1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine Treatment After Brain Irradiation Preserves Cognitive Function in Mice

Abstract

<jats:title>Abstract</jats:title><jats:sec id="s001"><jats:title>Background</jats:title><jats:p>Normal tissue toxicity to the CNS is an inevitable consequence of a successful radiotherapy of brain tumors or cancer metastases to the CNS. Cranial irradiation commonly leads to neurocognitive deficits that manifest months or years after treatment. Mechanistically, radiation-induced loss of neural stem/progenitor cells, neuro-inflammation and de-myelinization are contributing factors that lead to progressive cognitive decline.</jats:p></jats:sec><jats:sec id="s002"><jats:title>Methods</jats:title><jats:p>The effects of Compound #5 on irradiated murine neurospheres, microglia cells and patients-derived gliomaspheres were assessed in sphere-formation assays, flow cytometry and IL-6 ELISAs, Activation of the Hedgehog pathway was studied by qRT-PCR. The <jats:italic>in vivo</jats:italic> effects of Compound #5 were analyzed using flow cytometry, sphere-formation assays, immune-histochemistry, behavioral testing and an intracranial mouse model of glioblastoma.</jats:p></jats:sec><jats:sec id="s003"><jats:title>Results</jats:title><jats:p>We report that 1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine (Compound #5) mitigates radiation-induced normal tissue toxicity in the brains of mice. Compound #5 treatment significantly increased the number of neural stem/progenitor cells after brain irradiation in female animals, inhibited radiation-induced microglia activation and expression of the pro-inflammatory cytokine interleukin-6. Behavioral testing revealed that treatment with Compound #5 after radiotherapy successfully mitigates radiation-induced decline in motor, sensory and memory function of the brain. In mouse models of glioblastoma, Compound #5 showed no toxicity and did not interfere with the growth-delaying effects of radiation.</jats:p></jats:sec><jats:sec id="s004"><jats:title>Conclusions</jats:title><jats:p>We conclude that Compound #5 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 CNS warrants further investigation.</jats:p></jats:sec><jats:sec><jats:title>Importance of the Study</jats:title><jats:p>Successful radiotherapy of CNS malignancies inevitably lead to cognitive decline in cancer survivors and treatment options to mitigate this side effect are limited. We present evidence that a piperazine compound can prevent cognitive decline in mice after total brain irradiation without compromising the antitumor effect of radiation, suggesting that this compound could be used to mitigate radiation side effects in brain tumor patients undergoing radiotherapy.</jats:p></jats:sec>

Effects of Dopamine Receptor Antagonists and Radiation on Mouse Neural Stem/Progenitor Cells

“…However, the number of EGFP + NSPCs in Passage #2 neurospheres from individual animals of the same sex varied and none of the observed differential effects of DRAs between sexes reached the level of statistical significance (Figure 1C) . In agreement with our previous report (15), radiation predominately eliminated the Nestin-EGFP high population of cells from neurospheres, consistent with the known exquisite radiation sensitivity of neural stem cells. The differences between sexes in the total number of EGFP + cells in response to individual DRAs became smaller with increasing radiation doses in alignment with the generally non-sex-specific cell killing effects of ionizing radiation (Figure 1D/E) .…”

“…Nestin-EGFP + NSPCs were harvested from both male and female newborn pups and cultured as neurospheres. We have previously reported that Nestin promoter driven EGFP expression in this mouse strain is correlated with self-renewal capacity (15). Passage #2 neurospheres were pretreated with DRAs at 1 μM concentrations, irradiated with 0, 2 or 4 Gy and cultured for 2 weeks during which DRAs were added 3x/week (Figure 1A) .…”

Cross-translational models of late-onset cognitive sequelae and their treatment in pediatric brain tumor survivors

“…Anti-TNF-a treatment, for example, reduced acute brain pathology after 20-Gy cranial radiation in a mouse model (Wilson et al, 2009). In a more recent study, a compound identified through a high-throughput screen was shown to decrease IL-6 expression and correspondingly reduce GFAP and Iba1 labeling (for astrocytes and microglia respectively) following cranial radiation in a mouse model (10 Gy at 8 weeks); treated mice also showed improved performance on tests of novel object and object-in-place recognition and fear conditioning (Bhat et al, 2020). Since multiple cytokines appear to be involved in neuroinflammation, broad spectrum anti-inflammatory treatments represent an attractive intervention option.…”