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OBJECTIVE: To study the effect of Mr1.8×104 translocator protein (TSPO) selective ligand compound YL-IPA08 on postpartum anxiety-depressive behavior. METHODS: The model of postpartum depression in rats was established by classical hormone simulating postpregnancy (HSP) hormone withdrawal induced, and the effect of YL-IPA08 on spontaneous activity in rats was evaluated by the open field test(OFT), and the effect of YL-IPA08 on anxiety and depressive-like behavior in rats was evaluated by the elevated plus maze test (EPM) and forced swimming test (FST). The changes of TSPO expression in hippocampuls and prefrontal cortex of rats were detected by RT-PCR and Western blot. RESULTS: Compared with control group, the hormones of pregnancy hormones withdraw stimulating and drug treatment do not affect the spontaneous activity of rats (P>0.05), but the model group rats showed significant anxiety and depressive symptoms, which is characterized by elevated plus maze test (P<0.05, P<0.01),and forced swimming test (P<0.05).After the establishment of the model, three weeks of intragastric administration were started, YL-IPA08 (0.1 and 0.3 mg•kg-1, po) or positive control drug sertraline (10 mg•kg-1, po) can significantly reverse the above series of changes of postpartum anxiety and depressive behavior (P<0.05 or 0.01), and significantly increase the TSPO level in the hippocampus and prefrontal cortex of the model rats. CONCLUSION: YL-IPA08 shows anti-postpartum anxiety-depressive behavior in a series of rat behavior models, and the mechanism may be closely related to its enhancing central TSPO expression and promoting biosynthesis of following neurosteroids.
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Neurosteroids are the key molecules in the central nervous system that modulate neural functions. They can influence human mood and behavior in various physiological and pathophysiological situations. Neurosteroids have been implicated in the pathogenesis of depressive episodes, providing innovative therapies for psychiatric disorders such as depressive disorder and bipolar disorder. This paper reviewed the research progress on the role of neurosteroids in the treatment of depressive episodes.
ABSTRACT
Neurosteroids are the key molecules in the central nervous system that modulate neural functions. They can influence human mood and behavior in various physiological and pathophysiological situations. Neurosteroids have been implicated in the pathogenesis of depressive episodes, providing innovative therapies for psychiatric disorders such as depressive disorder and bipolar disorder. This paper reviewed the research progress on the role of neurosteroids in the treatment of depressive episodes.
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Anxiety is one of the psychiatric disorders. However, the pathogenesis of anxiety is still uncertain. Translocator protein (18×103, 18ku) (TSPO) ligands have been proved useful in the treatment of neurological and psychiatric disorders, especially anxiety. TSPO Ligands are promising candidates for fast-acting anxiolytic drugs with less severe side effects than benzodiazepines. This review summaries TSPO molecular structure, distribution, and its function of treating anxiety and illustrates the advantage of TSPO ligands in treating anxiety and its application prospect.
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OBJECTIVE: Changes in serum neurosteroid levels have been reported in stress-related disorders such as anxiety and depression, but not in patients with obsessive-compulsive disorder (OCD). We thus investigated such changes in patients with OCD. METHODS: We compared the serum levels of progesterone, pregnanolone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEA-S), cortisol and testosterone in 30 patients with OCD and 30 healthy controls. RESULTS: When male and female patients were evaluated together, DHEA and cortisol levels were significantly higher in patients with OCD than the control group. When the genders were evaluated separately, DHEA and cortisol levels were higher in female patients than the female controls. The increase in DHEA levels in female patients is likely an effect of the hypothalamic-pituitary-adrenal (HPA) axis. In contrast, cortisol levels in male patients were higher than the control group, while testosterone levels were lower. The increased cortisol and decreased testosterone levels in male patients likely involves the hypothalamic-pituitary-gonadal (HPG) axis. CONCLUSION: These findings suggest that neurosteroid levels in patients with OCD should be investigated together with the HPA and HPG axes in future studies.
Subject(s)
Female , Humans , Male , Anxiety , Axis, Cervical Vertebra , Dehydroepiandrosterone , Depression , Hydrocortisone , Obsessive-Compulsive Disorder , Pregnanolone , Progesterone , TestosteroneABSTRACT
Neurons and glia in the central nervous system can express the key enzymes for the synthesis of neurosteroids .Once the concentration of neurosteroids is high enough , they will exert paracrine effects .Synthesis of neurosteroids declines with age in brain .So does it under stressful circumstances .Recent research reports indicate that the decrease of neurosteroids is associated with the neuronal dysfunction and degeneration in the brain .This paper reviews recent research on the most studied neurosteroids ( for example , dehydroepiandrosterone , pregnenolone and their sulphate esters, progesterone and allopregnanolone ) in affecting neuronal survival , neurite outgrowth and neurogenesis , and the potential roles of these neurosteroids in the treatment of neurodegenerative disease as well .
