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Multiple sclerosis develops during reproductive years in a sex-specific manner. Various neuroendocrine changes have been described in this inflammatory, demyelinating, and debilitating disease. We here aimed to determine the extent and sex specificity of alterations in the hypothalamic-pituitary-gonadal axis in the rat model of multiple sclerosis named experimental autoimmune encephalomyelitis. During the disease course, the hypothalamic tissue showed transient upregulation of inflammatory marker genes Gfap, Cd68, Ccl2, and Il1b in both sexes, but accompanied by sex-specific downregulation of Kiss1 (in females only) and Gnrh1 (in males only) expression. In females, the expression of gonadotrope-specific genes Lhb, Cga, and Gnrhr was also inhibited, accompanied by decreased basal but not stimulated serum luteinizing hormone levels and a transient arrest of the estrous cycle. In contrast, Fshb expression and serum progesterone levels were transiently elevated, findings consistent with the maintenance of the corpora lutea, and elevated immunohistochemical labeling of ovarian StAR, a rate limiting protein in steroidogenic pathway. In males, downregulation of Gnrhr expression and basal and stimulated serum luteinizing hormone and testosterone levels were accompanied by inhibited testicular StAR protein expression. We propose that inflammation of hypothalamic tissue downregulates Kiss1 and Gnrh1 expression in females and males, respectively, leading to sex-specific changes downstream the axis. This is the peer reviewed version of the following article: Milosevic A, Janjic MM, Lavrnja I, Savic D, Bozic ID, Tesovic K, Jakovljevic M, Pekovic S, Stojilkovic SS, Bjelobaba I. The sex-specific patterns of changes in hypothalamic-pituitarygonadal axis during experimental autoimmune encephalomyelitis. Brain Behav Immun. 2020 [http://dx.doi.org/10.1016/j.bbi.2020.06.025]

Pituitary gonadotrophs play a key role in reproductive functions by secreting luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The LH secretory activity of gonadotroph is controlled by hypothalamic gonadotropin-releasing hormone (GnRH) via GnRH receptors and is accompanied by only minor effects on high basal Lhb gene expression. The secretory profiles of GnRH and LH are highly synchronized, with the latter reflecting a depletion of prestored LH in secretory vesicles by regulated exocytosis. In contrast, FSH is predominantly released by constitutive exocytosis, and secretory activity reflects the kinetics of Fshb gene expression controlled by GnRH, activin, and inhibin. Here is a review of recent data to improve the understanding of multiple patterns of gonadotroph gene expression and hormone secretion.

Adenosine-5′-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5′-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5′-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5′-triphosphate hydrolysis to adenosine-5′-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling.

The ecto-nucleoside triphosphate diphosphohydrolase 3 (NTPDase3), an enzyme involved in degradation of extracellular adenosine triphosphate (ATP), is expressed on nerve fibers in different brain regions, including cortex. Here we studied the expression and role of this enzyme after unilateral cortical stab injury in rats. In cortical sections of control rats, NTPDase3 immunoreactivity was associated with two types of fibers: thin processes, occasionally with small mushroom-like protrusions and slightly thicker fibers with more pronounced and more frequent varicosities, whereas immunopositive neuronal perycaria were never observed. Although NTPDase3-positive thin processes and thicker fibers, by general appearance, size and shape, could be dendrites and axons, respectively, they were never immunopositive for microtubule associated protein-2 or neurofilament H subunit. Cortical stab injury induced rapid (within 4 hours) focal varicose swelling that evolved over time to prominent beading of NTPDase3-positive fibers. The NTPDase3-positive fibers in all experimental groups also abundantly express NTPDase1, ecto-5'-nucleotidase and P2X2 receptor channels. Because the brain injury causes a massive ATP release, it is reasonable to conclude that purinoreceptors and ectonucleotidases play an important role in the process of neuritic beading. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. Serbian Ministry of Science and Technology [143005]

The aim of the present study was to analyze the activities of extracellular purine metabolizing enzymes, CD39 (apyrase, EC 3.6.1.5) and CD73 (ecto-5' nucleotidase, EC 3.1.3.5) in experimental autoimmune encephalomyelitis (EAE). The levels of ATP, ADP and AMP hydrolysis were analyzed in the blood serum and in the rat spinal cord plasma membrane preparation 8, 15 and 25 days after induction of EAE. The animals were divided in three groups: control (saline), CFA (adjuvant-only) and EAE (CFA and homogenate of spinal cords). Eight days after immunization, ATP, ADP and AMP hydrolysis in the blood serum and spinal cord membrane preparations were unaffected in EAE compared to both, control and CFA group. In the peak of disease, ATP, ADP and AMP hydrolysis in EAE group showed significant decrease in the blood serum and prominent increase in the spinal cord membrane preparation compared to CFA and control group. At the end of illness, as judged by disappearance of clinical manifestation of EAE, ATP, ADP and AMP hydrolysis, although closer to CFA levels, were still significantly different in respect to the CFA group. Modulation of ATP, ADP and AMP hydrolysis suggests that they operate during EAE and might represent the basis of novel therapeutic strategies in immune-mediated diseases, such as MS. (C) 2009 Elsevier Ltd. All rights reserved. null