Suppression Of Corticosterone Levels Research Articles

Safety of glucocorticoids can be improved by lower yet still effective dosages of liposomal steroid formulations in murine antigen-induced arthritis: Comparison of prednisolone with budesonide

The goal of this study was to compare the effects of liposomal and free glucocorticoid formulations on joint inflammation and activity of the hypothalamic-pituitary-adrenal (HPA) axis during experimental antigen-induced arthritis (AIA). A dose of 10 mg/kg liposomal prednisolone phosphate (PLP) gave a suppression of the HPA-axis, as measured by plasma corticosterone levels in mice with AIA and in naïve mice. In a subsequent dose-response study, we found that a single dose of 1 mg/kg liposomal prednisolone phosphate (PLP) was still equally effective in suppressing joint inflammation as 4 repeated once-daily injections of 10 mg/kg free PLP. Moreover, the 1 mg/kg liposomal PLP dose gave 22% less suppression of corticosterone levels than 10 mg/kg of liposomal PLP at day 14 of the AIA. In order to further optimize liposomal glucocorticoids, we compared liposomal PLP with liposomal budesonide phosphate (BUP) (1 mg/kg). At 1 day after treatment, liposomal BUP gave a significantly stronger suppression of joint swelling than liposomal PLP (lip. BUP 98% vs. lip. PLP 79%). Both formulations also gave a strong and lasting suppression of synovial infiltration in equal amounts. However, at day 21 after AIA, liposomal PLP still significantly suppressed corticosterone levels, whereas this suppression was not longer statistically significant for liposomal BUP. Conclusion: Liposomal delivery improves the safety of glucocorticoids by allowing for lower effective dosing. The safety of liposomal glucocorticoid may be further improved by encapsulating BUP rather than PLP.

Enduring Neurobehavioral Effects of Early Life Trauma Mediated Through Learning and Corticosterone Suppression

Early life trauma alters later life emotions, including fear. To better understand mediating mechanisms, we subjected pups to either predictable or unpredictable trauma, in the form of paired or unpaired odor-0.5 mA shock conditioning which, during a sensitive period, produces an odor preference and no learning respectively. Fear conditioning and its neural correlates were then assessed after the sensitive period at postnatal day (PN)13 or in adulthood, ages when amygdala-dependent fear occurs. Our results revealed that paired odor-shock conditioning starting during the sensitive period (PN8–12) blocked fear conditioning in older infants (PN13) and pups continued to express olfactory bulb-dependent odor preference learning. This PN13 fear learning inhibition was also associated with suppression of shock-induced corticosterone, although the age appropriate amygdala-dependent fear learning was reinstated with systemic corticosterone (3 mg/kg) during conditioning. On the other hand, sensitive period odor-shock conditioning did not prevent adult fear conditioning, although freezing, amygdala and hippocampal 2-DG uptake and corticosterone levels were attenuated compared to adult conditioning without infant conditioning. Normal levels of freezing, amygdala and hippocampal 2-DG uptake were induced with systemic corticosterone (5 mg/kg) during adult conditioning. These results suggest that the contingency of early life trauma mediates at least some effects of early life stress through learning and suppression of corticosterone levels. However, developmental differences between infants and adults are expressed with PN13 infants' learning consistent with the original learned preference, while adult conditioning overrides the original learned preference with attenuated amygdala-dependent fear learning.

Effects of Systemic and Intracerebroventricular Cysteamine on Dexamethasone-Induced Suppression of Corticosterone Levels in the Rat

To investigate whether somatostatin systems plays a significant role in the regulation of the hypothalamic-pituitary-adrenal axis, the effects of cysteamine, a drug which reduces somatostatin levels, on the dexamethasone-induced suppression of plasma corticosterone levels were examined in the rat. Male Long Evans rats were handled daily for 1 week prior to receiving a standard dexamethasone suppression test. On the 1st day, rats received a 9.00 a.m. saline injection and blood samples were taken from the tail at 1.00 p.m. On the 2nd day, rats received dexamethasone or saline at 9.00 a.m. and a second blood sample was taken at 1.00 p.m. Experimental groups were pretreated with systemic injections of cysteamine, 5 min or 14 h, prior to receiving dexamethasone. Additional groups, previously implanted with guide cannulae, were given an infusion of cysteamine or saline into the lateral ventricle 14 h prior to dexamethasone. Circulating corticosterone levels were determined by radioimmunoassay. Rats were sacrificed immediately following each experiment and the hypothalamus dissected and assayed for levels of somatostatin immunoreactivity. The results of the first experiment showed that dexamethasone (10 micrograms/kg) alone reduced plasma corticosterone levels from control values (174 +/- 36 ng/ml) to undetectable levels (less than 25 ng/ml). Pretreatment with cysteamine 5 min prior to dexamethasone, while having no significant effect on basal corticosterone levels, completely blocked the dexamethasone-induced suppression of corticosterone levels. Similar observations were obtained with rats pretreated with cysteamine 14 h prior to dexamethasone. In contrast, intracerebroventricular cysteamine pretreatment did not block the dexamethasone-induced suppression of corticosterone levels. These results add further evidence in support of an involvement of somatostatin systems in the regulation of the hypothalamic-pituitary-adrenal axis.