Brain-derived neurotrophic factor administration mediated oligodendrocyte differentiation and myelin formation in subcortical ischemic stroke.
OBJECTIVE
Translational research is beginning to reveal the importance of trophic factors as a therapy for cellular brain repair. The purpose of this study was to analyze whether brain-derived neurotrophic factor (BDNF) administration could mediate oligodendrogenesis and remyelination after white matter injury in subcortical stroke.


METHODS
Ischemia was induced in rats by injection of endothelin-1. At 24 hours, 0.4 μg/kg of BDNF or saline was intravenously administered to the treatment and control groups, respectively. Functional evaluation, MRI, and fiber tract integrity on tractography images were analyzed. Proliferation (KI-67) and white matter repair markers (A2B5, 2',3'-cyclic-nucleotide 3'-phosphodiesterase [CNPase], adenomatous polyposis coli [APC], platelet-derived growth factor receptor alpha [PDGFR-α], oligodendrocyte marker O4 [O4], oligodendrocyte transcription factor [Olig-2], and myelin basic protein [MBP]) were analyzed at 7 and 28 days.


RESULTS
The BDNF-treated animals showed less functional deficit at 28 days after treatment than the controls (P<0.05). Although T2-MRI did not show differences in lesion size at 7 and 28 days between groups, diffusion tensor imaging tractography analysis revealed significantly better tract connectivity at 28 days in the BDNF group than in the controls (P<0.05). Increased proliferation of oligodendrocyte progenitors was observed in treated animals at 7 days (P<0.05). Finally, the levels of white matter repair markers (A2B5, CNPase, and O4 at 7 days; Olig-2 and MBP at 28 days) were higher in the BDNF group than in the controls (P<0.05).


CONCLUSIONS
BDNF administration exerted better functional outcome, oligodendrogenesis, remyelination, and fiber connectivity than controls in rats subjected to subcortical damage in ischemic stroke.
From the Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Madrid, Spain (J.R.-C., M.G.-F., L.O.-O., B.R.-F., B.F., M.T.V.-C., E.D.-T.); and Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Madrid, Spain (T.N.H., S.C.).
Jaime
J
Ramos-Cejudo
From the Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Madrid, Spain (J.R.-C., M.G.-F., L.O.-O., B.R.-F., B.F., M.T.V.-C., E.D.-T.); and Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Madrid, Spain (T.N.H., S.C.). exuperio.diez@salud.madrid.org mariagutierrezfdez@hotmail.com.
María
M
Gutiérrez-Fernández
From the Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Madrid, Spain (J.R.-C., M.G.-F., L.O.-O., B.R.-F., B.F., M.T.V.-C., E.D.-T.); and Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Madrid, Spain (T.N.H., S.C.).
Laura
L
Otero-Ortega
From the Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Madrid, Spain (J.R.-C., M.G.-F., L.O.-O., B.R.-F., B.F., M.T.V.-C., E.D.-T.); and Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Madrid, Spain (T.N.H., S.C.).
Berta
B
Rodríguez-Frutos
From the Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Madrid, Spain (J.R.-C., M.G.-F., L.O.-O., B.R.-F., B.F., M.T.V.-C., E.D.-T.); and Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Madrid, Spain (T.N.H., S.C.).
Blanca
B
Fuentes
From the Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Madrid, Spain (J.R.-C., M.G.-F., L.O.-O., B.R.-F., B.F., M.T.V.-C., E.D.-T.); and Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Madrid, Spain (T.N.H., S.C.).
Maria Teresa
MT
Vallejo-Cremades
From the Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Madrid, Spain (J.R.-C., M.G.-F., L.O.-O., B.R.-F., B.F., M.T.V.-C., E.D.-T.); and Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Madrid, Spain (T.N.H., S.C.).
Teresa Navarro
TN
Hernanz
From the Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Madrid, Spain (J.R.-C., M.G.-F., L.O.-O., B.R.-F., B.F., M.T.V.-C., E.D.-T.); and Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Madrid, Spain (T.N.H., S.C.).
Sebastián
S
Cerdán
From the Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Madrid, Spain (J.R.-C., M.G.-F., L.O.-O., B.R.-F., B.F., M.T.V.-C., E.D.-T.); and Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Madrid, Spain (T.N.H., S.C.). exuperio.diez@salud.madrid.org mariagutierrezfdez@hotmail.com.
Exuperio
E
Díez-Tejedor
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000187:drug effects; D025601:Adenomatous Polyposis Coli Protein / Q000187:drug effects; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D056324:Diffusion Tensor Imaging; D008279:Magnetic Resonance Imaging; D004676:Myelin Basic Protein / Q000187:drug effects; D009186:Myelin Sheath / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects*; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000187:drug effects; D020521:Stroke / Q000209:etiology / Q000473:pathology*; D066127:White Matter / Q000187:drug effects* / Q000473:pathology
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D025601:Adenomatous Polyposis Coli Protein; D051792:Basic Helix-Loop-Helix Proteins; D019208:Brain-Derived Neurotrophic Factor; D004676:Myelin Basic Protein; D020796:Receptor, Platelet-Derived Growth Factor alpha
brain-derived neurotrophic factor; endothelin-1; subcortical stroke