Allopregnanolone与GABA在大鼠大脑的皮层细胞中对kainate诱导乳酸脱氢酶释放的不同作用

目的:观察allopregnanolone与γ氨基丁酸(GABA)对兴奋性毒性的作用.方法:对原代培养大鼠大脑的皮层细胞,采用kainate(KA)处理,诱发兴奋性毒性.通过测定释放至细胞培养基中的乳酸盐脱氢酶(LDH)活性。观察allopregna-nolone与GABA对兴奋性毒性的作用.结果:短期 或长期KA处理,均增加 LDH活性的释放,其作用呈剂量依赖性,EC_(50)值分别为(0.16±0.03)mol/L和(0.257±0.15)mmol/L.短期(3 h)allopreg-nanolone (10-1000 nmol/L)处理对0.2 mmol/L KA诱导的 LDH活性的释放无明显影响.而长期(24 h)allopregnanolone(10-1000 nmol/L)处理抑制KA诱导的LDH活性的释放,其作用呈剂量依赖性,EC_(50)值为(436±19)nmol/L.短期GABA(0.1-100μmo 1/L)处理,加剧KA(0.2 mmol/L)诱导的 LDH活性的释放,其作用呈剂量依赖性,EC_(50)值为(2.7±1.0)μmol/L.长期GABA处理,对KA诱导的LDH活性的释放无明显影响.结论;allopregnanolone和 GABA对KA诱导的兴奋性毒性有不同作用.     

Effects of the new generation selective estrogen receptor modulator EM-652 and oral administration of estradiol valerate on circulating,brain, and adrenal beta-endorphin and allopregnanolone levels in intact fertile and ovariectomized rats

OBJECTIVE: To investigate the effects of oral estradiol valerate (EV); EM-652, a new-generation selective estrogen receptor modulator; and both agents on central and peripheral beta-endorphin (beta-EP) and allopregnanolone levels in fertile and ovariectomized rats. DESIGN: Prospective study. SETTING: Animal laboratory in an academic research environment. ANIMALS: Thirteen groups of eight Wistar female rats received oral EV (0.01 or 0.05 mg/kg of body weight daily), EM-652 (0.1, 1, or 5 mg/kg daily), or EV (0.05 mg/kg daily) and EM-652 (0.1, 1, or 5 mg/kg/daily) for 14 days. INTERVENTION(S): beta-Endorphin levels content in the hypothalamus, hippocampus, anterior and neurointermediate pituitary, and plasma were measured. Allopregnanolone levels in the hypothalamus, hippocampus, anterior pituitary, adrenal glands, and serum were measured. MAIN OUTCOME MEASURE(S): beta-Endorphin and allopregnanolone levels. RESULT(S): In ovariectomized rats, administration of EV or EM-652 reverses changes in beta-EP and allopregnanolone levels induced by ovariectomy. Administration of EM-652 plus EV prevents the increase in beta-EP and allopregnanolone levels induced by EV in the hippocampus, hypothalamus, and pituitary but not in the adrenal glands and serum. CONCLUSIONS: In ovariectomized rats, EM-652 has an estrogen-like action that becomes antiestrogenic in the presence of EV administration. In fertile animals, EM-652 exerts estrogen-like or slight antiestrogenic effects.     

GABA receptors,progesterone and premenstrual dysphoric disorder

Premenstrual dysphoric disorder (PMDD) is characterized by depression, anxiety and other affective symptoms which recur in the luteal phase of the menstrual cycle. Evidence from animal models of depression and anxiety indicate the importance of neuroactive steroid hormones and the GABA(A) receptor in the etiology and potential treatment of mood disorders. These data are reviewed in the light of human clinical studies and specific animal models of PMDD.     

Long-term low-dose dehydroepiandrosterone oral supplementation in early and late postmenopausal women modulates endocrine parameters and synthesis of neuroactive steroids

OBJECTIVE: To evaluate the effects of a low-dose DHEA supplementation on hormonal parameters in early and late postmenopausal women. DESIGN: Prospective case study. SETTING: Postmenopausal women in a clinical research environment. PATIENT(S): Twenty postmenopausal women were divided in two groups according to age (50-55 and 60-65 years). INTERVENTION(S): All patients underwent hormonal evaluation before and at 3, 6, 9, and 12 months of therapy (25 mg/d of DHEA orally). Pelvic ultrasound examination and Kupperman score were performed before and after 3, 6, and 12 months of therapy. MAIN OUTCOME MEASURE(S): Plasma DHEA, DHEAS, estrone (E1), E2, P, androstenedione (A), T, dihydrotestosterone, 17alpha-hydroxyprogesterone (17-OHP), cortisol (F), allopregnanolone, beta-endorphin, sexual hormone-binding globulin (SHBG), LH, FSH, growth hormone (GH), and insulin-like growth factor-1 (IGF-1) concentrations. RESULT(S): The levels of all the steroids that derive from DHEA metabolism increased in plasma with DHEA administration. Also neurosteroids (namely allopregnanolone) and endorphin showed increased plasma levels, whereas both gonadotropins were significantly reduced. Endometrial thickness did not change throughout the study period. CONCLUSION(S): Administration of low doses (25 mg) of DHEA positively modulates several endocrine parameters in early and late postmenopausal women, inducing the increase of the androgenic, estrogenic, and progestogenic milieu and reducing the climateric symptoms, similarly to estroprogestin replacement therapy. These data suggest that DHEA supplementation is a more effective replacement therapy than a simple "dietary supplement."     

