Double-edged effects of tamoxifen-in-oil-gavage on an infectious murine model for multiple sclerosis
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Kirsten Hülskötter1,2, Wen Jin1,2, Lisa Allnoch1,2
1Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
Abstract:
Tamoxifen gavage is a commonly used method to induce genetic modifications in cre-loxP systems. As a selective estrogen receptor modulator (SERM), the compound is known to have immunomodulatory and neuroprotective properties in non-infectious central nervous system (CNS) disorders. It can even cause complete prevention of lesion development as seen in experimental autoimmune encephalitis (EAE). The effect on infectious brain disorders is scarcely investigated. In this study, susceptible SJL mice were infected intracerebrally with Theiler's murine encephalomyelitis virus (TMEV) and treated three times with a tamoxifen-in-oil-gavage (TOG), resembling an application scheme for genetically modified mice, starting at 0, 18, or 38 days post infection (dpi). All mice developed 'TMEV-induced demyelinating disease' (TMEV-IDD) resulting in inflammation, axonal loss, and demyelination of the spinal cord. TOG had a positive effect on the numbers of oligodendrocytes and oligodendrocyte progenitor cells, irrespective of the time point of application, whereas late application (starting 38 dpi) was associated with increased demyelination of the spinal cord white matter 85 dpi. Furthermore, TOG had differential effects on the CD4+ and CD8+ T cell infiltration into the CNS, especially a long lasting increase of CD8+ cells was detected in the inflamed spinal cord, depending of the time point of TOG application. Number of TMEV-positive cells, astrogliosis, astrocyte phenotype, apoptosis, clinical score, and motor function were not measurably affected. These data indicate that tamoxifen gavage has a double-edged effect on TMEV-IDD with the promotion of oligodendrocyte differentiation and proliferation, but also increased demyelination, depending on the time point of application. The data of this study suggest that tamoxifen has also partially protective functions in infectious CNS disease. These effects should be considered in experimental studies using the cre-loxP system, especially in models investigating neuropathologies.
Insights
Tamoxifen gavage in mice with infectious demyelinating disease promoted oligodendrocyte repair but also increased demyelination, depending on treatment timing. These findings are crucial for studies using tamoxifen in central nervous system research.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Tamoxifen (SERM) is used in cre-loxP systems and shows neuroprotection in non-infectious CNS disorders.
- Its effects on infectious brain disorders, like TMEV-IDD, are understudied.
- Understanding tamoxifen's impact in infectious CNS models is crucial for experimental design.
Purpose of the Study:
- To investigate the effects of tamoxifen gavage on TMEV-induced demyelinating disease (TMEV-IDD).
- To assess tamoxifen's impact on oligodendrocyte populations, demyelination, and immune cell infiltration in the CNS.
- To determine if the timing of tamoxifen administration influences TMEV-IDD outcomes.
Main Methods:
- SJL mice were intracerebrally infected with Theiler's murine encephalomyelitis virus (TMEV).
- Mice received tamoxifen-in-oil-gavage (TOG) at 0, 18, or 38 days post infection (dpi).
- Evaluated inflammation, demyelination, axonal loss, oligodendrocyte counts, immune cell infiltration, and clinical outcomes.
Main Results:
- TOG treatment increased oligodendrocyte and progenitor cell numbers regardless of timing.
- Late TOG application (38 dpi) correlated with increased spinal cord demyelination at 85 dpi.
- TOG differentially affected T cell infiltration, notably increasing CD8+ T cells in the CNS, with timing-dependent effects.
- No significant changes were observed in viral load, astrogliosis, apoptosis, clinical scores, or motor function.
Conclusions:
- Tamoxifen gavage exhibits a dual effect in TMEV-IDD, promoting oligodendrocyte repair while potentially exacerbating demyelination based on application timing.
- Tamoxifen may offer partial protective functions in infectious CNS diseases.
- These findings highlight the importance of considering tamoxifen's timing-dependent effects in cre-loxP studies, particularly those involving neuropathologies.
