Intranasally Administered MSC-Derived Extracellular Vesicles Reverse Cisplatin-Induced Cognitive Impairment

Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothe...
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Autor*in:	Bojana Milutinovic [verfasserIn] Rajasekaran Mahalingam [verfasserIn] Mayela Mendt [verfasserIn] Luis Arroyo [verfasserIn] Alexandre Seua [verfasserIn] Shruti Dharmaraj [verfasserIn] Elizabeth Shpall [verfasserIn] Cobi J. Heijnen [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	chemobrain cognition MSC extracellular vesicle white matter synaptic integrity

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 24(2023), 14, p 11862
Übergeordnetes Werk:	volume:24 ; year:2023 ; number:14, p 11862

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms241411862

Katalog-ID:	DOAJ093888309

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allfields	10.3390/ijms241411862 doi (DE-627)DOAJ093888309 (DE-599)DOAJf050b744e3d44fc487794e095cca7ddd DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Bojana Milutinovic verfasserin aut Intranasally Administered MSC-Derived Extracellular Vesicles Reverse Cisplatin-Induced Cognitive Impairment 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca<sup<2+</sup< signaling in recovery. Our data suggest that intranasal sEV treatment could become a novel therapeutic approach for the treatment of chemobrain. chemobrain cognition MSC extracellular vesicle white matter synaptic integrity Biology (General) Chemistry Rajasekaran Mahalingam verfasserin aut Mayela Mendt verfasserin aut Luis Arroyo verfasserin aut Alexandre Seua verfasserin aut Shruti Dharmaraj verfasserin aut Elizabeth Shpall verfasserin aut Cobi J. Heijnen verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 24(2023), 14, p 11862 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:24 year:2023 number:14, p 11862 https://doi.org/10.3390/ijms241411862 kostenfrei https://doaj.org/article/f050b744e3d44fc487794e095cca7ddd kostenfrei https://www.mdpi.com/1422-0067/24/14/11862 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 24 2023 14, p 11862
spelling	10.3390/ijms241411862 doi (DE-627)DOAJ093888309 (DE-599)DOAJf050b744e3d44fc487794e095cca7ddd DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Bojana Milutinovic verfasserin aut Intranasally Administered MSC-Derived Extracellular Vesicles Reverse Cisplatin-Induced Cognitive Impairment 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca<sup<2+</sup< signaling in recovery. Our data suggest that intranasal sEV treatment could become a novel therapeutic approach for the treatment of chemobrain. chemobrain cognition MSC extracellular vesicle white matter synaptic integrity Biology (General) Chemistry Rajasekaran Mahalingam verfasserin aut Mayela Mendt verfasserin aut Luis Arroyo verfasserin aut Alexandre Seua verfasserin aut Shruti Dharmaraj verfasserin aut Elizabeth Shpall verfasserin aut Cobi J. Heijnen verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 24(2023), 14, p 11862 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:24 year:2023 number:14, p 11862 https://doi.org/10.3390/ijms241411862 kostenfrei https://doaj.org/article/f050b744e3d44fc487794e095cca7ddd kostenfrei https://www.mdpi.com/1422-0067/24/14/11862 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 24 2023 14, p 11862
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allfieldsSound	10.3390/ijms241411862 doi (DE-627)DOAJ093888309 (DE-599)DOAJf050b744e3d44fc487794e095cca7ddd DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Bojana Milutinovic verfasserin aut Intranasally Administered MSC-Derived Extracellular Vesicles Reverse Cisplatin-Induced Cognitive Impairment 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca<sup<2+</sup< signaling in recovery. Our data suggest that intranasal sEV treatment could become a novel therapeutic approach for the treatment of chemobrain. chemobrain cognition MSC extracellular vesicle white matter synaptic integrity Biology (General) Chemistry Rajasekaran Mahalingam verfasserin aut Mayela Mendt verfasserin aut Luis Arroyo verfasserin aut Alexandre Seua verfasserin aut Shruti Dharmaraj verfasserin aut Elizabeth Shpall verfasserin aut Cobi J. Heijnen verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 24(2023), 14, p 11862 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:24 year:2023 number:14, p 11862 https://doi.org/10.3390/ijms241411862 kostenfrei https://doaj.org/article/f050b744e3d44fc487794e095cca7ddd kostenfrei https://www.mdpi.com/1422-0067/24/14/11862 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 24 2023 14, p 11862
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callnumber-first	Q - Science
author	Bojana Milutinovic
spellingShingle	Bojana Milutinovic misc QH301-705.5 misc QD1-999 misc chemobrain misc cognition misc MSC misc extracellular vesicle misc white matter misc synaptic integrity misc Biology (General) misc Chemistry Intranasally Administered MSC-Derived Extracellular Vesicles Reverse Cisplatin-Induced Cognitive Impairment
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topic_title	QH301-705.5 QD1-999 Intranasally Administered MSC-Derived Extracellular Vesicles Reverse Cisplatin-Induced Cognitive Impairment chemobrain cognition MSC extracellular vesicle white matter synaptic integrity
topic	misc QH301-705.5 misc QD1-999 misc chemobrain misc cognition misc MSC misc extracellular vesicle misc white matter misc synaptic integrity misc Biology (General) misc Chemistry
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title	Intranasally Administered MSC-Derived Extracellular Vesicles Reverse Cisplatin-Induced Cognitive Impairment
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title_sort	intranasally administered msc-derived extracellular vesicles reverse cisplatin-induced cognitive impairment
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title_auth	Intranasally Administered MSC-Derived Extracellular Vesicles Reverse Cisplatin-Induced Cognitive Impairment
abstract	Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca<sup<2+</sup< signaling in recovery. Our data suggest that intranasal sEV treatment could become a novel therapeutic approach for the treatment of chemobrain.
abstractGer	Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca<sup<2+</sup< signaling in recovery. Our data suggest that intranasal sEV treatment could become a novel therapeutic approach for the treatment of chemobrain.
abstract_unstemmed	Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca<sup<2+</sup< signaling in recovery. Our data suggest that intranasal sEV treatment could become a novel therapeutic approach for the treatment of chemobrain.
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Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca<sup<2+</sup< signaling in recovery. 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