Juniperonic Acid Biosynthesis is Essential in Caenorhabditis Elegans Lacking Δ6 Desaturase (fat-3) and Generates New ω-3 Endocannabinoids.

In eukaryotes, the C20:4 polyunsaturated fatty acid arachidonic acid (AA) plays important roles as a phospholipid component, signaling molecule and precursor of the endocannabinoid-prostanoid axis. Accordingly, the absence of AA causes detrimental effects. Here, compensatory mechanisms involved in AA deficiency in Caenorhabditis elegans were investigated. We show that the ω-3 C20:4 polyunsaturated fatty acid juniperonic acid (JuA) is generated in the C. elegansfat-3(wa22) mutant, which lacks Δ6 desaturase activity and cannot generate AA and ω-3 AA. JuA partially rescued the loss of function of AA in growth and development. Additionally, we observed that supplementation of AA and ω-3 AA modulates lifespan of fat-3(wa22) mutants. We described a feasible biosynthetic pathway that leads to the generation of JuA from α-linoleic acid (ALA) via elongases ELO-1/2 and Δ5 desaturase which is rate-limiting. Employing liquid chromatography mass spectrometry (LC-MS/MS), we identified endocannabinoid-like ethanolamine and glycerol derivatives of JuA and ω-3 AA. Like classical endocannabinoids, these lipids exhibited binding interactions with NPR-32, a G protein coupled receptor (GPCR) shown to act as endocannabinoid receptor in C. elegans. Our study suggests that the eicosatetraenoic acids AA, ω-3 AA and JuA share similar biological functions. This biosynthetic plasticity of eicosatetraenoic acids observed in C. elegans uncovers a possible biological role of JuA and associated ω-3 endocannabinoids in Δ6 desaturase deficiencies, highlighting the importance of ALA.

Practical considerations for the evaluation and management of Attention Deficit Hyperactivity Disorder (ADHD) in adults.

Attention deficit with or without hyperactivity disorder (ADHD) is one of the most frequent neuropsychiatric disorders, and affects 2-4% of adults. In contrast with many European countries, the identification and management of adult ADHD remains underdeveloped in France, and a subject of controversy. This review provides a practical update on current knowledge about ADHD in adults for French-speaking professionals who have to detect or manage adult patients with ADHD. ADHD is classified as a neurodevelopmental disorder in the recent update of the international diagnostic classification. While symptoms and impairment due to ADHD are frequently severe during childhood, they often evolve as children grow older, with frequent persistent disabilities in adulthood. In adulthood, the clinical presentation, as in childhood, involves the symptom triad of inattention, hyperactivity and impulsivity. However, differences are noted: hyperactivity is more often internalized, symptoms of inattention may be masked by anxiety symptoms or obsessive-like compensation strategies. ADHD is often diagnosed during childhood, but it is not rare for the diagnosis to be made later. Failure to recognise symptoms resulting in misdiagnosis, or alternatively well-developed compensation factors could be two underlying reasons for the long delay until diagnosis. Other symptoms, such as emotional deregulation or executive function-related symptoms are also usually observed in adults. In addition, in adults, ADHD is often associated with other psychiatric disorders (in 80% of cases); this makes the diagnosis even more difficult. These disorders encompass a broad spectrum, from mood disorders (unipolar or bipolar), to anxiety disorders, and other neurodevelopmental disorders and personality disorders, especially borderline and antisocial personality disorder. Substance-use disorders are very common, either as a consequence of impulsivity and emotional dysregulation or as an attempt at self-treatment. Sleep disorders, especially restless leg syndrome and hypersomnolence, could share common pathophysiological mechanisms with ADHD. ADHD and comorbidity-related symptoms are responsible for serious functional impairment, in various domains, leading to academic, social, vocational, and familial consequences. The impact on other psychiatric disorders as an aggravating factor should also be considered. The considerable disability and the poorer quality of life among adults with ADHD warrant optimal evaluation and management. The diagnostic procedure for ADHD among adults should be systematic. Once the positive diagnosis is made, the evaluation enables characterisation of the levels of severity and impairment at individual level. A full examination should also assess medical conditions associated with ADHD, to provide personalized care. In recent years, a growing number of assessment tools have been translated and validated in French providing a wide range of structured interviews and standardized self-report questionnaires for the evaluation of core and associated ADHD symptoms, comorbidities and functional impairment. The treatment of ADHD in adults is multimodal, and aims to relieve the symptoms, limit the burden of the disease, and manage comorbidities. The most relevant and validated psychological approaches are psycho-education, cognitive-behavioural therapy and "third wave therapies" with a specific focus on emotional regulation. Cognitive remediation and neurofeedback are promising strategies still under evaluation. Medications, especially psychostimulants, are effective for alleviating ADHD symptoms with a large effect size. Their safety and tolerance are satisfactory, although their long-term clinical benefit is still under discussion. In France, methylphenidate is the only stimulant available for the treatment of ADHD. Unfortunately, there is no authorization for its use among adults except in continuation after adolescence. Hence the prescription, which is subject to the regulations on narcotics, is off-label in France. This article aims to provide practical considerations for the management of ADHD and associated disorders in adults, in this particular French context.

