Claude Fortier : une grande histoire de la neuroendocrinologie

L’oeuvre de Claude Fortier est indissociable de l’histoire de la neuroendocrinologie. À travers ses travaux réalisés à Montréal avec Hans Selye, puis à Québec dans son laboratoire où se sont succédés de très nombreux neuroendocrinologistes réputés, c’est toute la saga de la recherche sur le CRH (corticotropin releasing hormone) et la régulation de l’axe hypothalamo-hypophyso-surrénalien (HPA) ou axe du stress que l’on peut relater. Parmi les travaux pionniers de Claude Fortier, on peut citer la mise en évidence de la rétroaction de l’activité centrale et hypophysaire de l’axe HPA par les glucocorticoïdes et la mise en évidence de récepteurs des glucocorticoïdes et des minéralocorticoïdes réglant distinctement la libération d’ACTH (adrenocorticotropic hormone). On lui doit aussi d’avoir été l’un des précurseurs dans l’utilisation de l’outil informatique en recherche biomédicale. Les retombées de ses découvertes dans les maladies du stress (anxiété, dépression, addiction) sont majeures. Claude Fortier ne fut pas seulement un grand homme de science, dont les travaux et ceux de ses collègues ont été récompensés par de nombreux prix et distinctions, mais il a aussi joué un rôle politique important dans l’organisation de la recherche au Québec dont la qualité est reconnue internationalement.The work of Claude Fortier is linked to the history of neuroendocrinology. Through him and his pioneer work in Montreal with Hans Selye, the « Man of stress », and at Laval University in Quebec City in his own laboratory, where all researchers involved in the study of the hypothalamo-hypophysial adrenal axis have been through, it is the whole saga of the search for the neuropeptide CRH (corticotropin releasing factor), and the harsh fight for the Nobel distinction that can be related. Among Claude Fortier’s scientific discoveries, the feedback mechanisms of glucocorticoid hormones on brain and pituitary function, the presence of both mineralo and glucocorticoid receptors in some brain structures, and the introduction of computer science in biomedical research, can be cited. The consequences of these discoveries are illustrated in the pathologies linked to stress (anxiety, depression, addiction). Claude Fortier was not only a great figure in biomedical science, honored by several distinctions, but also an important personality in the policy of research in which he played a prominent role in Quebec medical research and allowed it to rank among the best in the world

Characterization and quantitative topographical distribution of salmon calcitonin-binding sites in rat kidney sections

AbstractRenal binding sites for labelled salmon calcitonin (sCT) were studied using cryostat sections and autoradiography. Increasing concentrations of unlabelled sCT inhibited 125I-sCT binding. 125I-sCT bound to a single site with a Kd of 2 nM and a number of sites of 220 fmolmg protein. Mammalian calcitonins had low affinities and peptides unrelated to CT were devoid of any significant affinity for 125I-sCT receptors. Auto-radiograms disclosed a high concentration of 125I-sCT receptors mainly located in the outer medulla and heterogeneously in the renal cortex. The distribution of specific binding sites is in agreement with the current concepts of renal action of calcitonin

Hyperosmolarity potentiates toxic effects of benzalkonium chloride on conjunctival epithelial cells in vitro

