ß3-Adrenergic receptors, adipokines and neuroendocrine activation during stress induced by repeated immune challenge in male and female rats.

The main hypothesis of the study is that stress associated with repeated immune challenge has an impact on ß3-adrenergic receptor gene expression in the brain. Sprague-Dawley rats were intraperitoneally injected with increasing doses of lipopolysaccharide (LPS) for five consecutive days. LPS treatment was associated with body weight loss and increased anxiety-like behavior. In LPS-treated animals of both sexes, ß3-receptor gene expression was increased in the prefrontal cortex but not the hippocampus. LPS treatment decreased ß3-receptor gene expression in white adipose tissue with higher values in males compared to females. In the adipose tissue, LPS reduced peroxisome proliferator-activated receptor-gamma, leptin and adiponectin gene expression, but increased interleukin-6 expression, irrespective of sex. Repeated immune challenge resulted in increased concentrations of plasma aldosterone and corticosterone with higher values of corticosterone in females compared to males. Concentrations of dehydroepiandrosterone (DHEA) in plasma were unaffected by LPS, while DHEA levels in the frontal cortex were lower in the LPS-treated animals compared to the controls. Thus, changes of DHEA levels in the brain take place irrespective of the changes of this neurosteroid in plasma. We have provided the first evidence on stress-induced increase in ß3-adrenergic receptor gene expression in the brain. Greater reduction of ß3-adrenergic receptor expression in the adipose tissue and of the body weight gain by repeated immune challenge in male than in female rats suggests sex differences in the role of ß3-adrenergic receptors in the metabolic functions. LPS-induced changes in adipose tissue regulatory factors and hormone concentrations might be important for coping with chronic infections.

Early cognitive impairment along with decreased stress-induced BDNF in male and female patients with newly diagnosed multiple sclerosis.

The aim of this study was to evaluate neuroendocrine activation during stress in patients with recently diagnosed multiple sclerosis before starting the immunomodulatory therapy (EDSS score≤2.0). We verified the hypothesis that certain cognitive and affective dysfunction is present already at this early stage of the disease. The sample consisted of 38 subjects, which involved patients who were recently diagnosed multiple sclerosis and age- and sex-matched healthy volunteers. Stroop test served as mental stress model enabling measurement of cognitive performance. Present results showed increased state anxiety, depression scores and poorer performance in the Stroop test in the group of patients compared to healthy subjects. The cognitive dysfunction was particularly evident in male patients with simultaneously decreased concentrations of the brain-derived neurotrophic factor (BDNF) in plasma. The patients at this stage of the disease have not yet developed the hyperactivity of the hypothalamic-pituitary-adrenocortical axis. They showed normal levels of plasma copeptin and reduced aldosterone response to mental stress test in women only. Concentrations of plasma copeptin were higher in men compared to women. Very early stages of multiple sclerosis are accompanied by disturbances in psychological well-being, mild cognitive dysfunction and decreased plasma concentrations of BDNF, particularly in male patients.

Dissociation of adrenocorticotropin and corticosterone as well as aldosterone secretion during stress of hypoglycemia in vasopressin-deficient rats.

