Abstract
Accumulating evidence indicates that thyroid function and the thyroid hormones L-thyroxine (T4) and L-triiodothyronine (T3) are important factors contributing to the improvement of various pathologies of the central nervous system, including stroke, and various types of cancer, including glioblastoma multiforme (GBM). Low levels of T3 are correlated with the poorest outcome of post-stroke brain function, as well as an increased migration and proliferation of GBM tumor cells. Thyroid hormones are known to stimulate maturation and brain development. Aquaporin 4 (AQP4) is a key factor mediating the cell swelling and edema that occurs during ischemic stroke, and plays a potential role in the migration and proliferation of GBM tumor cells. In this study, as a possible therapeutic target for GBM, we investigated the potential role of T3 in the expression of AQP4 during different stages of mouse brain development. Pregnant mice at gestational day 18, or young animals at postnatal days 27 and 57, received injection of T3 (1 μg/g) or NaOH (0.02 N vehicle). The brains of mice sacrificed on postnatal days 0, 30, and 60 were perfused with 4% paraformaldehyde and sections were prepared for immunohistochemistry of AQP4. AQP4 immunofluorescence was measured in the mouse brains and human GBM cell lines. We found that distribution of AQP4 was localized in astrocytes of the periventricular, subpial, and cerebral parenchyma. Newborn mice treated with T3 showed a significant decrease in AQP4 immunoreactivity followed by an increased expression at P30 and a subsequent stabilization of aquaporin levels in adulthood. All GBM cell lines examined exhibited significantly lower AQP4 expression than cultured astrocytes. T3 treatment significantly downregulated AQP4 in GBM-95 cells but did not influence the rate of GBM cell migration measured 24 h after treatment initiation. Collectively, our results showed that AQP4 expression is developmentally regulated by T3 in astrocytes of the cerebral cortex of newborn and young mice, and is discretely downregulated in GBM cells. These findings indicate that higher concentrations of T3 thyroid hormone would be more suitable for reducing AQP4 in GBM tumorigenic cells, thereby resulting in better outcomes regarding the reduction of brain tumor cell migration and proliferation.
Highlights
T3-treated young mice showed a significant increase in Aquaporin 4 (AQP4) at postnatal day 30 (Student’s t-test: P < 0.0001), which remained stable until the 60th postnatal day (P60)
A diffuse fluorescence can be observed in the entire cerebral cortex, with a more pronounced distribution of AQP4 being observed on the surface of astrocytic end feet surrounding the cerebral capillaries and the cortical surface near the pia mater, as has previously been described in the literature
Treatment with T3 resulted in a biphasic expression of AQP4 in the cerebral cortex of mice, with a decrease in expression being observed at the beginning of postnatal life (P0: P < 0.01), followed by an increase in expression at 30 days of life, relative to the control group
Summary
Thyroid hormones play important roles during the development and maturation of the nervous system, being involved in the processes of myelination, cell growth, cell migration, in addition to their well-known metabolic effects (Oppenheimer et al, 1991; Trentin and Moura-Neto, 1995; Mullur et al, 2014).Several studies have shown that the main water channel protein in the brain, aquaporin 4 (AQP4) participates in important brain processes, including cell migration (Saadoun et al, 2005; Papadopoulos et al, 2008) and regulation of the flow of metabolites and ions (Ho et al, 2009) and that its expression can be regulated by the changes in metabolism (Deng et al, 2014), extracellular fluid volume, and tumorigenesis (Saadoun et al, 2002; Noell et al, 2012).The aquaporins (AQPs) are a family of integral membrane carrier proteins that mediate bidirectional water transport across the membrane cells in response to an osmotic gradient. Several studies have shown that the main water channel protein in the brain, aquaporin 4 (AQP4) participates in important brain processes, including cell migration (Saadoun et al, 2005; Papadopoulos et al, 2008) and regulation of the flow of metabolites and ions (Ho et al, 2009) and that its expression can be regulated by the changes in metabolism (Deng et al, 2014), extracellular fluid volume, and tumorigenesis (Saadoun et al, 2002; Noell et al, 2012). Certain isoforms of AQPs may mediate the transport of small solutes, such as glycerol, in addition to the transport of gasses (CO2, NH3, NO, and O2) and ions (K+ and Cl−) (Papadopoulos and Verkman, 2013)
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