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
Affiliations: Department Section of Vascular Neurology, Heart and Vascular Center, Semmelweis University, Budapest, Hungary | 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 | Heart and Vascular Center, Semmelweis University, Budapest, Hungary
Note: [] Corresponding author: Zoltán Nagy, M.D., Ph.D., Head of the Department Section of Vascular Neurology Heart and Vascular Center, Semmelweis University, 68 Városmajor utca, Budapest, H-1122, Hungary. Tel.: +36 1 458 6810; E-mail: nagyzg@erseb.sote.hu
Abstract: Purpose: 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. Conclusion: 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.
Keywords: Notch 1 and Jagged 1 induction, mRNA expression by TAQMAN array, middle cerebral artery occlusion, neuroprotection in stroke, astrocyte activation in reactive gliosis, edema
