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

Kruttika Bhat; Paul Medina; Ling He; Le Zhang; Mohammad Saki; Angeliki Ioannidis; Nhan T Nguyen; Sirajbir S Sodhi; David Sung; Clara E Magyar; Linda M Liau; Harley I Kornblum; Frank Pajonk

doi:10.1093/neuonc/noaa095

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

Neuro Oncol. 2020 Oct 14;22(10):1484-1494. doi: 10.1093/neuonc/noaa095.

Authors

Kruttika Bhat¹, Paul Medina¹, Ling He¹, Le Zhang¹, Mohammad Saki¹, Angeliki Ioannidis¹, Nhan T Nguyen¹, Sirajbir S Sodhi¹, David Sung¹, Clara E Magyar², Linda M Liau^{3

4}, Harley I Kornblum^{5

4}, Frank Pajonk^{1

4}

Affiliations

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

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.

Keywords: cognitive function; neural stem cells; radiation; radiation mitigation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain
Cognition*
Cranial Irradiation
Female
Hedgehog Proteins*
Mice
Mice, Inbred C57BL
Piperazines

Substances

Hedgehog Proteins
Piperazines
phenylpiperazine

Abstract

Publication types

MeSH terms

Substances

Grants and funding