Intranasal administration of aTf protects and repairs the neonatal white matter after a cerebral hypoxic-ischemic event.
Our previous studies showed that the intracerebral injection of apotransferrin (aTf) attenuates white matter damage and accelerates the remyelination process in a neonatal rat model of cerebral hypoxia-ischemia (HI) injury. However, the intracerebral injection of aTf might not be practical for clinical treatments. Therefore, the development of less invasive techniques capable of delivering aTf to the central nervous system would clearly aid in its effective clinical use. In this work, we have determined whether intranasal (iN) administration of human aTf provides neuroprotection to the neonatal mouse brain following a cerebral hypoxic-ischemic event. Apotransferrin was infused into the naris of neonatal mice and the HI insult was induced by right common carotid artery ligation followed by exposure to low oxygen concentration. Our results showed that aTf was successfully delivered into the neonatal HI brain and detected in the olfactory bulb, forebrain and posterior brain 30 min after inhalation. This treatment successfully reduced white matter damage, neuronal loss and astrogliosis in different brain regions and enhanced the proliferation and survival of oligodendroglial progenitor cells (OPCs) in the subventricular zone and corpus callosum (CC). Additionally, using an in vitro hypoxic model, we demonstrated that aTf prevents oligodendrocyte progenitor cell death by promoting their differentiation. In summary, these data suggest that iN administration of aTf has the potential to be used for clinical treatment to protect myelin and to induce remyelination in demyelinating hypoxic-ischemic events in the neonatal brain.
Department of Biological Chemistry, School of Pharmacy and Biochemistry, and Institute of Chemistry and Biological Physicochemistry (IQUIFIB), School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Argentina.
Mariano
M
Guardia Clausi
Pablo M
PM
Paez
Anthony T
AT
Campagnoni
Laura A
LA
Pasquini
Juana M
JM
Pasquini
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000235:genetics; D000281:Administration, Intranasal; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D001059:Apoproteins / Q000008:administration & dosage*; D000071183:Autophagy-Related Proteins; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control*; D001973:Bromodeoxyuridine / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003078:Colchicine / Q000494:pharmacology; D003337:Corpus Callosum / Q000187:drug effects / Q000473:pathology; D003571:Cytochalasin B / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020547:Lateral Ventricles / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D055495:Neurogenesis / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009836:Oligodendroglia / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D013997:Time Factors; D014168:Transferrin / Q000008:administration & dosage*; D000099216:Chondroitin Sulfate Proteoglycan 4
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D000941:Antigens; D001059:Apoproteins; D000071183:Autophagy-Related Proteins; D001973:Bromodeoxyuridine; D053148:Caspase 3; D003078:Colchicine; D003571:Cytochalasin B; D049452:Green Fluorescent Proteins; D007381:Intermediate Filament Proteins; D047908:Intracellular Signaling Peptides and Proteins; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D064231:Nestin; D018696:Neuroprotective Agents; D010982:Platelet-Derived Growth Factor; D011509:Proteoglycans; D055748:SOXB1 Transcription Factors; D014168:Transferrin; D000099216:Chondroitin Sulfate Proteoglycan 4; C577484:NES protein, human; C577485:Nes protein, mouse; C577486:Nes protein, rat; C428743:Rb1cc1 protein, mouse; C527783:Sox2 protein, mouse; C028284:apotransferrin; C485184:enhanced green fluorescent protein; C075278:platelet-derived growth factor A; C571338:Cnp protein, mouse