Effects of gamma-hydroxybutyrate on neurophysiological correlates of performance and conflict monitoring.

Performance and conflict monitoring (PM and CM) represent two essential cognitive abilities, required to respond appropriately to demanding tasks. PM and CM can be investigated using event-related brain potentials (ERP) and associated neural oscillations. Namely, the error-related negativity (ERN) represents a correlate of PM, whereas the N2 component reflects the process of CM. Both ERPs originate in the anterior cingulate cortex (ACC) and PM specifically has been shown to be susceptible to gamma-aminobutyric acid (GABA) A receptor activation. Contrarily, the specific effects of GABAB receptor (GABABR) stimulation on PM and CM are unknown. Thus, the effects of gamma-hydroxybutyrate (GHB; 20 and 35 mg/kg), a predominant GABABR agonist, on behavioral and electrophysiological correlates of PM and CM were here assessed in 15 healthy male volunteers, using the Eriksen-Flanker paradigm in a randomized, double-blind, placebo-controlled, cross-over study. Electroencephalographic (EEG) data were analyzed in the time and time-frequency domains. GHB prolonged reaction times, without affecting error rates or post-error slowing. Moreover, GHB decreased ERN amplitudes and associated neural oscillations in the theta/alpha1 range. Similarly, neural oscillations associated with the N2 were reduced in the theta/alpha1 range, while N2 amplitude was conversely increased. Hence, GHB shows a dissociating effect on electrophysiological correlates of PM and CM. Reduced ERN likely derives from a GABABR-mediated increase in dopaminergic signaling, disrupting the generation of prediction errors, whereas an enhanced N2 suggests an increased susceptibility towards external stimuli. Conclusively, GHB is the first drug reported, thus far, to have opposite effects on PM and CM, underlined by its unique electrophysiological signature.

Neuronal oscillations and synchronicity associated with gamma-hydroxybutyrate during resting-state in healthy male volunteers.

