Abstract
BackgroundCranial irradiation is a common therapy for the treatment of brain tumors, but unfortunately patients suffer from side effects, particularly cognitive impairment, caused by neurodegenerative and neuroinflammatory mechanisms. Finding a therapeutic agent protecting hippocampal neurons would be beneficial. Fingolimod (FTY720), a sphingosine-1-phosphate receptor modulator approved for multiple sclerosis, is an immunosuppressant and known to enhance proliferation and differentiation of neuronal precursor cells (NPCs).ObjectivesTo investigate whether pre-treatment with FTY720 protects NPCs in vitro and in vivo from irradiation-induced damage.MethodsNeuronal precursor cells were isolated from E13 C57BL/6 wildtype mice, treated at day 0 of differentiation with FTY720 and irradiated on day 6 with 1 Gy. NPCs were analyzed for markers of cell death (PI, caspase-3), proliferation (Ki67), and differentiation (DCX, βIII-tubulin). Adult C57BL/6 wildtype mice were treated with FTY720 (1 mg/kg) and received a single dose of 6 Gy cranial irradiation at day 7. Using immunohistochemistry, we analyzed DCX and BrdU as markers of neurogenesis and Iba1, GFAP, and CD3 to visualize inflammation in the dentate gyrus (DG) and the subventricular zone (SVZ). B6(Cg)-Tyrc-2J/J DCX-luc reporter mice were used for bioluminescence imaging to evaluate the effect of FTY720 on neurogenesis in the DG and the spinal cord of naïve mice.ResultsFTY720 protected NPCs against irradiation induced cell death in vitro. Treatment with FTY720 dose-dependently reduced the number of PI+ cells 24 and 96 h after irradiation without effecting proliferation or neuronal differentiation. In vivo treatment resulted in a significant survival of DCX+ neurons in the DG and the SVZ 4 weeks after irradiation as well as a slight increase of proliferating cells. FTY720 inhibited microglia activation 24 h after X-ray exposure in the DG, while astrocyte activation was unaffected and no lymphocyte infiltrations were found. In naïve mice, FTY720 treatment for 4 weeks had no effect on neurogenesis.ConclusionFTY720 treatment of NPCs prior to X-ray exposure and of mice prior to cranial irradiation is neuroprotective. No effects on neurogenesis were found.
Highlights
Cranial irradiation is a common therapy for primary and metastatic brain tumors, patients often suffer from side effects like cognitive impairments and depression due to late delayed brain injury (Son et al, 2015b)
We investigated whether undifferentiated neural precursor cell (NPC) obtained from E13 mice express the receptors S1PR1, S1PR3, and S1PR5, which are all potential targets of FTY720
The highest expression level was shown for S1PR1 (0.002656 ± 0.001813), the expression of S1PR3 was more than threefold lower (0.0005388 ± 0.0002118), and the lowest expression was found for S1PR5 (6.03 × 10−5 ± 0.559 × 10−5)
Summary
Cranial irradiation is a common therapy for primary and metastatic brain tumors, patients often suffer from side effects like cognitive impairments and depression due to late delayed brain injury (Son et al, 2015b). It has been shown that treatment with valproic acid (VPA) or lithium prior to irradiation protects hippocampal neurons from cell death and attenuates cognitive decline in preclinical models (Khasraw et al, 2012; Thotala et al, 2015). Another potentially therapeutic agent is the sphingosine-1-phosphate receptor modulator fingolimod (FTY720). Cranial irradiation is a common therapy for the treatment of brain tumors, but patients suffer from side effects, cognitive impairment, caused by neurodegenerative and neuroinflammatory mechanisms. Fingolimod (FTY720), a sphingosine-1-phosphate receptor modulator approved for multiple sclerosis, is an immunosuppressant and known to enhance proliferation and differentiation of neuronal precursor cells (NPCs)
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