Cell-penetrating, antioxidant SELENOT mimetic protects dopaminergic neurons and ameliorates motor dysfunction in Parkinson's disease animal models.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction for which there is an unmet need for better treatment options. Although oxidative stress is a common feature of neurodegenerative diseases, notably PD, there is currently no efficient therapeutic strategy able to tackle this multi-target pathophysiological process. Based on our previous observations of the potent antioxidant and neuroprotective activity of SELENOT, a vital thioredoxin-like selenoprotein, we designed the small peptide PSELT from its redox active site to evaluate its antioxidant properties in vivo, and its potential polyfunctional activity in PD models. PSELT protects neurotoxin-treated dopaminergic neurons against oxidative stress and cell death, and their fibers against neurotoxic degeneration. PSELT is cell-permeable and acts in multiple subcellular compartments of dopaminergic neurons that are vulnerable to oxidative stress. In rodent models of PD, this protective activity prevented neurodegeneration, restored phosphorylated tyrosine hydroxylase levels, and led to improved motor skills. Transcriptomic analysis revealed that gene regulation by PSELT after MPP+ treatment negatively correlates with that occurring in PD, and positively correlates with that occurring after resveratrol treatment. Mechanistically, a major impact of PSELT is via nuclear stimulation of the transcription factor EZH2, leading to neuroprotection. Overall, these findings demonstrate the potential of PSELT as a therapeutic candidate for treatment of PD, targeting oxidative stress at multiple intracellular levels.

Characterizing the metabolic perturbations induced by activity-based anorexia in the C57Bl/6 mouse using 1H NMR spectroscopy.

BACKGROUND & AIMS: Anorexia nervosa (AN) is a severe psychological and potentially life-threatening eating disorder. The activity-based anorexia (ABA) mouse model is commonly used to investigate physiological abnormalities associated with this disorder. Characterizing the holistic biochemical alterations induced by anorexia is essential to understanding AN pathophysiology as well as to define biomarkers for prognosis. METHODS: To unravel the adaptive biochemical mechanisms occurring in this model in response to self-starvation, the urinary, plasma and fecal metabolic phenotypes of mice under different experimental conditions were compared. This included control mice with and without physical activity (CT and CTPA mice), a group with limited food access (LFA), and a group with both limited food access and physical activity (ABA). Using 1H nuclear magnetic resonance (NMR) spectroscopy, several biochemical perturbations were observed. RESULTS: Physical activity altered the abundance of 14 fecal metabolites, including those involved in gut microbial metabolism and proteolysis. Food restriction disrupted a wide range of metabolic pathways including gut microbial metabolism, proteolysis and fatty acid breakdown (24 urinary and 6 plasma metabolites). The combined impact of food restriction and physical activity resulted in the same pattern of metabolic disruption (24 urine, 6 plasma). CONCLUSIONS: This work defined the metabolic signatures of ABA mice and provides novel insights into biological adaptations of mice in response to both food restriction and physical activity. These results should be further confirmed in AN patients.

Aberrant adrenal sensitivity to vasopressin in adrenal tumours associated with subclinical or overt autonomous hypercortisolism: is this explained by an overexpression of vasopressin receptors?

OBJECTIVE: Abnormal responsiveness to arginine vasopressin (AVP) was previously observed in cortisol-producing adrenocortical tumours but the mechanism remains unclear. The aim of this study was to characterize the effect of AVP on cortisol secretion from adrenocortical tumours compared to normal human adrenal gland. DESIGN: A multicentre study based on pharmacological, molecular and immunohistochemical experiments performed in adenomatous and normal adrenal tissues. PATIENTS: Twenty patients with adrenocortical adenomas and subclinical Cushing's syndrome (SCCS) or Cushing's syndrome (CS) were compared to six control normal subjects. MEASUREMENTS: In vivo and in vitro cortisol response to vasopressin, vasopressin receptor subtype mRNA measurement by real-time polymerase chain reaction (RT-PCR), immunohistochemical localization of AVP and its V1a receptor in tumour and normal adrenal tissues. RESULTS: Terlipressin in vivo enhanced cortisol plasma levels in 17/20 SCCS and 3/6 CS but in none of the control subjects. In vitro cortisol response to AVP was observed in nine tumours studied, with enhanced efficacy and/or potency of AVP in three SCCS tumours compared to normal tissues. AVP receptor subtype mRNA levels were similar in SCCS, CS cells and normal adrenal cells. Some SCCS tumour steroidogenic cells showed AVP and V1a receptor immunoreactivity. CONCLUSIONS: SCCS and CS adrenocortical tumours often exhibit in vivo and in vitro hyper-responsiveness to AVP, which is not related to vasopressin receptor overexpression, but may be explained by more efficient coupling pathways or by the indirect action of AVP through an autocrine/paracrine mechanism.

Structure-activity relationships of a series of analogs of the endozepine octadecaneuropeptide (ODN(11)(-)(18)) on neurosteroid biosynthesis by hypothalamic explants.

We have previously shown that the endozepine octadecaneuropeptide (ODN) stimulates the biosynthesis of neurosteroids from frog hypothalamic explants. In the present study, we have investigated the structure-activity relationships of a series of analogs of the C-terminal octapeptide of ODN (OP) on neurosteroid formation. We found that OP and its cyclic analog cyclo1-8OP stimulate in a concentration-dependent manner the synthesis of various steroids including 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone and dehydroepiandrosterone. Deletion or Ala-substitution of the Arg1 or Pro2 residues of OP did not affect the activity of the peptide. In contrast, deletion or replacement of any of the amino acids of the C-terminal hexapeptide fragment totally abolished the effect of OP on neurosteroid biosynthesis. The present study indicates that the C-terminal hexapeptide of ODN/OP is the minimal sequence retaining full biological activity on steroid-producing neurons.