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  • br Experimental procedures br Results br Discussion

    2024-02-07


    Experimental procedures
    Results
    Discussion Major depressive disorder is among the leading causes of disability worldwide (Vos et al., 2015). One of the major causal or exacerbating factors of depression is long term stress or psychological trauma (Liu and Alloy, 2010). Dysregulation of the HPA axis activation is common in depressed patients, and elevated plasma glucocorticoids and corticotrophin releasing hormone levels were frequently reported (Varghese and Brown, 2001). CORT has been shown to involve in hippocampal dysfunction and damage (Sousa et al., 1999, Almeida et al., 2000, Zhu et al., 2006), whereas OT has been shown to mediate antistress and antidepressant-like effects in both animals and humans (Uvnas-Moberg and Petersson, 2005, Matsuzaki et al., 2012). The present study attempted to explore the possible neuroprotective effect of OT against CORT-induced neuronal damage in hippocampal neurons. We used primary cultures of hippocampal neurons prepared from early postnatal mice as an in vitro cellular model to explore the neuroprotective function of OT in the brain. Hippocampal neurons retain their morphological and functional characteristics even when they are grown in primary cultures. To verify the suitability of the primary cultures in our experiments, we examined the expression of OTR in these cultures. Leonzino et al. (2016) reported that OTR expression was detected in cultured hippocampal neurons already at DIV1 and increased over time. Immunocytochemistry of OTR showed that they are mainly expressed in neurons, but surrounding glial cells also have some degree of expression. Regarding subcellular localization, OTRs are mainly located on the soma of neurons, but in some cases, their expression extends to primary dendrites. Cultured hippocampal neurons also express abundant GRs and mineralocorticoid receptors (Crochemore et al., 2005). Early expression of OTR and GR suggests that there might be an interplay between OT and glucocorticoids in the development of the BPTES during pre- and post-natal periods, possibly by OT protecting developing neurons from the strains and stresses imposed by the process of labor and the outside world. CORT has been shown to cause hippocampal damage in a number of ways; altering dendritic tree of hippocampal neurons (Woolley et al., 1990, Watanabe et al., 1992, Magariños et al., 1996), apoptosis of hippocampal neurons (Zhu et al., 2006, Liu et al., 2011), and inhibition of adult neurogenesis in dentate gyrus (Yu et al., 2004). Our group focused on CORT-induced apoptosis in hippocampal neurons. Our findings highlighted two salient points: firstly, high concentrations of CORT were required to induce neuronal death in mouse hippocampal neurons, and secondly, glial cells in cultures were refractory to CORT-induced apoptosis. CORT induced apoptosis in primary cultures of hippocampal neurons in a dose-dependent manner. Significant apoptosis started to be seen with 50 μM CORT, and the number of apoptotic cells increased with increase in CORT concentration. Our findings are similar to what was observed in other groups. Nakatani et al. (2014) reported that high exposure of CORT (100 μM for 72 h) was required to induce significant cytotoxicity in primary mouse hippocampal cultures. Xu et al. (2011) also reported that CORT administration at a concentration greater than 50 μM for 24 h induced significant cell death in mouse hippocampal cell line HT-22. In contrast, 1 μM CORT was enough to cause significant decrease in neuronal viability in primary rat hippocampal neurons (Liu et al., 2011). Our findings and others suggest that there is a species difference in susceptibility of hippocampal neurons to the damaging effects of CORT. However, even at high CORT stimulation, glial cells were resistant to CORT-triggered apoptosis. Yu et BPTES al. (2011) also reported that, unlike hippocampal neurons, astrocytes are resistant to glucocorticoid-induced apoptosis. They also reasoned that astrocytes might have lesser production of reactive oxygen species as well as a greater capacity to buffer their cytotoxic actions (Yu et al., 2011). The differential action of CORT on neurons and glial cells is interesting, and will require further research to understand why glial cells are less prone to the deleterious effects of CORT.