pituitrin and Neurodegenerative-Diseases

This review focuses on the cellular and molecular aspects underlying familial neurohypophyseal diabetes insipidus (DI), a rare disorder that is usually transmitted in an autosomal-dominant fashion. The disease, manifesting in infancy or early childhood and gradually progressing in severity, is caused by fully penetrant heterozygous mutations in the gene encoding prepro-vasopressin-neurophysin II, the precursor of the antidiuretic hormone arginine vasopressin (AVP). Post mortem studies in affected adults have shown cell degeneration in vasopressinergic hypothalamic nuclei. Studies in cells expressing pathogenic mutants and knock-in rodent models have shown that the mutant precursors are folding incompetent and fail to exit the endoplasmic reticulum (ER), as occurs normally with proteins that have entered the regulated secretory pathway. A portion of these mutants is eliminated via ER-associated degradation (ERAD) by proteasomes after retrotranslocation to the cytosol. Another portion forms large disulfide-linked fibrillar aggregates within the ER, in which wild-type precursor is trapped. Aggregation capacity is independently conferred by two domains of the prohormone, namely the AVP moiety and the C-terminal glycopeptide (copeptin). The same domains are also required for packaging into dense-core secretory granules and regulated secretion, suggesting a disturbed balance between the physiological self-aggregation at the trans-Golgi network and avoiding premature aggregate formation at the ER in the disease. The critical role of ERAD in maintaining physiological water balance has been underscored by experiments in mice expressing wild-type AVP but lacking critical components of the ERAD machinery. These animals also develop DI and show amyloid-like aggregates in the ER lumen. Thus, the capacity of the ERAD is exceeded in autosomal dominant DI, which can be viewed as a neurodegenerative disorder associated with the formation of amyloid ER aggregates. While DI symptoms develop prior to detectable cell death in transgenic DI mice, the eventual loss of vasopressinergic neurons is accompanied by autophagy, but the mechanism leading to cell degeneration in autosomal dominant neurohypophyseal DI still remains unknown.

Topics: Animals; Autophagy; Diabetes Insipidus, Neurogenic; Endoplasmic Reticulum; Glycopeptides; Humans; Neurodegenerative Diseases; Protein Aggregates; Proteolysis; Vasopressins

Spontaneously hypertensive rats (SHR) pathologically elevate blood pressure with age. This elevation is accompanied by specific neuronal degeneration in the hypothalamus and enlargement of the lateral ventricles. The aim of this study was to assess the neuroprotective effect of the monoamine oxidase B (MAO-B) inhibitor, rasagiline on paraventricular (PVN) hypothalamic degeneration in SHR. The S-enantiomer of rasagiline, S-PAI, a much weaker MAO inhibitor, and two antihypertensive drugs, captopril and hydralazine were also tested. Normotensive Wistar Kyoto (WKY) rats served as controls. One month-old SHR or WKY rats were treated daily for 3-4 months. Systolic blood pressure was recorded, parvocellular vasopressin (VP) immunopositive cells were counted and the area of the third ventricle measured. In saline-treated SHR, blood pressure rose significantly and the number of VP parvocellular cells was reduced by about 60% relative to WKY. Rasagiline, 1 mg/kg/day, reduced PVN neuronal cell death in SHR up to 112% relative to saline-treated SHR; 0.3 mg/kg/day exerted a smaller but significant effect. These actions were accompanied by parallel reductions in systolic blood pressure. Captoril, hydralazine and S-PAI did not prevent death of VP neurons. In SHR, the volume of the third ventricle was about double that of WKY. Rasagiline significantly prevented this ventricular dilation. These results indicate than rasagiline protects from cell death in an in vivo animal model in a dose-dependant manner and could be of use as a neuroprotector in the central nervous system.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Indans; Male; Monoamine Oxidase Inhibitors; Nerve Degeneration; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred SHR; Rats, Wistar; Third Ventricle; Treatment Outcome; Vasopressins