Changes in gene expression in brain structures related to visceral sensation, autonomic functions, food intake, and cognition in melanoma-bearing mice.

The brain exerts complex effects on the initiation and progression of cancer in the body. However, the influence of cancer localized in peripheral tissues on the brain has been only partially described. Therefore, we investigated gene expression in brain structures that participate in transmitting viscerosensory signals, regulating autonomic functions and food intake, as well as cognition in C57Bl/6J mice with B16-F10 melanoma. In addition, we investigated the relationship between peripheral inflammation and neuroinflammation. We found increased neuronal activity in the nucleus of the solitary tract of tumor-bearing mice, whereas neuronal activity in the A1/C1 catecholaminergic cell group, parabrachial nucleus, lateral hypothalamic area, ventromedial nucleus of the hypothalamus, paraventricular nucleus of the hypothalamus, and hippocampus was decreased. In the majority of investigated brain structures, we found increased gene expression of IL-1ß, whereas gene expression of IL-6 and NF-κB was reduced or unchanged compared with controls. Melanoma-bearing mice also showed increased gene expression of tyrosine hydroxylase in the A1/C1 catecholaminergic cell group, nucleus of the solitary tract, and locus coeruleus, as well as reduced mRNA levels of hypocretin neuropeptide precursor protein in the lateral hypothalamic area, and proopiomelanocortin in the arcuate nucleus. In addition, we found reduced mRNA levels of Bcl-2, brain-derived neurotrophic factor, and doublecortin in the hippocampus. Our data indicate that skin melanoma induces complex changes in the brain, and these changes are most probably caused by cancer-related signals mediated by pro-inflammatory cytokines.

Exposure to a single immobilization or lipopolysaccharide challenge increases expression of genes implicated in the development of Alzheimer's disease in the mice brain cortex.

OBJECTIVES: Despite extensive research efforts, mechanisms participating on development of Alzheimer's disease (AD) are covered only partially. Data from the last decades indicate that various stressors, as etiological factors, may play a role of in the AD. Therefore, we investigated the effect of two acute stressors, immobilization (IMO) and lipopolysaccharide (LPS), on the AD-related neuropathology. METHODS: Adult C57BL/6J mice males were exposed to a single IMO stress or a single intraperitoneal injection of LPS (250 µg/kg body weight). After terminating the experiments, the brains were removed and their cortices isolated. Gene expression of pro-inflammatory cytokines, as well as expression of genes implicated in the AD neuropathology were determined. In addition, mediators related to the activation of the microglia, monocytes, and perivascular macrophages were determined in brain cortices, as well. RESULTS: In comparison with the control animals, we found increased gene expression of proinflammatory mediators in mice brain cortex in both IMO and LPS groups. In stressed animals, we also showed an increased expression of genes related to the AD neuropathology, as well as positive correlations between genes implicated in AD development and associated neuroinflammation. CONCLUSIONS: Our data indicate that acute exposure to a strong IMO stressor, composed of the combined physical and psychological challenges, induces similar inflammatory and other ADrelated neuropathological changes as the immune LPS treatment. Our data also indicate that cytokines are most likely released from the peripheral immune cells, as we detected myeloid cells activity, without any microglia response. We hypothesize that stress induces innate immune response in the brain that consequently potentiate the expression of genes implicated in the AD-related neuropathology.

Stressors affect urocortin 1 and urocortin 2 gene expression in rat spleen: The role of glucocorticoids.

The mechanisms underlying stress-related modulation of immune function via urocortin 1 and urocortin 2 have been only vaguely described. Therefore, we investigated the effect of LPS injection or immobilization stress on gene expression of urocortin 1 and urocortin 2 in the rat spleen, along with the potential involvement of glucocorticoids. Our data showed: a) different regulation of urocortin 1 and urocortin 2 gene expression in the rat spleen under different stressful conditions (LPS vs. immobilization stress) and b) diverse effects of stress-induced adrenal glucocorticoids on this process. Our findings indicate a specific, rather than general regulation of splenic immune function by urocortins during stressful conditions.

Brain Under Stress and Alzheimer's Disease.

Modern society is characterized by the ubiquity of stressors that affect every individual to different extents. Furthermore, experimental, clinical, and epidemiological data have shown that chronic activation of the stress response may participate in the development of various somatic as well as neuropsychiatric diseases. Surprisingly, the role that stress plays in the etiopathogenesis of Alzheimer's disease (AD) has not yet been studied in detail and is therefore not well understood. However, accumulated data have shown that neuroendocrine and behavioral changes accompanying the stress response affect neuronal homeostasis and compromise several key neuronal processes. Mediators of the neuroendocrine stress response, if elevated repeatedly or chronically, exert direct detrimental effects on the brain by impairing neuronal metabolism, plasticity, and survival. Stress-induced hormonal and behavioral reactions may also participate in the development of hypertension, atherosclerosis, insulin resistance, and other peripheral disturbances that may indirectly induce neuropathological processes participating in the development and progression of AD. Importantly, stress-induced detrimental effects as etiological factors of AD are attractive because they can be reduced by several approaches including behavioral and pharmacological interventions. These interventions may therefore represent an important strategy for prevention or attenuation of the progression of AD.

Sympathectomy reduces tumor weight and affects expression of tumor-related genes in melanoma tissue in the mouse.

Accumulated evidence indicates that sympathetic nerves may potentiate tumor growth, including melanoma. To elucidate possible mechanisms for this effect, we performed chemical sympathectomy by intraperitoneal (i.p.) injection of the neurotoxin 6-hydroxydopamine hydrobromide (100 mg/kg of body weight); in nine adult male C57BL/6J mice; nine control mice received i.p. vehicle (VEH). Seven days later, all mice were injected subcutaneously with 3 × 10(3) B16-F10 melanoma cells. Mice were euthanized 20 d after injection of melanoma cells, for measurement of tumor weight and expression of genes related to sympathetic signaling, apoptosis, hypoxia and angiogenesis in tumor tissue. To assess potential involvement of the hypothalamo-pituitary-adrenocortical axis in the effect of sympathectomy on melanoma growth, concentrations of plasma corticosterone and level of glucocorticoid receptor mRNA in tumor tissue were determined. We found that sympathectomy significantly attenuated melanoma growth (tumor weight 0.29 ± 0.16 g versus 1.02 ± 0.30 g in controls; p < 0.05). In tumor tissue from sympathectomized mice, we found significantly increased gene expression (measured by real-time PCR), relative to VEH-injected controls, of tyrosine hydroxylase, neuropeptide Y and glucocorticoid receptor (all p < 0.05), and alpha1, beta1 and beta3 adrenergic receptors (all p < 0.025), and factors related to apoptosis (Bcl-2 and caspase-3; p < 0.05) and hypoxia (hypoxia inducible factor 1 alpha) (p = 0.005). Plasma corticosterone concentrations were significantly elevated (p < 0.05) in these mice. Our findings indicate that sympathectomy induces complex changes in the tumor microenvironment reducing melanoma growth. Such complex changes should be considered in the prediction of responses of cancer patients to interventions affecting sympathetic signaling in tumor tissue and its environment.