RATIONALE: Gamma-hydroxybutyrate (GHB) is a putative neurotransmitter, a drug of abuse, an anesthetic agent, and a treatment for neuropsychiatric disorders. In previous electroencephalography (EEG) studies, GHB was shown to induce an electrophysiological pattern of "paradoxical EEG-behavioral dissociation" characterized by increased delta and theta oscillations usually associated with sleep during awake states. However, no detailed source localization of these alterations and no connectivity analyses have been performed yet. OBJECTIVES AND METHODS: We tested the effects of GHB (20 and 35 mg/kg, p.o.) on current source density (CSD), lagged phase synchronization (LPS), and global omega complexity (GOC) of neuronal oscillations in a randomized, double-blind, placebo-controlled, balanced cross-over study in 19 healthy, male participants using exact low-resolution electromagnetic tomography (eLORETA) of resting-state high-density EEG recordings. RESULTS: Compared to placebo, GHB increased CSD of theta oscillations (5-7 Hz) in the posterior cingulate cortex (PCC) and alpha1 (8-10 Hz) oscillations in the anterior cingulate cortex. Higher blood plasma values were associated with higher LPS values of delta (2-4 Hz) oscillations between the PCC and the right inferior parietal lobulus. Additionally, GHB decreased GOC of alpha1 oscillations. CONCLUSION: These findings indicate that alterations in neuronal oscillations in the PCC mediate the psychotropic effects of GHB. Theta oscillations emerging from the PCC in combination with stability of functional connectivity within the default mode network might explain the GHB-related "paradoxical EEG-behavioral dissociation." Our findings related to GOC suggest a reduced number of relatively independent neuronal processes, an effect that has also been demonstrated for other anesthetic agents.

Gamma-hydroxybutyrate enhances mood and prosocial behavior without affecting plasma oxytocin and testosterone.

Gamma-hydroxybutyrate (GHB) is a GHB-/GABAB-receptor agonist. Reports from GHB abusers indicate euphoric, prosocial, and empathogenic effects of the drug. We measured the effects of GHB on mood, prosocial behavior, social and non-social cognition and assessed potential underlying neuroendocrine mechanisms. GHB (20mg/kg) was tested in 16 healthy males, using a randomized, placebo-controlled, cross-over design. Subjective effects on mood were assessed by visual-analogue-scales and the GHB-Specific-Questionnaire. Prosocial behavior was examined by the Charity Donation Task, the Social Value Orientation test, and the Reciprocity Task. Reaction time, memory, empathy, and theory-of-mind were also tested. Blood plasma levels of GHB, oxytocin, testosterone, progesterone, dehydroepiandrosterone (DHEA), cortisol, aldosterone, and adrenocorticotropic-hormone (ACTH) were determined. GHB showed stimulating and sedating effects, and elicited euphoria, disinhibition, and enhanced vitality. In participants with low prosociality, the drug increased donations and prosocial money distributions. In contrast, social cognitive abilities such as emotion recognition, empathy, and theory-of-mind, and basal cognitive functions were not affected. GHB increased plasma progesterone, while oxytocin and testosterone, cortisol, aldosterone, DHEA, and ACTH levels remained unaffected. GHB has mood-enhancing and prosocial effects without affecting social hormones such as oxytocin and testosterone. These data suggest a potential involvement of GHB-/GABAB-receptors and progesterone in mood and prosocial behavior.

Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla.

The endocannabinoid system (ECS) comprises the cannabinoid receptors CB1 and CB2 and their endogenous arachidonic acid-derived agonists 2-arachidonoyl glycerol and anandamide, which play important neuromodulatory roles. Recently, a novel class of negative allosteric CB1 receptor peptide ligands, hemopressin-like peptides derived from alpha hemoglobin, has been described, with yet unknown origin and function in the CNS. Using monoclonal antibodies we now identified the localization of RVD-hemopressin (pepcan-12) and N-terminally extended peptide endocannabinoids (pepcans) in the CNS and determined their neuronal origin. Immunohistochemical analyses in rodents revealed distinctive and specific staining in major groups of noradrenergic neurons, including the locus coeruleus (LC), A1, A5 and A7 neurons, which appear to be major sites of production/release in the CNS. No staining was detected in dopaminergic neurons. Peptidergic axons were seen throughout the brain (notably hippocampus and cerebral cortex) and spinal cord, indicative of anterograde axonal transport of pepcans. Intriguingly, the chromaffin cells in the adrenal medulla were also strongly stained for pepcans. We found specific co-expression of pepcans with galanin, both in the LC and adrenal gland. Using LC-MS/MS, pepcan-12 was only detected in non-perfused brain (∼ 40 pmol/g), suggesting that in the CNS it is secreted and present in extracellular compartments. In adrenal glands, significantly more pepcan-12 (400-700 pmol/g) was measured in both non-perfused and perfused tissues. Thus, chromaffin cells may be a major production site of pepcan-12 found in blood. These data uncover important areas of peptide endocannabinoid occurrence with exclusive noradrenergic immunohistochemical staining, opening new doors to investigate their potential physiological function in the ECS. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'.

