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Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery

The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and...

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Autores principales: Novorolsky, Robyn J., Kasheke, Gracious D. S., Hakim, Antoine, Foldvari, Marianna, Dorighello, Gabriel G., Sekler, Israel, Vuligonda, Vidyasagar, Sanders, Martin E., Renden, Robert B., Wilson, Justin J., Robertson, George S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10360135/
https://www.ncbi.nlm.nih.gov/pubmed/37484823
http://dx.doi.org/10.3389/fncel.2023.1226630
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author Novorolsky, Robyn J.
Kasheke, Gracious D. S.
Hakim, Antoine
Foldvari, Marianna
Dorighello, Gabriel G.
Sekler, Israel
Vuligonda, Vidyasagar
Sanders, Martin E.
Renden, Robert B.
Wilson, Justin J.
Robertson, George S.
author_facet Novorolsky, Robyn J.
Kasheke, Gracious D. S.
Hakim, Antoine
Foldvari, Marianna
Dorighello, Gabriel G.
Sekler, Israel
Vuligonda, Vidyasagar
Sanders, Martin E.
Renden, Robert B.
Wilson, Justin J.
Robertson, George S.
author_sort Novorolsky, Robyn J.
collection PubMed
description The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca(2+)) uptake supports NVU function by buffering Ca(2+) and stimulating energy production. However, excessive mitochondrial Ca(2+) uptake causes toxic mitochondrial Ca(2+) overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca(2+) uptake and efflux in the brain are mediated by the mitochondrial Ca(2+) uniporter complex (MCU(cx)) and sodium/Ca(2+)/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCU(cx) inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca(2+) overloading. These findings suggest that combining MCU(cx) inhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCU(cx) inhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCU(cx), or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.
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spelling pubmed-103601352023-07-22 Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery Novorolsky, Robyn J. Kasheke, Gracious D. S. Hakim, Antoine Foldvari, Marianna Dorighello, Gabriel G. Sekler, Israel Vuligonda, Vidyasagar Sanders, Martin E. Renden, Robert B. Wilson, Justin J. Robertson, George S. Front Cell Neurosci Neuroscience The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca(2+)) uptake supports NVU function by buffering Ca(2+) and stimulating energy production. However, excessive mitochondrial Ca(2+) uptake causes toxic mitochondrial Ca(2+) overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca(2+) uptake and efflux in the brain are mediated by the mitochondrial Ca(2+) uniporter complex (MCU(cx)) and sodium/Ca(2+)/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCU(cx) inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca(2+) overloading. These findings suggest that combining MCU(cx) inhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCU(cx) inhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCU(cx), or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues. Frontiers Media S.A. 2023-07-07 /pmc/articles/PMC10360135/ /pubmed/37484823 http://dx.doi.org/10.3389/fncel.2023.1226630 Text en Copyright © 2023 Novorolsky, Kasheke, Hakim, Foldvari, Dorighello, Sekler, Vuligonda, Sanders, Renden, Wilson and Robertson. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Novorolsky, Robyn J.
Kasheke, Gracious D. S.
Hakim, Antoine
Foldvari, Marianna
Dorighello, Gabriel G.
Sekler, Israel
Vuligonda, Vidyasagar
Sanders, Martin E.
Renden, Robert B.
Wilson, Justin J.
Robertson, George S.
Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery
title Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery
title_full Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery
title_fullStr Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery
title_full_unstemmed Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery
title_short Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery
title_sort preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10360135/
https://www.ncbi.nlm.nih.gov/pubmed/37484823
http://dx.doi.org/10.3389/fncel.2023.1226630
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