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  • br Methods br Results br Discussion Among three


    Discussion Among three main signaling pathways activated by bFGF, the MAPK pathway was found to be involved in the upregulation of GR levels. So far, there have been a few candidates that could connect activated ERK to the upregulation of GR. One likely candidate is the zinc finger-containing transcription factor, zif268/Egr1 (early growth response protein 1, also known as nerve growth factor-induced protein A, NGFI-A), which can bind and stimulate the promoter of the GR (NR3C1) gene (McGowan et al., 2009), and it is transiently induced thorough the ERK/MAPK pathway after growth factor stimulation (Harada et al., 2001). zif268/Egr1 has also been reported to regulate the expression of several genes, such as glutamic parecoxib australia decarboxylases 67 (Luo et al., 2008) and low affinity neurotrophin receptor p75NTR (Gao et al., 2007). zif268/Egr1 binding sites have been identified in the promoter region of GR, not in MR, which may explain the reason why U0126 (MAPK inhibitor) blocked only the upregulation of GR induced by bFGF. Unlike GR, the bFGF-induced upregulation of MR could not be blocked by the inhibitors for any of the three signaling pathways. bFGF binds to all FGF receptors with different affinity, which can activate signal transducer and activator of transcription 1, 3, and 5 (STAT1, 3, and 5) signaling pathways other than the three signaling pathways investigated here (Ornitz and Itoh, 2015). Although further studies are needed to elucidate more details on the molecular mechanisms underlying bFGF-induced GR and MR upregulations in cortical neurons, it is possible that STAT signaling pathways are associated with this regulatory mechanism. Unexpectedly, the PI3K inhibitor (LY294002) showed a tendency of reducing the DEX-induced FKBP5 mRNA transcription. Given that LY294002 inhibitor did not reduce the bFGF-induced increase of GR protein expression, it did suppress the FKBP5 mRNA expression levels independent of bFGF and GR functions. We previously reported that rats receiving stress via chronic restrain exhibited a decrease in GR expression in the cortex that was associated with anxiety- and depression-like behaviors as well as elevated concentration levels of glucocorticoids in the blood (Chiba et al., 2012). Moreover, male rats that had experienced maternal separation during the first 3 weeks of life (3 h/day) exhibited a decrease in GR expression in the hippocampus and depressive-like behaviors in adulthood (Aisa et al., 2007). Conversely, environmental enrichment in early postnatal days led to an increase in hippocampal GR expression and in a decrease in anxiety behaviors in rats (Sampedro-Piquero et al., 2014; Soares et al., 2015). There is also a considerable amount of evidence showing that an administration of antidepressant drugs increases GR and MR expression levels in the hippocampus of the rat brain (Pepin et al., 1989; Seckl and Fink, 1992; Przegaliński et al., 1993) and in cultured neurons (Lai et al., 2003). Furthermore, transgenic mice that have genetically reduced GR expression in their forebrain regions developed both physiological and behavioral abnormalities including impaired negative feedback regulation of the HPA axis and increased depression-like behaviors, which were normalized by antidepressant treatments (Boyle et al., 2005; Arnett et al., 2011). These studies support the hypothesis that reduced GR expression in the brain, especially in the forebrain regions, may be associated with the pathogenesis of stress-related psychiatric disorders. Thus, compensating reduced GR levels may be an important therapeutic target (Anacker et al., 2011). A possible association between depressive symptoms and bFGF activity has also been suggested (Turner et al., 2006, 2012). For instance, antidepressants were able to upregulate bFGF expression in the cerebral cortex (Bachis et al., 2008), and administration of bFGF improved depression-like behaviors (Turner et al., 2008).