Antiparasitic compounds from Cupania cinerea with activities against Plasmodium falciparum and Trypanosoma brucei rhodesiense.

In a survey of plants from Ecuador with antiprotozoal activity, Cupania cinerea was found to show significant in vitro activity against the Plasmodium falciparum K1 strain and Trypanosoma brucei rhodesiense. Subsequently, activity-guided isolation of the n-hexane and dichloromethane extracts from the bark of C. cinerea afforded two diterpene glycosides (1 and 2), named cupacinoside and 6'-de-O-acetylcupacinoside, and a lactonized triterpene bearing an oxepin moiety named cupacinoxepin (3), together with the known compounds scopoletin (4), caryophyllene oxide (5), two bisabolane sesquiterpenes (6 and 7), lichexanthone (8), gustastatin (9), lupenone (10), betulone (11), 17ß,21ß-epoxyhopan-3-one (12), taraxerol (13), and taraxerone (14). For compound 3, X-ray crystallography was employed to elucidate the relative configuration. For cupacinosides (1) and (2) and cupacinoxepin (3), in vitro activities against the P. falciparum K1 strain (IC(50)1, 1.3; 2, 1.8; and 3, 8.7 µM) and T. b. rhodesiense (IC(50)1, 4.5; 2, 15.8; and 3, 71.6 µM) were found. Cytotoxicity toward L-6 cells is discussed for all the compounds isolated.

Jacaranone-derived glucosidic esters from Jacaranda glabra and their activity against Plasmodium falciparum.

In a survey of plants from Ecuador with antiprotozoal activity, Jacaranda glabra was found to show promising activity against the Plasmodium falciparum K1 strain. Subsequently, activity-guided isolation of the dichloromethane extract from the leaves of J. glabra afforded four new phenylethanoid glucosides containing jacaranone-type moieties (1-4), named jacaglabrosides A-D. Their chemical structures were identified using NMR spectroscopy and MS techniques. The compounds were found to be active in vitro against the P. falciparum K1 strain (IC(50) 1, 1.02; 2, 0.56; 3, 0.56; and 4, 0.55 microg/mL) and generally possessed a low cytotoxicity toward L-6 cells, with the exception of compound 1 (IC(50) 1, 8.3; 2, >90; 3, 87; and 4, 85 microg/mL).

Gene dosage effect for human triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase in partial trisomy 12p13 and trisomy 18p.

An 8-year-old girl with profound mental retardation and a neurologic syndrome associated with morphologic abnormalities was found to have a supernumerary small submetacentric chromosome. Several members of her family carried a balanced translocation t(12;18)(p12;q11), and the child's karyotype could be explained by 3:1 maternal segregation (tertiary trisomy). The proband was trisomic for 12p13 and 18p. A gene dosage effect was demonstrated for triosephosphate isomerase and glyceraldehyde-3-phosphate in erythrocytes and leukocytes allowing us to assign the corresponding loci to the tip of the chromosome 12 short arm.

[Partial deletion of the short arm of the chromosome 9]. / Délétion partielle du bras court du chromosome 9

Monosomy 9p is reported in a boy with trigonocephaly and advanced bone age.

X monosomy and 21 trisomy in a sibship.

The case of a sibship of 4, 2 members of which present aneuploïdy (45,X and 47,XX,21+) is reported. The paternal grandfather and grandmother are first cousins and there is a large number of centromeric associations in the father.