title: Selegiline promotes NOTCH-JAGGED signaling in astrocytes of the peri-infarct region and improves the functional integrity of the neurovascular unit in a rat model of focal ischemia.
abstract: OBJECTIVE
  Our experiments aimed at exploring potential neurorestorative mechanisms of selegiline, a compound routinely used in the treatment of Parkinson's disease and previously shown to improve the functional recovery of stroke patients.
  
  
  METHODS
  Selegiline was administered continuously via osmotic mini-pumps between 48 and 216 hours following middle cerebral artery occlusion (MCAO) in rats. Twenty-four hours before sacrifice, the animals underwent magnetic resonance imaging (MRI). After decapitation, the peri-infarct region was dissected to perform a TAQMAN array gene expression study, and brains were fixed for immunolabeling.
  
  
  RESULTS
  In addition to the previously known induction of anti-apoptosis genes, selegiline significantly increased the mRNA level of Notch 1 receptor and its ligand Jagged 1. Immunohistochemistry demonstrated elevated Notch 1 and Jagged 1 immunoreactivities in the peri-infarct region. Double labeling with glial markers revealed that both Notch 1 and Jagged 1 were expressed in astrocytes but not in microglia. MRI examination indicated significantly reduced edema in selegiline-treated rats compared to control MCAO rats, and increased capillary network density was found in the peri-infarct region of the selegiline-treated animals.
  
  
  CONCLUSIONS
  Our results suggest that selegiline treatment enhances Notch-Jagged signaling in astrocytes, reduces peri-lesional edema and potentially helps preserve the capillary network following focal ischemia.
authors.affiliation: Department Section of Vascular Neurology, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Nardai
authors.affiliation: Laboratory of Neuromorphology and Human Brain Tissue Bank, Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary NAP Laboratory of Molecular and Systems Neurobiology, Institute of Biology, Hungarian Academy of Sciences and Eötvös Loránd University, Budapest, Hungary.
authors.forename: Arpád
authors.initials: A
authors.lastname: Dobolyi
authors.affiliation: Laboratory of Neuromorphology and Human Brain Tissue Bank, Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pál
authors.affiliation: Department Section of Vascular Neurology, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Skopál
authors.affiliation: Department Section of Vascular Neurology, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Nándor
authors.initials: N
authors.lastname: Pintér
authors.affiliation: Department Section of Vascular Neurology, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Kinga
authors.initials: K
authors.lastname: Lakatos
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Béla
authors.initials: B
authors.lastname: Merkely
authors.affiliation: Department Section of Vascular Neurology, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Nagy
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005786:Gene Expression Regulation / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D011938:Rec A Recombinases / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects; D012642:Selegiline / Q000627:therapeutic use*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D059467:Transcriptome; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D012642:Selegiline; D011938:Rec A Recombinases
keywords: Notch 1 and Jagged 1 induction; astrocyte activation in reactive gliosis; edema; mRNA expression by TAQMAN array; middle cerebral artery occlusion; neuroprotection in stroke