pituitrin and Multiple-Sclerosis

In this postmortem study, we investigated the relationship between multiple sclerosis (MS) lesions in the hypothalamus and the state of activity of corticotropin-releasing hormone (CRH)-producing neurons that control the hypothalamus-pituitary-adrenal (HPA) axis. A high incidence (15/16) of MS lesions was found in the hypothalamus, of which more than 50% was active, that is, contained activated macrophages. MS patients have increased numbers of CRH-immunoreactive neurons coexpressing vasopressin (CRH/VP neurons), a sign of chronic activation of CRH neurons and increased CRH mRNA expression. Active MS lesions correlated with a low number of hyperactive CRH/VP neurons. High human leukocyte antigen (HLA)-DR, -DP, -DQ expression, a measure for macrophage and microglial activation, correlated with low CRH mRNA expression. The nearer the HLA expression was situated to the CRH neurons, the stronger the inhibiting effect, suggesting that activated microglial cells or macrophages suppress these neurons. The more active MS lesions were present in the hypothalamus, the shorter was the disease duration until the moment of death, indicating an unfavorable course of the disease. Thus, MS patients have a chronically activated CRH system, but, in the subgroup of patients with active MS lesions in the hypothalamus, this activation is impaired and the disease course is worse.

Topics: Adult; Aged; Aged, 80 and over; Corticotropin-Releasing Hormone; Female; HLA Antigens; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Image Processing, Computer-Assisted; Immunohistochemistry; In Situ Hybridization; Macrophage Activation; Male; Microglia; Middle Aged; Multiple Sclerosis; Neurons; Pituitary-Adrenal System; RNA, Messenger; Vasopressins

New class of therapies, including bipolar therapies (BPT) and "paradoxical" unipolar therapies (PUT) were firstly proposed in relation to a clinical insight and to some results of biological investigations, then they gave rise to mathematical modeling which brought a justification of these therapies, at least from a theoretical point of view. After recalling the mathematical model for the regulation of agonistic antagonistic couples, and reporting the fundamental types of control simulation by means of it, we point out the validity of therapeutical applications inferred from this model. These therapy modalities, including BPT and PUT, now concern the following diseases: astrocytomas, epilepsia and trials on multiple sclerosis. Even if such attempts are in their early stage, noticeably for the last case where biological changes have mainly been studied, it seems that a large span of treatments is open to BPT and PUT. Improvement of these techniques in the future depends, in our opinion, on a parallel working on the dynamics of the mathematical model and the dynamics, perceived by clinical insight and confirmed by biological investigations, of the body reactions to such strategies. Justification of BPT and PUT was given, by resorting to the notion of "pathological homeostasis" which, too often, intervenes in order to nullify the effects of unilateral (not paradoxical) therapies. This research has elicited some therapies which use two agents with antagonistic effects or only an agent with effects similar to the agent already in excess in the body--in both cases at nearly physiological doses.

Topics: Adaptation, Physiological; Adrenal Cortex Hormones; Animals; Astrocytoma; Brain; Brain Neoplasms; Computer Simulation; Epilepsy; Homeostasis; Humans; Models, Theoretical; Multiple Sclerosis; Vasopressins

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).

Topics: Adult; Age Factors; Aged; Cell Count; Corticotropin-Releasing Hormone; Female; Humans; Hypothalamus; Male; Middle Aged; Multiple Sclerosis; Neurons; Regression Analysis; Sex Factors; Vasopressins

Computerized Chou-Fasman analysis of the secondary structure of human T-cell leukemia viruses (HTLV-I, HTLV-II) and human immunodeficiency virus (HIV) envelope proteins revealed that only one antigenic epitope (amino acids EAL) is shared by the three viruses. A similar antigenic epitope is also found in human and rat brain hormone vasopressin-neurophysin. If autoantibodies in multiple sclerosis (MS) are made to the epitope EAL, they may cross-react with the envelope proteins of HTVL. It is speculated that in AIDS patients, antibodies to the antigenic epitope EAL of HIV may cross-react with brain vasopressin-neurophysin, leading to a decline in this brain peptide hormone. Thus it is hypothesized that treatment of both MS and AIDS patients with a synthetic polymer containing the amino acids EAL might eliminate the antibodies to vasopressin-neurophysin and thus alleviate some of the clinical symptoms.

Topics: Acquired Immunodeficiency Syndrome; Animals; Antibodies, Viral; Autoantibodies; Cross Reactions; HIV; Humans; Multiple Sclerosis; Neuropeptides; Neurophysins; Vasopressins; Viral Envelope Proteins

We have reported previously that autoantibodies in sera from patients with multiple sclerosis (MS) were reactive with rat brain, including pituitary, and with swine pituitary in areas thought to contain peptides of the somatotropin family and/or vasopressin/oxytocin. We have now tested the same patient sera for their specificity to antigenic determinants which are common to animal and human peptides. Localization of the binding sites of the MS sera was demonstrated in rat pituitaries and brains using the double immunofluorescence staining method, employing anti-bovine somatotropin (STH), anti-ovine prolactin (PRL), anti-neurophysin I and II, anti-somatostatin, and anti-vasopressin as reference antibodies. In the pituitary, the positive MS sera reacted specifically with cells which were also reactive with anti-bSTH. In the brain, positivity of MS sera was mainly localized in structures reactive with anti-neurophysin I and II and anti-vasopressin. Absorption experiments, immunocytochemical model assays, and radioimmunoassays, however, did not show specific binding of the MS sera to any of the above-mentioned peptides. Therefore, while these data present additional evidence on the localization of the immunocytochemical reaction sites of the MS autoantibodies, they do not enable us to identify the specificity of these antibodies.

Topics: Animals; Antibody Specificity; Autoantibodies; Brain; Growth Hormone; Humans; Immunochemistry; Multiple Sclerosis; Neurophysins; Oxytocin; Pituitary Gland; Prolactin; Rats; Vasopressins

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Adult; Female; Humans; Lysine; Male; Multiple Sclerosis; Pituitary-Adrenal System; Vasopressins

Topics: Adrenocorticotropic Hormone; Glucocorticoids; Humans; Multiple Sclerosis; Pituitary-Adrenal System; Vasopressins

Topics: Adrenocorticotropic Hormone; Blood Glucose; Endocrine Glands; Female; Humans; Hydrocortisone; Hypoglycemia; Insulin; Lysine; Male; Multiple Sclerosis; Nervous System Diseases; Pituitary-Adrenal Function Tests; Vasopressins

Topics: 17-Hydroxycorticosteroids; 17-Ketosteroids; Acute Disease; Adrenocorticotropic Hormone; Adult; Chronic Disease; Female; Humans; Hypothalamo-Hypophyseal System; Male; Metyrapone; Middle Aged; Multiple Sclerosis; Neurologic Manifestations; Pituitary-Adrenal Function Tests; Pituitary-Adrenal System; Stimulation, Chemical; Vasopressins

Topics: 17-Hydroxycorticosteroids; 17-Ketosteroids; Adrenocorticotropic Hormone; Adult; Female; Humans; Long-Term Care; Male; Metyrapone; Multiple Sclerosis; Pituitary Function Tests; Vanilmandelic Acid; Vasopressins