Related Experiment Video
Updated: Aug 12, 2025
Assessing Cell Cycle Progression of Neural Stem and Progenitor Cells in the Mouse Developing Brain after Genotoxic Stress
Published on: May 7, 2014
Effects of Dopamine Receptor Antagonists and Radiation on Mouse Neural Stem/Progenitor Cells
Background:
Dopamine receptor antagonists are psychotropic drugs that have been originally developed against psychiatric disorders. We recently identified dopamine receptor antagonists as potential anti-cancer agents and some have entered clinical trials against glioblastoma. Radiotherapy is known to cause cognitive impairment in patients receiving cranial irradiation through the elimination of neural stem/progenitor cells and subsequent loss of neurogenesis.
Methods:
Using transgenic mice that report the presence of neural stem/progenitor cells through Nestin promoter-driven expression of enhanced green fluorescent protein, the effects of dopamine receptor antagonists alone or in combination with radiation on murine neural stem/progenitor cells were assessed in sphere-formation assays, flow cytometry and immunofluorescence in vitro and in vivo .
Results:
We report that several dopamine receptor antagonists show sex-dependent effects on neural stem/progenitor cells both in vitro and in vivo . Hydroxyzine, trifluoperazine, amisulpride, nemonapride or quetiapine alone or in combination with radiation significantly increased the number of neural stem/progenitor cells in female neurospheres but not in male mice. Dopamine receptor antagonists either protected neural stem/progenitor cells from radiation or expanded the stem cell pool, thus indicating that this combination therapy against glioblastoma will not increase radiation-induced cognitive decline through increasing elimination of neural stem/progenitor cells and subsequent loss of neurogenesis.
Conclusions:
We conclude that a therapeutic window for dopamine receptor antagonists in combination with radiation potentially exist, making it a novel combination therapy against glioblastoma. Normal tissue toxicity of this combination potentially differs depending on age and sex and should be taken into consideration when designing clinical trials.
Key Points:
- Neural stem/progenitor cells show sex-dependent sensitivity to dopamine receptor antagonists- Dopamine receptor antagonists active against GBM increase Neural stem/progenitor cells counts.
Importance Of The Study:
Combination therapy of dopamine receptor antagonists with radiation have entered clinical trials against glioblastoma but the normal tissue toxicity of this combination has not been fully explored yet. Here we present evidence that some dopamine receptor antagonists show sex-dependent effects on neural stem/progenitor cells either by protecting neural stem/progenitor cells from radiation or inducing an expansion of the stem cell pool, suggesting that this combination therapy against glioblastoma will not increase radiation-induced cognitive decline through increasing elimination of neural stem/progenitor cells and subsequent loss of neurogenesis. Normal tissue toxicity of this combination potentially differs depending on age and sex and should be further explored in clinical trials.
Insights
Dopamine receptor antagonists, used with radiation for glioblastoma, show sex-dependent effects on neural stem cells. This combination may not worsen cognitive decline, but toxicity varies by sex and age.
Area of Science:
- Neuroscience
- Oncology
- Pharmacology
Background:
- Dopamine receptor antagonists, initially for psychiatric disorders, are explored as anti-cancer agents for glioblastoma.
- Radiotherapy for brain tumors can cause cognitive impairment by affecting neural stem/progenitor cells and neurogenesis.
Approach:
- Investigated effects of dopamine receptor antagonists on neural stem/progenitor cells in mice using sphere-formation assays, flow cytometry, and immunofluorescence.
- Assessed drug effects alone and in combination with radiation, both in vitro and in vivo.
Key Points:
- Neural stem/progenitor cells exhibit sex-dependent responses to dopamine receptor antagonists.
- Dopamine receptor antagonists used in glioblastoma treatment increase neural stem/progenitor cell counts.
Conclusions:
- A therapeutic window for combining dopamine receptor antagonists with radiation against glioblastoma may exist.
- Potential sex- and age-dependent normal tissue toxicity requires consideration in clinical trial design.
