Hewitt Connell (pintincome4)

The hypothalamic-pituitary-adrenal axis is the primary neuroendocrine system activated to re-establish homeostasis during periods of stress, including critical illness and major surgery. During critical illness, evidence suggests that locally induced inflammation of the adrenal gland could facilitate immune-adrenal cross-talk and, in turn, modulate cortisol secretion. It has been hypothesized that immune cells are necessary to mediate the effect of inflammatory stimuli on the steroidogenic pathway that has been observed in vivo. To test this hypothesis, we developed and characterized a trans-well co-culture model of THP1 (human monocytic cell)-derived macrophages and ATC7 murine zona fasciculata adrenocortical cells. We found that co-culture of ATC7 and THP1 cells results in a significant increase in the basal levels of IL-6 mRNA in ATC7 cells, and this effect was potentiated by treatment with LPS. Addition of LPS to co-cultures of ATC7 and THP1 significantly decreased the expression of key adrenal steroidogenic enzymes (including StAR and DAX-1), and this was also found in ATC7 cells treated with pro-inflammatory cytokines. Moreover, 24-h treatment with the synthetic glucocorticoid dexamethasone prevented the effects of LPS stimulation on IL-6, StAR and DAX-1 mRNA in ATC7 cells co-cultured with THP1 cells. Our data suggest that the expression of IL-6 and steroidogenic genes in response to LPS depends on the activation of intra-adrenal immune cells. Moreover, we also show that the effects of LPS can be modulated by glucocorticoids in a time- and dose-dependent manner with potential implications for clinical practice.Infantile spasms (IS) is a serious epileptic syndrome that frequently occurs in infancy. Adrenocorticotropic hormone (ACTH) is generally the first-line treatment for IS; however, side effects limit its application. Melatonin (MT) has been used in clinical treatment for sleep disorders with only minor side effects. Further, MT was shown to be a powerful anticonvulsant in an animal model of epilepsy. In this research, we aimed to compare the anticonvulsant efficacy of ACTH and/or MT for treatment of IS and explore the mechanisms underlying the anticonvulsant activity of MT, using an N-methyl-d-aspartate (NMDA)-induced IS model in neonatal rats following exposure to prenatal stress. Latency to the onset of spasms and the total number of spasms were recorded to assess spasm severity. Treatment with ACTH and/or MT significantly reduced the number of spasms and prolonged the latency period. Additionally, expression of GR-α, HDAC2, BNDF, TrkB, and C-Cbl were significantly increased by induction with NMDA, and this effect was reversed by ACTH and/or MT treatment. Hence, our data suggest that combined ACTH and MT treatment is effective for reducing the number of spasms and increasing the latency period in NMDA rats, by restoring dysregulation of the HPA axis. These findings have the potential to provide a new strategy for the treatment of IS.Behavioural flexibility is a cognition-related function that enables subjects to adapt to a changing environment. Orbitofrontal cortex (OFC) and hippocampus (HC) have been involved in cognitive flexibility, but the interaction between these structures might be of particular functional significance. CA We applied a disconnection model in C57BL/6JRj mice to investigate the importance of OFC and ventral HC (vHC) interaction. Spatial acquisition and reversal performance in the Morris water maze (MWM) was compared between animals with small contralateral excitotoxic lesions to OFC and vHC, ipsilateral lesions (i.e., OFC-vHC lesions in the same hemisphere), as well as small bilateral OFC or vHC lesions. Spatial learning and memory performance was mostly unimpaired or only slightly impaired in our brain-lesioned animals compared to sham-lesioned control mice. However, contralaterally lesioned mice were significantly impaired during the early phase of reversal learning, whereas the other le