Cortisol is increased in postmortem cerebrospinal fluid of multiple sclerosis patients: relationship with cytokines and sepsis.

Hypothalmo-pituitary-adrenal (HPA) axis activity is altered in patients with multiple sclerosis (MS), resulting in elevated basal levels and enhanced response of cortisol in stimulation tests. HPA axis hyperactivation in MS is thought to be the result of complex interactions of genetic, immunologic, and neuroendocrinological mechanisms. In order to investigate whether cytokine levels in the central nervous system are associated with the activation of the HPA axis in MS, we measured cortisol, interleukin (IL)-6, IL-10 and TNF-alpha levels in postmortem cerebrospinal fluid (CSF) of 18 patients with severe MS and 50 controls. We also investigated the cortisol and cytokine levels in the CSF of a group of MS patients and controls who died with sepsis, in order to see whether acute infectious situations affect the association between cortisol and cytokines. The cortisol levels in MS patients were increased by 80% in comparison to controls (p=0.008). There was no difference in IL-6 levels between the groups, while IL-10 and TNF-alpha levels of the majority of subjects were below detection limits. There was a positive correlation between cortisol and IL-6 only in control patients with sepsis (r=0.89, p=0.019), but not within the MS patents with sepsis or MS and control groups without sepsis. Cortisol levels in postmortem serum and CSF were highly correlated (r>0.78, p<0.001). We concluded that the basal level of cortisol is significantly increased in the CSF of MS patients and that IL-6 is not responsible for this rise. The relationship between cortisol and IL-6 in sepsis is discussed.

Glucocorticoid treatment is associated with decreased expression of processed AVP but not of proAVP, neurophysin or oxytocin in the human hypothalamus: are PC1 and PC2 involved?

OBJECTIVES: We reported earlier that vasopressin (AVP) peptide expression is significantly decreased in the postmortem hypothalamus of glucocorticoid (GC) treated patients, while such a decrease was not observed in AVP prohormone (proAVP) expression. This indicated a GC-induced suppression of AVP synthesis at the posttranslational level. Here, we investigated in detail whether this decreased levels of AVP expression in GC treated patients might be due to the down regulation of the prohormone convertases PC-1 and PC-2, and the molecular chaperone 7B2, as was reported previously in some AVP-related disorders. MATERIALS & METHODS: An immunocytochemical study was performed on post-mortem hypothalami of GC exposed patients and controls, in which quantification of proAVP, AVP, neurophysin (NP) and oxytocin (OXT) expression were done along with the quantification of PC1, PC2 and 7B2 expression in the paraventricular nucleus, by using a computerized image analysis system. RESULTS: Expression of processed AVP in GC exposed patients was significantly decreased (p=0.021), while the amount of proAVP expression was unchanged. Despite the strong correlation between AVP and NP (the other cleavage product of proAVP) expression in the GC group (r=0.917, p=0.004), the mean NP immunoreactivity did not show a significant decrease in this group. Also the OXT expression was similar in both groups. Although in most of the GC treated patients, the expression intensities of PC1 and PC2 were decreased parallel to the decrease in AVP, the mean expression levels of neither of PC1 and PC2, nor of 7B2 were statistically different between the groups (p=0.20-0.80). CONCLUSION: We conclude that the suppression of AVP expression by GCs is not mediated solely by the down regulation of PC1, PC2 or 7B2. Other mechanisms, which may contribute to the GC-induced posttranslational suppression of AVP, are discussed.

Glucocorticoids suppress corticotropin-releasing hormone and vasopressin expression in human hypothalamic neurons.

Glucocorticoids are widely used in clinical practice in a variety of immune-mediated and neoplastic diseases, mostly for their immunosuppressive, leukopenic, antiedematous, or malignancy-suppressive actions. However, their usage is limited because of serious and sometimes life-threatening side-effects. Endogenous glucocorticoids are secreted by the adrenal cortex under the control of the hypothalamus and the pituitary gland. This hypothalamo-pituitary-adrenal axis, in turn, is under the negative feedback control of glucocorticoids. Although the suppression of adrenocortical and pituitary gland functions by glucocorticoids has been shown in humans, a feedback effect at the level of the hypothalamus, as shown in rat, has not been reported to date. The present study shows for the first time that glucocorticoids suppress both CRH and vasopressin (AVP) in the human hypothalamus. We studied immunocytochemically the postmortem hypothalami of nine corticosteroid-exposed subjects and eight controls. The number of CRH-expressing cells in the hypothalamic paraventricular nucleus of glucocorticoid-exposed patients was only 3.3% of that in the controls, and the total immunoreactivities for AVP were 31% and 33% of that in the controls in the supraoptic nucleus and the paraventricular nucleus, respectively, whereas the immunoreactivity for oxytocin did not differ between the two groups. Suppression of hypothalamic CRH and AVP neurons by glucocorticoids may have important consequences for neuroendocrinological mechanisms such as the disturbance of water balance during the treatment as well as the immunological processes in the brain and the pathogenesis of the withdrawal syndrome after discontinuation of corticosteroid treatment. In addition, as both AVP and CRH neurons also project to other brain structures and influence memory, mood, and behavior, their suppression by glucocorticoids may be responsible for at least part of the central nervous system side-effects of glucocorticoids.

Increased activity of hypothalamic corticotropin-releasing hormone neurons in multiple sclerosis.

Clinical observations and animal studies suggest that the hypothalamo-pituitary-adrenal (HPA) axis plays a role in the susceptibility to and the recovery from multiple sclerosis (MS). Since the HPA-axis is under the control of corticotropin-releasing hormone (CRH) neurons of the hypothalamus, we determined 2 parameters for activation of the CRH neurons in the hypothalamic paraventricular nucleus (PVN) in MS patients. Since the HPA-axis is more activated in MS, we expected an increased activity of CRH neurons. We also expected to see an age-related increase in CRH activity, because of the possible role of the HPA-axis in the age-related decrease in susceptibility to MS. The number of CRH cell profiles and the proportion of CRH neurons co-expressing vasopressin were used as parameters for activity. CRH cell population became more activated both in control and MS patients, from 40 years of age onwards, when the prevalence of MS starts to decrease in the population. The CRH neurons showed a significantly higher level of activation in MS patients than in controls, as appeared from the 3-fold increase in CRH cell number and the 4.5-fold increase in cells co-expressing CRH and vasopressin (AVP).