1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine treatment after brain irradiation preserves cognitive function in mice.
cognitive function
neural stem cells
radiation
radiation mitigation
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
14 10 2020
14 10 2020
Historique:
pubmed:
16
4
2020
medline:
29
4
2021
entrez:
16
4
2020
Statut:
ppublish
Résumé
Normal tissue toxicity is an inevitable consequence of primary or secondary brain tumor radiotherapy. Cranial irradiation commonly leads to neurocognitive deficits that manifest months or years after treatment. Mechanistically, radiation-induced loss of neural stem/progenitor cells, neuroinflammation, and demyelination are contributing factors that lead to progressive cognitive decline. The effects of 1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine (NSPP) on irradiated murine neurospheres, microglia cells, and patient-derived gliomaspheres were assessed by sphere-formation assays, flow cytometry, and interleukin (IL)-6 enzyme-linked immunosorbent assay. Activation of the hedgehog pathway was studied by quantitative reverse transcription PCR. The in vivo effects of NSPP were analyzed using flow cytometry, sphere-formation assays, immunohistochemistry, behavioral testing, and an intracranial mouse model of glioblastoma. We report that NSPP mitigates radiation-induced normal tissue toxicity in the brains of mice. NSPP treatment significantly increased the number of neural stem/progenitor cells after brain irradiation in female animals, and inhibited radiation-induced microglia activation and expression of the pro-inflammatory cytokine IL-6. Behavioral testing revealed that treatment with NSPP after radiotherapy was able to successfully mitigate radiation-induced decline in memory function of the brain. In mouse models of glioblastoma, NSPP showed no toxicity and did not interfere with the growth-delaying effects of radiation. We conclude that NSPP has the potential to mitigate cognitive decline in patients undergoing partial or whole brain irradiation without promoting tumor growth and that the use of this compound as a radiation mitigator of radiation late effects on the central nervous system warrants further investigation.
Sections du résumé
BACKGROUND
Normal tissue toxicity is an inevitable consequence of primary or secondary brain tumor radiotherapy. Cranial irradiation commonly leads to neurocognitive deficits that manifest months or years after treatment. Mechanistically, radiation-induced loss of neural stem/progenitor cells, neuroinflammation, and demyelination are contributing factors that lead to progressive cognitive decline.
METHODS
The effects of 1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine (NSPP) on irradiated murine neurospheres, microglia cells, and patient-derived gliomaspheres were assessed by sphere-formation assays, flow cytometry, and interleukin (IL)-6 enzyme-linked immunosorbent assay. Activation of the hedgehog pathway was studied by quantitative reverse transcription PCR. The in vivo effects of NSPP were analyzed using flow cytometry, sphere-formation assays, immunohistochemistry, behavioral testing, and an intracranial mouse model of glioblastoma.
RESULTS
We report that NSPP mitigates radiation-induced normal tissue toxicity in the brains of mice. NSPP treatment significantly increased the number of neural stem/progenitor cells after brain irradiation in female animals, and inhibited radiation-induced microglia activation and expression of the pro-inflammatory cytokine IL-6. Behavioral testing revealed that treatment with NSPP after radiotherapy was able to successfully mitigate radiation-induced decline in memory function of the brain. In mouse models of glioblastoma, NSPP showed no toxicity and did not interfere with the growth-delaying effects of radiation.
CONCLUSIONS
We conclude that NSPP has the potential to mitigate cognitive decline in patients undergoing partial or whole brain irradiation without promoting tumor growth and that the use of this compound as a radiation mitigator of radiation late effects on the central nervous system warrants further investigation.
Identifiants
pubmed: 32291451
pii: 5820197
doi: 10.1093/neuonc/noaa095
pmc: PMC7566405
doi:
Substances chimiques
Hedgehog Proteins
0
Piperazines
0
phenylpiperazine
J9225CBI7D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1484-1494Subventions
Organisme : NCI NIH HHS
ID : P30 CA016042
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA211015
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA200234
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI067769
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Références
Int J Radiat Oncol Biol Phys. 2018 Sep 1;102(1):53-58
pubmed: 30102203
Curr Stem Cell Rep. 2017 Dec;3(4):342-347
pubmed: 29423356
Radiother Oncol. 2000 Nov;57(2):113-8
pubmed: 11054513
JAMA. 2016 Jul 26;316(4):401-409
pubmed: 27458945
Biochem Biophys Res Commun. 2019 Dec 10;520(3):532-537
pubmed: 31615656
J Neurooncol. 2019 Jan;141(2):393-401
pubmed: 30460632
Nat Rev Cancer. 2020 Jan;20(1):26-41
pubmed: 31601988
Ann Neurol. 2007 Nov;62(5):515-20
pubmed: 17786983
Eur J Cancer. 2001 Sep;37(13):1590-8
pubmed: 11527683
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14071-6
pubmed: 12391318
Cancer Cell Int. 2017 Dec 4;17:117
pubmed: 29225516
Oncotarget. 2016 Nov 1;7(44):71580-71593
pubmed: 27689403
Int J Radiat Biol. 2019 Apr;95(4):427-435
pubmed: 30252569
Eur J Cancer Care (Engl). 2018 Nov;27(6):e12912
pubmed: 30204287
Neuro Oncol. 2013 Oct;15(10):1429-37
pubmed: 23956241
J Clin Oncol. 2014 Dec 1;32(34):3810-6
pubmed: 25349290
Stem Cells Transl Med. 2020 Jan;9(1):106-119
pubmed: 31464098
Sci Rep. 2019 Jul 1;9(1):9460
pubmed: 31263197
Oncotarget. 2018 Jun 5;9(43):27000-27015
pubmed: 29930746
Mol Med. 2011 Jan-Feb;17(1-2):103-12
pubmed: 20957337
J Comp Neurol. 2004 Feb 9;469(3):311-24
pubmed: 14730584
Cancers (Basel). 2019 Jun 29;11(7):
pubmed: 31261863
Neuro Oncol. 2015 Jan;17(1):29-44
pubmed: 25267803
Am J Med Genet A. 2019 Dec;179(12):2517-2531
pubmed: 31639285
Sci Rep. 2016 Aug 12;6:31545
pubmed: 27516055
Int J Mol Sci. 2019 Oct 26;20(21):
pubmed: 31717816
Radiother Oncol. 2019 Mar;132:8-15
pubmed: 30825974
Proc Natl Acad Sci U S A. 2016 Apr 26;113(17):4836-41
pubmed: 27044087
Mol Ther. 2019 Aug 7;27(8):1467-1482
pubmed: 31153826
J Clin Oncol. 2015 May 20;33(15):1653-9
pubmed: 25897156
Front Oncol. 2017 Aug 18;7:166
pubmed: 28868253
Mol Cell Neurosci. 2002 Nov;21(3):512-20
pubmed: 12498791
Zentralbl Neurochir. 1977;38(2):199-200
pubmed: 607710
Transl Cancer Res. 2014 Apr 1;3(2):124-137
pubmed: 24904783
J Clin Oncol. 2016 Apr 1;34(10):1043-9
pubmed: 26811522