogo receptor (NgR) in the ischemic brain. To test whether TO901317 regulates the phosphorylation of phosphatidylinositol 3-kinase (p-PI3K) and Akt (p-Akt) activity in the ischemic brain, MCAo mice were treated with or without TO901317 starting 24 h after MCAo daily for 4 days and were then killed at 5 days after MCAo. TO901317 treatment significantly increased p-PI3K and p-Akt activity, but did not increase total PI3K expression in the ischemic brain. Using primary cortical neuron (PCN) culture, TO901317 significantly increased synaptophysin expression, p-PI3K activity, and decreased NgR expression compared with nontreated controls. TO901317 also significantly increased neurite outgrowth, and inhibition of the PI3K/Akt pathway by LY294002 decreased neurite outgrowth in both controls and TO901317-treated groups in cultured hypoxic PCN. These data indicate that TO901317 promotes synaptic plasticity and axonal regeneration, and that PI3K/Akt signaling activity contributes to neurite outgrowth.
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan 48202, USA. jieli@neuro.hfh.edu
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
authors.forename: Alex
authors.initials: A
authors.lastname: Zacharek
authors.forename: Xu
authors.initials: X
authors.lastname: Cui
authors.forename: Amjad
authors.initials: A
authors.lastname: Shehadah
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.forename: Cynthia
authors.initials: C
authors.lastname: Roberts
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000648:ultrastructure; D058851:GPI-Linked Proteins; D006845:Hydrocarbons, Fluorinated / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008026:Ligation; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000473:pathology; D009185:Myelin Proteins / Q000187:drug effects; D009416:Nerve Regeneration / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects*; D000070816:Nogo Receptor 1; D051058:Oncogene Protein v-akt / Q000096:biosynthesis / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000187:drug effects; D016622:Silver Staining; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use*; D016708:Synaptophysin / Q000096:biosynthesis / Q000235:genetics; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D016564:Amyloid beta-Protein Precursor; D058851:GPI-Linked Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; D051058:Oncogene Protein v-akt; D057093:Orphan Nuclear Receptors; D019869:Phosphatidylinositol 3-Kinases; D011956:Receptors, Cell Surface; D013449:Sulfonamides; D016708:Synaptophysin; C419790:Rtn4r protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides