Increased Number of Corticotropin-Releasing Hormone Expressing Neurons in the Hypothalamic Paraventricular Nucleus of Patients with Multiple Sclerosis

Purba, Jan S.; Raadsheer, F.C.; Hofman, Michel A.; Ravid, Rivka; Polman, Chris H.; Kamphorst, Wouter; Swaab, Dick F.

doi:10.1159/000126989

Cited by 56 publications

(26 citation statements)

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“…Considering that two phenotypic CRF neurons occur in the PVN (one non-AVP-producing and the other AVP-coproducing) [32] and that the signal-driving ACTH secretion depends on the nature, intensity, and duration of the stressor [2], it is tempting to speculate that, in contrast to AA in EAE, the non-AVP-producing neuron is the predominant driving neuron, at least in the later stages of the disease (after 11 days). This notion is reinforced by results in humans with multiple sclerosis, which show an increased number of CRF-expressing neurons in the PVN [33].…”

Section: Discussionmentioning

confidence: 83%

Hypothalamic Response to Experimental Allergic Encephalomyelitis: Role of Substance P

Ruocco

Fernandes²,

Namer³

et al. 2003

Neuroimmunomodulation

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Adjuvant-induced arthritis (AA) is thought to be a model for experimental chronic stress that has as main features decreased adrenocorticotropin hormone (ACTH) plasma levels and a rise in median eminence content of arginine vasopressin (AVP) due to the activity of substance P. In experimental allergic encephalomyelitis (EAE), another chronic stress model, the role of substance P action is not clear. In this paper we tried to clarify the role of substance P in Lewis rats, which are susceptible to this disease. EAE was induced using myelin basic protein plus complete Freund’s adjuvant injected into the hind limbs. One day later injections of an antagonist to substance P (RP 67580), saline, and substance P were administered daily for 12–14 days through a stainless steel cannula into the lateral ventricle of the brain, and then the rats were killed. The rats were divided into groups of controls, sham, diseased controls (no intracerebroventricular injections) and EAE (injected intracerebroventricularly). Plasma was used for the quantification of ACTH and corticosterone but not AVP which was assayed in hypothalamic median eminence extracts. In noninjected diseased rats the plasma levels of ACTH and corticosterone were significantly higher than in noninjected control rats, whereas the AVP concentrations in the median eminence were unchanged. The substance P antagonist did not affect the levels of these hormones in plasma or the median eminence. Substance P decreased the plasma levels of ACTH and corticosterone but did not increase the median eminence content of vasopressin. Administration of the antagonist 30 min before an equivalent dose of substance P increased the plasma levels of the two hormones, but did not change the content of AVP. Based on the lack of response to the antagonist RP 67580 we suggest that the substance P has different roles in EAE and AA at least in the later stages of EAE (after 11 days of immunization).

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Section: Discussionmentioning

confidence: 83%

Hypothalamic Response to Experimental Allergic Encephalomyelitis: Role of Substance P

Ruocco

Fernandes²,

Namer³

et al. 2003

Neuroimmunomodulation

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“…Increased HPA axis activity has been reported in patients with MS under basal conditions and in response to challenge tests (Michelson et al 1994;Reder et al 1994;Grasser et al 1996;Wei & Lightman, 1997;Fassbender et al 1998;Then Bergh et al 2001). Post-mortem analysis of brains from MS patients has revealed an increase in the number of CRF-positive, AVP-positive neurons in the PVN with no change in the CRF-positive, AVP-negative population (Erkut et al 1995;Purba et al 1995). These data suggest an increased role for AVP in MS. Further support for an increased role for AVP is provided by the observation that MS patients have an increased HPA axis response to AVP compared with controls (Michelson et al 1994).…”

mentioning

confidence: 85%

Neuroendocrine Function and Chronic Inflammatory Stress

Harbuz

2002

Experimental Physiology

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The HPA axis and the response to acute stress The end-point of the activation of the HPA axis is the release of glucocorticoids (cortisol in man, corticosterone in rodents) from the adrenal cortex into the general circulation. The synthesis and release of glucocorticoids are controlled by ACTH released from the anterior pituitary gland. ACTH is synthesised from the precursor proopiomelanocortin (POMC) mRNA. The release of ACTH is regulated by the corticotrophin releasing factors corticotrophin-releasing factor(1-41) (CRF) and arginine vasopressin (AVP), which are released from the median eminence and synthesised in the parvocellular cells of the paraventricular nucleus (PVN). Under normal conditions approximately 50 % of these CRF neurons contain AVP; the remainder contain CRF but no vasopressin. CRF and AVP exert a synergistic action on the release of ACTH. The PVN acts as a co-ordinating centre receiving signals from many brain areas to regulate the response to stress. The glucocorticoids are able to regulate their own synthesis by negative feedback mediated by two corticosteroid receptors, the type II (glucocorticoid) receptor, which is found in the pituitary, PVN and other brain areas such as the hippocampus, and the type I receptor, which is found in the hippocampus. The hippocampus has a tonic inhibitory input to the PVN. In response to acute stress, the HPA axis is activated evoking the release of CRF and AVP into the The factors regulating susceptibility and severity of autoimmune diseases are poorly understood. That neuroendocrine factors are critical modulators in this regard is self-evident. For example, there are major gender differences in susceptibility with women at greater risk than men of, for example, rheumatoid arthritis (RA) and multiple sclerosis (MS). The hypothalamo-pituitary-adrenal (HPA) axis has rightly attracted a considerable amount of attention. Of particular interest has been the hypothesis that susceptibility to autoimmune disease may be related to an impaired responsiveness of the HPA axis; that is, an inability to mount an appropriate cortisol response with which to down-regulate the immune system might allow the immune system to rampage unchecked and attack self. This hypothesis links regulation of the release from the adrenal gland of the potent anti-inflammatory glucocorticoids to the disease process. Endogenous glucocorticoids are crucial for the regulation of the severity of the disease process. The hypothesis proposing a link between a hyporesponsive HPA axis and susceptibility to disease is compelling. However, evidence from a number of sources has suggested that this may not be the entire story and alterations in the activity of the HPA axis have not been consistently observed in patients with RA. This review will concentrate on recent findings concerning the HPA axis in determining susceptibility to, and in regulating the severity of, inflammatory processes in autoimmune disease. These studies have revealed that a single exposure to endotoxin can confer protection to sub...

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“…amic CRH neurons as indicated by increased numbers of CRH expressing neurons and an increase in the fraction of these neurons that co-express AVP (Erkut, Hofman, Ravid, & Swaab, 1995;Purba, Raadsheer, Hofman, Ravid, Polman, Kamphorst, & Swaab, 1995;Swaab, 1997). Detailed cHnical studies revealed subtle HPA dysregulations e.g.…”

Section: Immune Activation Induced Hpa Changes and Depressionmentioning

confidence: 99%