1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine treatment after brain irradiation preserves cognitive function in mice

Author:

Bhat Kruttika1,Medina Paul1,He Ling1,Zhang Le1,Saki Mohammad1,Ioannidis Angeliki1,Nguyen Nhan T1,Sodhi Sirajbir S1,Sung David1,Magyar Clara E2,Liau Linda M34,Kornblum Harley I54,Pajonk Frank14

Affiliation:

1. Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

2. Translational Pathology Core Laboratory, Image Analysis/Virtual Microscopy, Department of Pathology and Laboratory Medicine, Los Angeles, California

3. Department of Neurosurgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

4. Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California

5. NPI-Semel Institute for Neuroscience and Human Behavior at UCLA, Los Angeles, California

Abstract

AbstractBackgroundNormal 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.MethodsThe 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.ResultsWe 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.ConclusionsWe 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.

Funder

National Cancer Institute

National Institute of Allergy and Infectious Diseases

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Neurology (clinical),Oncology

Reference37 articles.

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