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The female brain operates in a constantly changing chemical milieu caused by cyclical changes in gonadal hormones during the estrous cycle (menstrual cycle in women). Such hormones are highly lipophilic and pass readily from the plasma to the brain where they can influence neuronal function. It is becoming clear that the rapid reduction in peripheral circulating progesterone, which occurs during the late diestrous phase of the cycle, can trigger a withdrawal-like response, in which changes in GABA A receptor expression render hyper-responsive certain brain areas involved in processing responses to stressful stimuli. The periaqueductal gray matter (PAG) is recognised as an important region for integrating anxiety/defence responses. Withdrawal from progesterone, via actions of its neuroactive metabolite allopregnanolone, triggers up-regulation of extrasynaptic GABA A receptors on GABAergic neurons in the PAG. As a consequence, ongoing GABAergic tone on the output cells decreases, leading to an increase in functional excitability of the circuitry and enhanced responsiveness to stressful stimuli during the late diestrous phase. These changes during late diestrus could be prevented by short-term neurosteroid administration, timed to produce a more gradual fall in the peripheral concentration of allopregnanolone than the rapid decrease that occurs naturally, thus removing the trigger for the central withdrawal response.
Subject(s)
Animals , Female , Rats , Anxiety/metabolism , Brain/metabolism , Estrous Cycle/metabolism , Progesterone/physiology , Receptors, GABA-A/metabolism , Anxiety/physiopathology , Estrous Cycle/physiologyABSTRACT
Aim To investigate the effect of dehydroepiandrosterone(DHEA)on the levels of NR2B and GBR1 expressed in primary cultured rat cerebral cortical neurons.Methods Primary cultured rat cerebral cortical neurons were treated with DHEA of different concentrations (1,10,100 μmol·L~(-1))and the expression of amino acids receptor subunit NR2B and GBR1 were detected by immunocytochemistry.Results Compared with control group,the expression intensity of NR2B increased by 15.6%,19.9% and 49.4% after DHEA-L,DHEA-M and DHEA-H treatment(P<0.05 or P<0.01);the expression intensity of GBR1 increased by 14.5% and 58.5% after DHEA-M and DHEA-H treatment(P<0.05 or P<0.01).Conclusion DHEA can enhance the expression of neuron receptor subunit NR2B and GBR1.
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Aim To investigate effects of glutamate(GLU) and ?-aminobutyric acid(GABA) on levels of neurosteroids synthesized and released by primary cultured rat brain cortical astrocytes.Methods Primary cultured rat brain cortical astrocytes were treated with GLU or GABA for 48 h respectively.Unconjugated(dehydroepiandrosterone,DHEA;pregnenolone,PREG;allopregnanolone,AP) and conjugated neurosteroids(dehydroepiandrosterone sulfate,DHEAS;pregnenolone sulfate,PREGS) in culture media were extracted by solid phase extraction(SPE) and analyzed by HPLC-MS.Results Compared with saline control group,GLU treatment decreased PREG and PREGS levels and increased DHEAS level significantly;GABA treatment decreased PREG level and increased AP level significantly.Conclusion Both GLU and GABA were shown to inhibit the genesis of PREG.While GLU significantly promoted the genesis of DHEAS and GABA promoted the genesis of AP.The genesis of PREGS was also inhibited by GLU treatment in primary cultured cortical astrocytes.
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Aim To investigate the effect and mechanism of action of chronic morphine treatment on the neurosteroidogensis of primary cultured rat cerebral cortical neurons(CCNs).Methods The effect of morphine on the production of pregnenolone(PREG),dehydroepiandrosterone(DHEA),allopregnanolone(AP),pregnenlolone sulfate(PS)and dehydroepiandrosterone sulfate(DS)in cell culture media was measured by solid-phase extraction and LC-MS,with methyltestosterone(MT)or estrogen sulfate(ES)as internal standards.The dependence-like changes of CCNs were determined by testing the p-CREB level in the nuclear lysates using western blot.Results Compared with the control group,morphine treatment significantly reduced levels of PREG and DS respectively;opioid agonist DAMGO significantly reduced levels of PREG,DS and PS respectively,and increased the level of AP significantly.Compared with the morphine group,?-opioid-antagonist CTAP concomitant with morphine increased the level of PREG significantly.Compared with the control group,chronic morphine treatment or DAMGO treatment significantly increased the level of p-CREB in the CCNs.Compared with the morphine treatment group,?-antagonsit CTAP significantly reduced the level of p-CREB.Conclusion ?-opioid receptor mediated the inhibitory effect of morphine on levels of neurosteroids,and changes of neurosteroid levels might be related to morphine dependence.