AIMS: In vasopressin-deficient rat pups stressor-induced adrenocorticotropin (ACTH) and corticosterone elevations markedly dissociate. We have shown recently that during the postnatal period mineralocorticoid secretion is more sensitive to stressor exposure than that of glucocorticoids. We have therefore hypothesized that in vasopressin-deficient pups during hypoglycemia, a stressor triggering aldosterone release mainly via ACTH, aldosterone release will change in parallel with ACTH. An additional aim was to reveal at which stage of the development occurs the shift from aldosterone to corticosterone as primarily stressor-induced adrenocortical hormone. MAIN METHODS: Vasopressin-deficient (di/di) and control Brattleboro rats were used both postnatally (10-day-old rats) and in adulthood. KEY FINDINGS: Hypoglycemia induced similar ACTH elevations in pups and adults with significantly lower levels in di/di rats. In contrast, vasopressin-deficiency resulted in elevated resting aldosterone and stressor-induced corticosterone levels in pups without genotype differences in adults. Thus, aldosterone levels also dissociated from ACTH secretion. During stress, pups showed only minimal corticosterone increase, with relatively high aldosterone elevation. Resting levels of gluco- and mineralocorticoid receptor mRNA were smaller, while corticosterone-deactivating enzyme (11ß-HSD2) mRNA level were higher in the hippocampus of 10-day-old rats compared to adults. SIGNIFICANCE: AVP does not seem to substantially regulate the stressor-induced aldosterone production, but both hormones contribute to salt-water regulation. Postnatally higher stressor-induced aldosterone than corticosterone production was still detectable in 40-day-old rats, although to a lesser extent, supporting a shift in the balance between stressor-induced glucocorticoid and mineralocorticoid hormone release throughout the development occurring in rats after postnatal day 40.

Molecular changes induced by repeated restraint stress in the heart: the effect of oxytocin receptor antagonist atosiban.

Even though stress belongs to the most common lifestyle risk factors of cardiovascular diseases, there are only limited data on direct influence of stressors on the heart. The aim of the present study was to explore selected protein signaling pathways in response to repeated immobilization stress in the heart tissue. Effects of simultaneous treatment with atosiban, an oxytocin receptor antagonist, on stress-induced changes in the heart were also investigated. Male Wistar rats were exposed to repeated immobilization (2 h daily, lasting 2 weeks). The results showed increased phosphorylation of Akt kinase, enhanced levels of Bcl-2, and decreased levels of cleaved caspase-3 in the left ventricle in response to chronic stress independently of the treatment. Exposure to restraint led to the rise of HSP-90 and p53 in vehicle-treated rats only. Stress failed to modify MMP-2 activity and ultrastructure of the heart tissue. Treatment with the oxytocin/vasopressin receptor antagonist atosiban reversed stress-induced rise in HSP-90 and p53 proteins. In conclusion, our data demonstrate that repeated restraint stress induces Akt kinase activation and this is associated with elevation of anti-apoptotic proteins (Bcl-2) and down-regulation of pro-apoptotic proteins (cleaved caspase-3). These findings suggest that activation of pro-survival anti-apoptotic Akt kinase pathway plays an important role in molecular mechanisms underlying responses and adaptation of the rat heart to repeated stress exposure. The results further indicate a regulatory role of oxytocin/vasopressin in the control of stress-induced activation in HSP-90 and related proteins.

Effect of blockade of mGluR5 on stress hormone release and its gene expression in the adrenal gland.

The aim of this study was to verify the presence of metabotropic glutamate receptor subtype 5 (mGluR5) in the adrenal gland of male rats of 2 different strains, and to test the hypothesis that treatment with mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) affects hormone release and adrenal gene expression of mGluR5 under conditions of stress. The results clearly show the gene expression of mGluR5 in the adrenal gland in both the adrenal cortex and medulla. Treatment with the glutamate release inhibitor riluzole (4 mg·(kg body mass)(-1)·day(-1) for 2 weeks) failed to modify mRNA levels of either the mGluR5 or NR1 subunit of the NMDA receptor in the adrenal glands, as measured by real-time PCR. Blockade of mGluR5 with MPEP (1 mg·kg(-1) for 4 days) increased corticosterone but not catecholamine release during restraint stress (20 min). Treatment with MPEP had no effect on mRNA levels coding for steroidogenic factors StAR and SF-1, and decreased mGluR5 gene expression in the adrenal gland. In conclusion, mGluR5 is not likely to play a significant role in stress-induced catecholamine release. Pharmacological blockade of mGluR5 has a modest influence on the hypothalamic-pituitary-adrenocortical axis, as reflected in adrenal hypertrophy and increased corticosterone concentrations.