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

International audienc

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

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)

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

International audienc

Cellular localization of apelin and its receptor in the anterior pituitary: evidence for a direct stimulatory action of apelin on ACTH release.

International audienceApelin is a bioactive peptide recently identified as the endogenous ligand of the human orphan G protein-coupled receptor APJ. The presence of apelin-immunoreactive nerve fibers, together with the detection of apelin receptor mRNA in the parvocellular part of the paraventricular nucleus and the stimulatory action of apelin on corticotropin-releasing hormone release, indicate that apelin modulates adrenocorticotropin (ACTH) release via an indirect action on the hypothalamus. However, a direct action of apelin in the anterior pituitary cannot be excluded. Here, we provided evidence for the existence of an apelinergic system within the adult male rat pituitary gland. Double immunofluorescence staining indicated that apelin is highly coexpressed in the anterior pituitary, mainly in corticotrophs (96.5 +/- 0.3%) and to a much lower extent in somatotropes (3.2 +/- 0.2%). Using in situ hybridization combined with immunohistochemistry, a high expression of apelin receptor mRNA was also found in corticotrophs, suggesting a local interaction between apelin and ACTH. In an ex vivo perifusion system of anterior pituitaries, apelin 17 (K17F, 10(-6) M) significantly increased basal ACTH release by 41%, whereas apelin 10 (R10F, 10(-6) M), an inactive apelin fragment, was ineffective. In addition, K17F but not R10F induced a dose-dependent increase in K(+)-evoked ACTH release, with maximal increase being observed for a 10(-6) M concentration. Taken together, these data outline the potential role of apelin as an autocrine/paracrine-acting peptide on ACTH release and provide morphological and neuroendocrine basis for further studies that explore the physiological role of apelin in the regulation of anterior pituitary functions

Combined 3DISCO clearing method, retrograde tracer and ultramicroscopy to map corneal neurons in a whole adult mouse trigeminal ganglion

International audienceTissue clearing and subsequent imaging of intact transparent tissues have provided an innovative way to analyze anatomical pathways in the nervous system. In this study, we combined a recent 3-dimensional imaging of solvent cleared organ (3DISCO) procedure, light-sheet microscopy, fluorescent retrograde tracer, and Imaris software to 3D map corneal sensory neurons within a whole adult mouse trigeminal ganglion (TG). We first established the optimized steps to easily and rapidly clear a fixed TG. We found that the 3DISCO procedure gave excellent results and took less than 3 h to clear the TG. In a second set of experiments, a retrograde tracer (cholera toxin B Alexa 594-conjugated) was applied to de-epithelialized cornea to retrograde-labeled corneal sensory neurons. Two days later, TGs were cleared by the 3DISCO method and serial imaging was performed using light-sheet ultramicroscopic technology. High-resolution images of labeled neurons can be easily and rapidly obtained from a 3D reconstructed whole mouse TG. We then provided a 3D reconstruction of corneal afferent neurons and analyzed their precise localization in the TG. Thus, we showed that neurons supplying corneal sensory innervation exhibit a highly specific limited dorsomedial localization within the TG. We report that our combined method offers the possibility to perform manual (on 20 μm sections) and automated (on 3D reconstructed TG) counting of labeled cells in a cleared mouse TG. To conclude, we illustrate that the combination of the 3DISCO clearing method with light-sheet microscopy, retrograde tracer, and automatic counting represents a rapid and reliable method to analyze a subpopulation of neurons within the peripheral and central nervous system