International audiencePurpose: Benzalkonium chloride (BAK), the most commonly used preservative in eye drops, is known to induce ocular irritation symptoms and dry eye in long-term treated patients and animal models. As tear film hyperosmolarity is diagnostic of some types of dry eye disease, we determined in vitro on conjunctival epithelial cells the cytoxicity of BAK in hyperosmolar conditions through cell viability, apoptosis, and oxidative stress assays.Methods: The Wong Kilbourne derivative of Chang conjunctival epithelial cells were cultured for 24 h or 48 h either in NaCl-induced hyperosmolar conditions (400–425–500 mOsM), in low concentrations of BAK (10−4%, 3.10−4%, and 5.10−4%), or in combination of both. We investigated cell viability through lysosomal integrity evaluation, cell death (cell membrane permeability and chromatin condensation), and oxidative stress (reactive oxygen species, superoxide anion) using spectrofluorimetry. Immunohistochemistry was performed for cytoskeleton shrinkage (phalloidin staining), mitochondrial permeability transition pore (cytochrome c release), the apoptosis effector active caspase-3, and the caspase-independent apoptosis factor AIF. We also observed early effects induced by the experimental conditions on the conjunctival cell layers using phase contrast imaging of live cells.Results: As compared to standard culture solutions, hyperosmolar stress potentiated BAK cytotoxicity on conjunctival cells through the induction of oxidative stress; reduction of cell viability; cell membrane permeability increase; cell shrinkage with cell blebbing, as shown in phase contrast imaging of live cells; and chromatin condensation. Like BAK, but to a much lesser extent, hyperosmolarity increased cell death in a concentration-dependent manner through a caspase-dependent apoptosis characterized by a release of cytochrome c in the cytoplasm from mitochondria and the activation of caspase-3. Moreover, the caspase-independent apoptosis factor AIF was found translocated from mitochondria to the nucleus in both conditions.Conclusions: This study showed increased cytotoxic effects of BAK in hyperosmotic conditions, with characteristic cell death processes, namely caspase-dependent and independent apoptosis and oxidative stress. As BAK is known to disrupt tear film, which could promote evaporative dry eye and tear hyperosmolarity, BAK could promote the conditions enhancing its own cytotoxicity. This in vitro hyperosmolarity model thus highlights the risk of inducing a vicious cycle and the importance of avoiding BAK in patients with dry eye conditions

The Chemokine CCL2 Protects Against Methylmercury Neurotoxicity

Industrial pollution due to heavy metals such as mercury is a major concern for the environment and public health. Mercury, in particular methylmercury (MeHg), primarily affects brain development and neuronal activity, resulting in neurotoxic effects. Because chemokines can modulate brain functions and are involved in neuroinflammatory and neurodegenerative diseases, we tested the possibility that the neurotoxic effect of MeHg may interfere with the chemokine CCL2. We have used an original protocol in young mice using a MeHg-contaminated fish-based diet for 3 months relevant to human MeHg contamination. We observed that MeHg induced in the mice cortex a decrease in CCL2 concentrations, neuronal cell death, and microglial activation. Knock-out (KO) CCL2 mice fed with a vegetal control food already presented a decrease in cortical neuronal cell density in comparison with wild-type animals under similar diet conditions, suggesting that the presence of CCL2 is required for normal neuronal survival. Moreover, KO CCL2 mice showed a pronounced neuronal cell death in response to MeHg. Using in vitro experiments on pure rat cortical neurons in culture, we observed by blockade of the CCL2/CCR2 neurotransmission an increased neuronal cell death in response to MeHg neurotoxicity. Furthermore, we showed that sod genes are upregulated in brain of wild-type mice fed with MeHg in contrast to KO CCL2 mice and that CCL2 can blunt in vitro the decrease in glutathione levels induced by MeHg. These original findings demonstrate that CCL2 may act as a neuroprotective alarm system in brain deficits due to MeHg intoxicatio

CXCR3 Antagonism of SDF-1(5-67) Restores Trabecular Function and Prevents Retinal Neurodegeneration in a Rat Model of Ocular Hypertension

Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed. Here we show that the chemokine CXCL12, its truncated form SDF-1(5-67), and the receptors CXCR4 and CXCR3 are expressed in human glaucomatous trabecular tissue and a human trabecular cell line. SDF-1(5-67) is produced under the control of matrix metallo-proteinases, TNF-α, and TGF-β2, factors known to be involved in glaucoma. CXCL12 protects in vitro trabecular cells from apoptotic death via CXCR4 whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase activation. Ocular administration of SDF-1(5-67) in the rat increases intraocular pressure. In contrast, administration of a selective CXCR3 antagonist in a rat model of ocular hypertension decreases intraocular pressure, prevents retinal neurodegeneration, and preserves visual function. The protective effect of CXCR3 antagonism is related to restoration of the trabecular function. These data demonstrate that proteolytic cleavage of CXCL12 is involved in trabecular pathophysiology, and that local administration of a selective CXCR3 antagonist may be a beneficial therapeutic strategy for treating ocular hypertension and subsequent retinal degeneration

Feeding mice with diets containing mercury-contaminated fish flesh from French Guiana: a model for the mercurial intoxication of the Wayana Amerindians

International audienc

Paul Bert: le brillant élève de Claude Bernard

International audienc