title: Treatment with UDP-glucose, GDNF, and memantine promotes SVZ and white matter self-repair by endogenous glial progenitor cells in neonatal rats with ischemic PVL.
abstract: Periventricular leukomalacia (PVL) is one of the foremost neurological conditions leading to long-term abnormalities in premature infants. Since it is difficult to prevent initiation of this damage in utero, promoting the innate regenerative potential of the brain after birth may provide a more feasible, prospective therapy for PVL. Treatment with UDP-glucose (UDPG), an endogenous agonist of G protein-coupled receptor 17 (GPR17) that may enhance endogenous self-repair potentiality, glial cell line-derived neurotrophic factor (GDNF), a neurotrophic factor associated with the growth and survival of nerve cells, and memantine, a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors that block ischemia-induced glutamate signal transduction, has been reported to achieve functional, neurological improvement in neonatal rats with PVL. The aim of the present study was to further explore whether UDPG, GDNF and/or memantine could promote corresponding self-repair of the subventricular zone (SVZ) and white matter (WM) in neonatal rats with ischemia-induced PVL. SVZ or WM tissue samples and cultured glial progenitor cells derived from a 5 day-old neonatal rat model of PVL were utilized for studying response to UDPG, GDNF and memantine in vivo and in vitro, respectively. Labeling with 5'-bromo-2'-deoxyuridine and immunofluorescent cell lineage markers after hypoxia-ischemia or oxygen-glucose deprivation (OGD) revealed that UDPG, GDNF and memantine each significantly increased glial progenitor cells and preoligodendrocytes (preOLs), as well as more differentiated immature and mature oligodendrocyte (OL), in both the SVZ and WM in vivo or in vitro. SVZ and WM glial cell apoptosis was also significantly reduced by UDPG, GDNF or memantine, both in vivo and in vitro. These results indicated that UDPG, GDNF or memantine may promote endogenous self-repair by stimulating proliferation of glial progenitor cells derived from both the SVZ and WM, activating their differentiation into more mature OLs, and raising the survival rate of these newly generated glial cells in neonatal rats with ischemic PVL.
authors.affiliation: Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai 200092, China.
authors.forename: W-J
authors.initials: WJ
authors.lastname: Li
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Jianshe East Road No. 1, Zhengzhou 450052, China.
authors.forename: F-X
authors.initials: FX
authors.lastname: Mao
authors.affiliation: Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai 200092, China. Electronic address: hjchenk@163.com.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai 200092, China.
authors.forename: L-H
authors.initials: LH
authors.lastname: Qian
authors.affiliation: Hematology Research and Advanced Diagnostics Laboratories, 510 Research Institute, Children's Hospital of Orange County, 1201 W. La Veta Avenue, Orange, CA 92868, United States. Electronic address: jbuzby@uci.edu.
authors.forename: J S
authors.initials: JS
authors.lastname: Buzby
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage; D005947:Glucose / Q000172:deficiency; D007969:Leukomalacia, Periventricular / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008559:Memantine / Q000008:administration & dosage; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011897:Random Allocation; D011918:Rats, Inbred SHR; D055153:Stem Cell Niche / Q000187:drug effects* / Q000502:physiology; D014532:Uridine Diphosphate Glucose / Q000008:administration & dosage; D066127:White Matter / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D005947:Glucose; D014532:Uridine Diphosphate Glucose; D008559:Memantine
keywords: GDNF; GPR17; UDP-glucose; memantine; oligodendrocytes