The Effects of Apelin on the Electrical Activity of Hypothalamic Magnocellular Vasopressin and Oxytocin Neurons and Somatodendritic Peptide Release

Apelin, a novel peptide originally isolated from bovine stomach tissue extracts, is widely but selectively distributed throughout the nervous system. Vasopressin and oxytocin are synthesised in the magnocellular neurons of the hypothalamic supraoptic (SON) and paraventricular nuclei (PVN), which are apelin-rich regions in the central nervous system. We made extracellular electrophysiological recordings from the transpharyngeally exposed SON of urethane-anaesthetised rats to assess the role of apelin in the control of the firing activity of identified magnocellular vasopressin and oxytocin neurons in vivo. Apelin-13 administration onto SON neurons via microdialysis revealed cell-specific responses; apelin-13 increased the firing rates of vasopressin cells, but had no effect on the firing rate of oxytocin neurons. A direct excitatory effect of apelin-13 on vasopressin cell activity is also supported by our in vitro studies showing depolarisation of membrane potential and increase in action potential firing. To assess the effects of apelin-13 on somato/dendritic peptide release we used in vitro release studies from SON explants in combination with highly sensitive and specific radioimmunoassays. Apelin-13 decrease basal (by 78%, p<0.05, n=6) and potassium-stimulated (by 57%, p<0.05, n=6) vasopressin release but had no effect on somato/dendritic oxytocin release. Taken together, our data suggest a local autocrine feedback action of apelin on magnocellular vasopressin neurons. Furthermore, these data show a marked dissociation between axonal and dendritic vasopressin release with a decrease in somato/dendritic release but an increase in electrical activity at the cell bodies, indicating that release from these two compartments can be regulated wholly independently

CNS targets of adipokines

This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this record.Our understanding of adipose tissue as an endocrine organ has been transformed over the last twenty years. During this time a number of adipocyte-derived factors or adipokines have been identified. This paper will review evidence for how adipokines acting via the central nervous system (CNS) regulate normal physiology and disease pathology. The reported CNS-mediated effects of adipokines are varied and include the regulation of energy homeostasis, autonomic nervous system activity, the reproductive axis, neurodevelopment, cardiovascular function, and cognition. Due to the wealth of information available and the diversity of their known functions, the archetypal adipokines leptin and adiponectin will be the focused on extensively. Other adipokines with established CNS actions will also be discussed. Due to the difficulties associated with studying CNS function on a molecular level in humans, the majority of our knowledge, and as such the studies described in this paper, comes from work in experimental animal models; however, where possible the relevant data from human studies are also highlighted

Tyrosine-hydroxylase immunoreactivity in the mouse transparent brain and adrenal glands

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AOP and IATA applied to ocular surface toxicity

International audienceUntil now, the Draize test on rabbits has been the only test performed to anticipate ocular toxicity of pharmaceutical compounds, mainly irritation. The OECD is urging the scientific community to develop and validate alternative methods to reduce the need for animal testing. Since the models and tests used cannot reflect the entire biologic response, it is necessary to combine them into integrated approaches to testing and assessment (IATA) to obtain robust data. IATAs, along with adverse outcome pathways (AOP) that encompass molecular cascades and key events, require the best combinations of tests. This commentary manuscript describes these OECD tools and proposes original approaches for ocular surface AOP and an IATA for toxicity-induced dry eye (TIDE)

