ETUDE DU STRESS OXYDATIF ET DE L'ACTIVATION DU CYCLE CELLULAIRE DANS LA SUBSTANCE NOIRE AU COURS DE L'APOPTOSE DEVELOPPEMENTALE DES NEURONES DOPAMINERGIQUES CHEZ LE RAT (DOCTORAT (NEUROSCIENCES))

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Emerging RNA editing biomarkers will foster drug development

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In situ examination of tyrosine hydroxylase activity in the rat locus coeruleus using (3',5')-[(3)H(2)]-alpha-fluoromethyl-tyrosine as substrate of the enzyme.

Tyrosine hydroxylase (TH) activity can be modified by changes in the specific activity of the enzyme (SA(TH)) or in the levels of active enzyme. We developed a methodology making it possible to measure with excellent anatomical resolution TH enzymatic activity and TH protein quantity by quantitative autoradiography and immunoautoradiography, respectively, from adjacent sections taken at serial intervals along the longitudinal extent of a same brain. SA(TH) was estimated by the slope of linear regressions established between TH activity and TH quantity measured at each anatomical plane. To evaluate TH activity, we used (3',5')-[(3)H(2)]-(D, L)-alpha-fluoromethyl-tyrosine [(3)H(2)]-MFMT, which is transformed by TH to [(3)H]-MFM-dopa, a potent and irreversible substrate for aromatic amino acid decarboxylase. We found that the SA(TH) in the cell body area of the LC (PKA) was 48% lower than that evaluated in the surrounding pericoerulean neuropil (PCN). In the PCN, 22% only of TH level exhibited a level of enzymatic activity above threshold. We also examined how SA(TH) was distributed in the LC 15 min and 3 days after RU 24722 treatment, a potent phasic and tonic activator of TH enzyme in noradrenergic neurons. Two distinct mechanisms have been observed: the short-term effect was due to an increase in the SA(TH) in the PKA only, while the long-term effect was mainly caused by an increase in the number of active TH proteins in the PCN. These results suggest that the fine regulation of TH activity which occurs in the different compartments of LC neurons may be critical in the functions involving the LC.FLWINinfo:eu-repo/semantics/publishe

Aggressive behavior during social interaction in mice is controlled by the modulation of tyrosine hydroxylase expression in the prefrontal cortex.

International audienceThe Balb/c strain and the C57BL/6 strain show constitutive differences for tyrosine hydroxylase expression, and noradrenaline (NA) prefrontal transmission. Male mice of these strains also show striking differences in social interaction behaviors, with an increased aggressiveness for the Balb/c strain. To test a potential link between these neurobiological and behavioral parameters, we evaluated the behavioral effects of chronic treatment of mice with BC19, a noreburnamine compound previously known as RU24722, found to modify cell organisation, tyrosine hydoxylase (TH) expression, and its activity into the locus coeruleus (LC). We compared the pharmacological effects between the two strains in social behaviors. Our results show that the emergence of additional TH-expressing (TH+) neurons in the rostral part of the LC of Balb/c mice was associated with an increase in the density of TH+ and noradrenergic (NA+) fibers in the molecular layer in the cingular (Cg1) and prelimbic (PrL) parts of the prefrontal cortex (PFC). BC19 treatment resulted in the near-equalization of the LC number of TH+ neurons and of the density of TH+ and NA+ fibers between both strains. The aggressiveness in Balb/c mice was considerably diminished by BC19 treatment, while the originally non aggressive behavior of C57Bl/6 mice was much less affected by BC19 treatment, despite a moderate increase in some offensive behaviors. In additional control experiments, we checked the effect of BC19 on a separate test for anxiety and assessed the effect of noradrenergic N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) mediated lesions in C57BL/6 mice on social behaviors. In the present study we show that the BC19 effect in Balb/c mice was independent of anxiety as measured in the light/dark test and that DSP-4 lesions in C57BL/6 mice produced a robust increase in aggressive social interaction. Altogether, these results show that the noradrenergic system, and particularly its projections to the PFC, strongly modulates aggressive behaviors

Correction: Brain region-specific alterations of RNA editing in PDE8A mRNA in suicide decedents

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A Pilot Clinical Study on Post-Operative Recurrence Provides Biological Clues for a Role of Candida Yeasts and Fluconazole in Crohn’s Disease

Background and aims: This study prompted by growing evidence of the relationship between the yeast Candida albicans and Crohn’s disease (CD) was intended to assess the effect of a 6-month course of the antifungal fluconazole (FCZ) on post-operative recurrence of CD. Methods: Mycological samples (mouth swabs and stools) and serum samples were collected from 28 CD patients randomized to receive either FCZ (n = 14) or placebo (n = 14) before surgical resection. Serological analysis focused on levels of calprotectin, anti-glycan antibodies, and antibody markers of C. albicans pathogenic transition. Levels of galectin-3 and mannose binding lectin (MBL) involved in C. albicans sensing and inflammation were also measured. Results: 1, 2, 3, and 6 months after surgery, endoscopy revealed recurrence in 5/12 (41.7%) patients in the FCZ group and 5/9 (55.6%) in the placebo group, the small cohort preventing any clinical conclusions. In both groups, surgery was followed by a marked decrease in C. albicans colonization and biomarkers of C. albicans pathogenic transition decreased to non-significant levels. Anti-glycan antibodies also decreased but remained significant for CD. Galectin-3 and calprotectin also decreased. Conversely, MBL levels, which inversely correlated with anti-C. albicans antibodies before surgery, remained stable. Building biostatistical multivariate models to analyze he changes in antibody and lectin levels revealed a significant relationship between C. albicans and CD. Conclusion: Several combinations of biomarkers of adaptive and innate immunity targeting C. albicans were predictive of CD recurrence after surgery, with area under the curves (AUCs) as high as 0.86. FCZ had a positive effect on biomarkers evolution. ClinicalTrials.gov ID: NCT02997059, 19 December 2016. University Hospital Lille, Ministry of Health, France. Effect of Fluconazole on the Levels of Anti-Saccharomyces cerevisiae Antibodies (ASCA) After Surgical Resection for Crohn’s Disease. Multicenter, Randomized, and Controlled in Two Parallel Groups Versus Placebo

Biochemical and autoradiographic measurements of brain serotonin synthesis rate in the freely moving rat: a reexamination of the alpha-methyl-L-tryptophan method.

Biochemical approaches were used in freely moving rats to determine, under steady-state conditions, the brain/arterial plasma partition coefficients of L-tryptophan and alpha-[3H]methyl-L-tryptophan, from which the lumped constant for the alpha-methyl-L-tryptophan method of estimating the rate of brain serotonin synthesis is calculated. The lumped constants were significantly different in the various structures examined: 0.149 +/- 0.003 in the raphe dorsalis, 0.103 +/- 0.002 in the raphe centralis, 0.087 +/- 0.003 in the reticular formation, and 0.62 +/- 0.08 in the pineal gland. From these data we proposed a two-compartment model to calculate the rate of serotonin synthesis by quantitative autoradiography using a three-time point experiment. Rates of synthesis for the raphe dorsalis and the reticular formation (620 +/- 57 and 80 +/- 35 pmol/g of tissue/min, respectively) were similar to those measured simultaneously by biochemical means, but rates were 50% higher for the raphe centralis (568 +/- 90 vs. 381 +/- 31 pmol/g of tissue/min). The lack of dynamic equilibrium of the tracer between plasma and tissue pools may explain the discrepancy between the two methods. Our findings did not confirm previous data, indicating that the application of the autoradiographic method to measure the rate of brain serotonin synthesis using alpha-methyl-L-tryptophan as tracer has limitations