Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in Rats
It has been demonstrated that the K+-dependent Na+/Ca2+ exchanger, NCKX2, is a new promising stroke neuroprotective target. However, because no pharmacological activator of NCKX2 is still available, microRNA (miRNA) may represent an alternative method to modulate NCKX2 expression. In particular, by...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253119303324 |
| _version_ | 1819044882959826944 |
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| author | Ornella Cuomo Pasquale Cepparulo Serenella Anzilotti Angelo Serani Rossana Sirabella Paola Brancaccio Natascia Guida Valeria Valsecchi Antonio Vinciguerra Pasquale Molinaro Luigi Formisano Lucio Annunziato Giuseppe Pignataro, MD PhD |
| author_facet | Ornella Cuomo Pasquale Cepparulo Serenella Anzilotti Angelo Serani Rossana Sirabella Paola Brancaccio Natascia Guida Valeria Valsecchi Antonio Vinciguerra Pasquale Molinaro Luigi Formisano Lucio Annunziato Giuseppe Pignataro, MD PhD |
| author_sort | Ornella Cuomo |
| collection | DOAJ |
| description | It has been demonstrated that the K+-dependent Na+/Ca2+ exchanger, NCKX2, is a new promising stroke neuroprotective target. However, because no pharmacological activator of NCKX2 is still available, microRNA (miRNA) may represent an alternative method to modulate NCKX2 expression. In particular, by bioinformatics analysis, miR-223-5p emerged as a possible modulator of NCKX2 expression. In the light of these premises, the aims of the present study were: (1) to evaluate miR-223-5p and NCKX2 expression in the temporoparietal cortex and striatum of rats subjected to transient middle cerebral artery occlusion; (2) to evaluate whether miR-223-5p targets the 3′ UTR of the NCKX2 transcript; and (3) to evaluate the effect of miR-223-5p modulation on brain ischemic volume and neurological deficits. Our results showed that miR-223-5p expression increased in a time-dependent manner in the striatum of ischemic rats in parallel with NCKX2 downregulation, and that the transfection of cortical neurons with miR-223-5p induced a reduction of NCKX2 expression. Moreover, a luciferase assay showed that miR-223-5p specifically interacts with the NCKX2 3′ UTR subregion (+7037 to +8697), thus repressing NCKX2 translation. More interestingly, intracerebroventricular infusion of anti-miR-223-5p prevented NCKX2 downregulation after ischemia, thus promoting neuroprotection. The present findings support the idea that blocking miR-223-5p by antimiRNA is a reasonable strategy to reduce the neurodetrimental effect induced by NCKX2 downregulation during brain ischemia. |
| first_indexed | 2024-12-21T10:19:45Z |
| format | Article |
| id | doaj.art-d5de7584c93d4d1a9c8576dbbe4a279e |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-21T10:19:45Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-d5de7584c93d4d1a9c8576dbbe4a279e2022-12-21T19:07:30ZengElsevierMolecular Therapy: Nucleic Acids2162-25312019-12-011810631071Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in RatsOrnella Cuomo0Pasquale Cepparulo1Serenella Anzilotti2Angelo Serani3Rossana Sirabella4Paola Brancaccio5Natascia Guida6Valeria Valsecchi7Antonio Vinciguerra8Pasquale Molinaro9Luigi Formisano10Lucio Annunziato11Giuseppe Pignataro, MD PhD12Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDivision of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyIRCCS SDN Napoli, 80142 Naples, ItalyDivision of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDivision of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDivision of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyIRCCS SDN Napoli, 80142 Naples, ItalyDivision of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDivision of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDivision of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDivision of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyIRCCS SDN Napoli, 80142 Naples, Italy; Corresponding author: Lucio Annunziato, IRCCS SDN Napoli, 80142 Naples, Italy.Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; Corresponding author: Giuseppe Pignataro, Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.It has been demonstrated that the K+-dependent Na+/Ca2+ exchanger, NCKX2, is a new promising stroke neuroprotective target. However, because no pharmacological activator of NCKX2 is still available, microRNA (miRNA) may represent an alternative method to modulate NCKX2 expression. In particular, by bioinformatics analysis, miR-223-5p emerged as a possible modulator of NCKX2 expression. In the light of these premises, the aims of the present study were: (1) to evaluate miR-223-5p and NCKX2 expression in the temporoparietal cortex and striatum of rats subjected to transient middle cerebral artery occlusion; (2) to evaluate whether miR-223-5p targets the 3′ UTR of the NCKX2 transcript; and (3) to evaluate the effect of miR-223-5p modulation on brain ischemic volume and neurological deficits. Our results showed that miR-223-5p expression increased in a time-dependent manner in the striatum of ischemic rats in parallel with NCKX2 downregulation, and that the transfection of cortical neurons with miR-223-5p induced a reduction of NCKX2 expression. Moreover, a luciferase assay showed that miR-223-5p specifically interacts with the NCKX2 3′ UTR subregion (+7037 to +8697), thus repressing NCKX2 translation. More interestingly, intracerebroventricular infusion of anti-miR-223-5p prevented NCKX2 downregulation after ischemia, thus promoting neuroprotection. The present findings support the idea that blocking miR-223-5p by antimiRNA is a reasonable strategy to reduce the neurodetrimental effect induced by NCKX2 downregulation during brain ischemia.http://www.sciencedirect.com/science/article/pii/S2162253119303324 |
| spellingShingle | Ornella Cuomo Pasquale Cepparulo Serenella Anzilotti Angelo Serani Rossana Sirabella Paola Brancaccio Natascia Guida Valeria Valsecchi Antonio Vinciguerra Pasquale Molinaro Luigi Formisano Lucio Annunziato Giuseppe Pignataro, MD PhD Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in Rats Molecular Therapy: Nucleic Acids |
| title | Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in Rats |
| title_full | Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in Rats |
| title_fullStr | Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in Rats |
| title_full_unstemmed | Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in Rats |
| title_short | Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in Rats |
| title_sort | anti mir 223 5p ameliorates ischemic damage and improves neurological function by preventing nckx2 downregulation after ischemia in rats |
| url | http://www.sciencedirect.com/science/article/pii/S2162253119303324 |
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