La douleur oculaire chronique : mieux la comprendre pour mieux la traiter

International audienceDry eye symptoms are one of the leading complaints in ophthalmology. They include visual disturbance, various types of symptoms and variable intensity of pain and discomfort that may become chronic or permanent and thus affect significantly the quality of life of patients. Nevertheless, the pathophysiological mechanisms of ocular surface pain remain largely unknown. A better clinical characterization of chronic ocular pain and an understanding of the molecular and cellular mechanisms involved are crucial issues for developing effective management and therapeutic strategy to alleviate ocular pain. In this review, we first describe the nociceptive corneal nerve pathways and the classification of corneal sensitive receptors neurons. The second part of this review gives an update of the preclinical and clinical data related to the inflammatory processes linked to inflammatory ocular pain. The last section describes the various diagnostic tools used in the clinic to evaluate corneal sensitivity and corneal inflammation.La sècheresse oculaire est un des premiers motifs de consultation en ophtalmologie. Sa prévalence varie de 5 à 35 % chez des sujets âgés de plus de 50 ans. Cette pathologie du segment antérieur de l’œil est caractérisée par des sensations de douleur variables dans leurs intensités, allant du simple inconfort à une douleur oculaire prononcée. Les douleurs oculaires sont très invalidantes et très difficiles à traiter, et leurs mécanismes physiopathologiques demeurent mal connus de nos jours. Ce constat impose un approfondissement de nos connaissances fondamentales sur l’anatomie du système nociceptif cornéen et sur les mécanismes cellulaires impliqués dans l’initiation et la chronicisation de la douleur oculaire. Cette revue présente, dans une première partie, l’anatomie de l’innervation cornéenne et les différentes classes de récepteurs sensitifs cornéens. La seconde partie fait un état des lieux des données précliniques et cliniques portant sur les mécanismes inflammatoires mis en jeu dans cette pathologie. Enfin la dernière partie de cette revue décrit les différents dispositifs actuellement utilisés pour évaluer la douleur et l’inflammation oculaire en clinique humaine

Glaucoma: A Degenerative Optic Neuropathy Related to Neuroinflammation?

International audienceGlaucoma is one of the leading causes of irreversible blindness in the world and remains a major public health problem. To date, incomplete knowledge of this disease's pathophysiology has resulted in current therapies (pharmaceutical or surgical) unfortunately having only a slowing effect on disease progression. Recent research suggests that glaucomatous optic neuropathy is a disease that shares common neuroinflammatory mechanisms with "classical" neurodegenerative pathologies. In addition to the death of retinal ganglion cells (RGCs), neuroinflammation appears to be a key element in the progression and spread of this disease. Indeed, early reactivity of glial cells has been observed in the retina, but also in the central visual pathways of glaucoma patients and in preclinical models of ocular hypertension. Moreover, neuronal lesions are not limited to retinal structure, but also occur in central visual pathways. This review summarizes and puts into perspective the experimental and clinical data obtained to date to highlight the need to develop neuroprotective and immunomodulatory therapies to prevent blindness in glaucoma patients

Role of angiotensin III in hypertension

International audienceThe hyperactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. Among the main bio-active peptides of the brain RAS, angiotensin (Ang) II and Ang III display the same affinity for type 1 and type 2 Ang II receptors. Both peptides, injected intracerebroventricularly, similarly increase blood pressure (BP); however, because Ang II is converted in vivo to Ang III, the identity of the true effector is unknown. In this article, we review new insights into the predominant role of brain Ang III in the control of BP, underlining the fact that brain aminopeptidase A (APA), the enzyme-forming central Ang III, could constitute a putative central therapeutic target for the treatment of hypertension. This justifies the development of potent systemically active APA inhibitors, such as RB150, as prototypes of a new class of antihypertensive agents for the treatment of certain forms of hypertension

Dual enkephalinase inhibitor PL265: a novel topical treatment toalleviate corneal pain and inflammation

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3D Distribution of Tyrosine Hydroxylase, Vasopressin and Oxytocin Neurons in the Transparent Postnatal Mouse Brain

International audienceOver the years, advances in immunohistochemistry techniques have been a critical step in detecting and mapping neuromodulatory substances in the central nervous system. The better quality and specificity of primary antibodies, new staining procedures and the spectacular development of imaging technologies have allowed such progress. Very recently, new methods permitting tissue transparency have been successfully used on brain tissues. In this work, we combined whole-mount immunostaining for tyrosine hydroxylase (TH), oxytocin (OXT) and arginine vasopressin (AVP), with iDISCO+ clearing method, light-sheet microscopy and semi automated counting of 3D-labelled neurons to obtain a 3D distribution of these neuronal populations in a 5-day postnatal (P5) mouse brain. Segmentation procedure and 3D reconstruction allowed us to map with high resolution TH staining the various catecholaminergic cell groups and their ascending and descending fiber pathways. We show that TH pathways are present in the whole P5 mouse brain, similar to what was observed in the adult rat brain