Effects of the Synthetic Neurosteroid

Abstract

Background:Most currently available active antidepressant drugs are selective serotonin/noradrenaline reuptake inhibitors. However, as their clinical efficacy is not immediate, long-term administration is often accompanied by substantial side effects, and numerous patients remain non- or partial responders. We have recently found that the synthetic neurosteroid derivative 3β-methoxypregnenolone, which binds to the microtubule-associated protein-2, can provide a novel therapeutic approach in experimental model of depressive disorders in rats. To further validate the antidepressant-like efficacy of 3β-methoxypregnenolone, we investigated effects of a longer treatment (4-week oral administration; 50mg/kg/d) in a nonrodent species, the tree shrew, exposed to psychosocial stress that elicits close-to-human alterations observed in patients with depressive disorders.Methods:During the experimental period, physiological parameters were registered, including core body temperature and electroencephalogram, while animals were videotaped to analyze their avoidance behavior. Morning urine samples were collected for measurements of cortisol and noradrenaline levels.Results:We found that treatment with 3β-methoxypregnenolone abolished stress-triggered avoidance behavior and prevented hormone hypersecretion, hypothermia, and sleep disturbances, further suggesting its antidepressant-like efficacy. Comparative treatment with fluoxetine also prevented some of the physiological alterations, while the hypersecretion of cortisol and sleep disturbances were not or partially restored by fluoxetine, suggesting a better efficacy of 3β-methoxypregnenolone. Alpha-tubulin isoforms were measured in hippocampi: we found that 3β-methoxypregnenolone reversed the specific decrease in acetylation of α-tubulin induced by psychosocial stress, while it did not modify the psychosocial stress-elicited reduction of tyrosinated α-tubulin.Conclusions:Taken together, these data strongly suggest a potent antidepressant-like effect of 3β-methoxypregnenolone on translational parameters.

Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders

“…Because not all systemically administered endogenously occurring neurosteroids readily cross the BBB and because these compounds can be metabolized to hormonally active steroids with different mechanisms of action, the therapeutic potential of these compounds is limited. For this reason, synthetic analogs of neurosteroids, which are more resistant to metabolism and better able to cross the BBB, are under investigation for use as anxiolytics, antidepressants, cognitive enhancers, anesthetics, and anticonvulsants (132, 388, 389). For example, synthetic neuroactive steroids bearing a hemisuccinate group are more resistant to hydrolysis than the corresponding sulfate esters and are partly unionized at physiological pH, allowing increased passage across the BBB.…”

Microtubules: A Key to Understand and Correct Neuronal Defects in CDKL5 Deficiency Disorder?

“…The development and testing of synthetic derivatives with improved stability and that cannot be metabolised into the downstream steroids might represent a possibility for CDD. Of note, MAPREG is a synthetic PREG derivative that has anti-depressant activities in rat models of depression [112] and in the primate-like tree-shrew [113]. Like PREG, MAPREG/MAP4343 promotes MT dynamics apparently through its binding to MAP2.…”

Potentialités thérapeutiques des neurostéroïdes en psychiatrie

“…De façon très intéressante, ce composé a montré une efficacité rapide pour prévenir le comportement de type dépressif et les perturbations cognitives observés chez le rat ayant subi un isolement social (Bianchi & Baulieu, 2012). Administré chez le toupaye soumis à un stress social, MAP4343 s'est également révélé efficace pour réduire le comportement d'évitement de l'animal et normaliser ses anomalies biologiques liées au stress, notamment celles affectant les concentrations urinaires de noradrénaline et de cortisol, le niveau de sommeil paradoxal ou encore la température corporelle (Paresys et al, 2016). À la suite de ces données précliniques ainsi que d'autres non encore publiées, MAP4343 fait actuellement l'objet d'un développement clinique pour le traitement de la dépression.…”