四氢孕酮对小鼠不同惊厥模型的保护作用

目的观察四氢孕酮对不同动物惊厥模型的保护作用。方法C57小鼠腹腔注射四氢孕酮15min后观察其对最大电休克实验(maximalelectricalseizure,MES)或印防己所致惊厥的保护作用。结果在MES试验 ,四氢孕酮或苯巴比妥产生剂量依赖性的保护作用。苯巴比妥的ED50 为2.40mg·kg-1,95 %可信限为1.22至4.72mg·kg-1。四氢孕酮的ED50为0.086mg·kg-1,95 %可信限为0.037至0.201mg·kg-1,显著较苯巴比妥强 (P<0.01)。四氢孕酮对印防己所致惊厥保护作用的ED50为0.12mg·kg-1。两药各1/2ED50量的联合用药在MES试验产生80 %的保护作用 ,高于50 %。提示四氢孕酮和苯巴比妥具协同抗惊厥作用。在印防己致惊厥试验 ,四氢孕酮亦产生剂量依赖性保护作用 ,ED50 为0.123mg·kg-1,95 %可信限为0.085至0.263mg·kg-1。结论腹腔注射四氢孕酮对MES或印防己所致惊厥具有剂量依赖性的保护作用 ;对MES ,四氢孕酮的保护作用显著大于苯巴比妥 ,并与后者有协同作用。     

Augmentation of endogenous neurosteroid synthesis alters experimental status epilepticus dynamics

Neurosteroids can modulate γ-aminobutyric acid type A receptor-mediated inhibitory currents. Recently, we discovered that the neurosteroids progesterone, 5α-dihydroprogesterone, allopregnanolone, and pregnanolone are reduced in the cerebrospinal fluid of patients with status epilepticus (SE). However, it is undetermined whether neurosteroids influence SE. For this reason, first we evaluated whether the inhibitor of adrenocortical steroid production trilostane (50 mg/kg) could modify the levels of neurosteroids in the hippocampus and neocortex, and we found a remarkable increase in pregnenolone, progesterone, 5α-dihydroprogesterone, and allopregnanolone levels using liquid chromatography tandem mass spectrometry. Second, we characterized the dynamics of SE in the presence of the varied neurosteroidal milieu by a single intraperitoneal kainic acid (KA; 15 mg/kg) injection in trilostane-treated rats and their controls. Convulsions started in advance in the trilostane group, already appearing 90 minutes after the KA injection. In contrast to controls, convulsions prevalently developed as generalized seizures with loss of posture in the trilostane group. However, this effect was transient, and convulsions waned 2 hours before the control group. Moreover, electrocorticographic traces of convulsions were shorter in trilostane-treated rats, especially at the 180-minute (P < .001) and 210-minute (P < .01) time points. These findings indicate that endogenous neurosteroids remarkably modulate SE dynamics.     

Depression gets old fast: do stress and depression accelerate cell aging?

Depression has been likened to a state of “accelerated aging,” and depressed individuals have a higher incidence of various diseases of aging, such as cardiovascular and cerebrovascular diseases, metabolic syndrome, and dementia. Chronic exposure to certain interlinked biochemical pathways that mediate stress‐related depression may contribute to “accelerated aging,” cell damage, and certain comorbid medical illnesses. Biochemical mediators explored in this theoretical review include the hypothalamic–pituitary–adrenal axis (e.g., hyper‐ or hypoactivation of glucocorticoid receptors), neurosteroids, such as dehydroepiandrosterone and allopregnanolone, brain‐derived neurotrophic factor, excitotoxicity, oxidative and inflammatory stress, and disturbances of the telomere/telomerase maintenance system. A better appreciation of the role of these mediators in depressive illness could lead to refined models of depression, to a re‐conceptualization of depression as a whole body disease rather than just a “mental illness,” and to the rational development of new classes of medications to treat depression and its related medical comorbidities. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

四氢孕酮与苯巴比妥对保护小鼠最大电休克惊厥的协同作用(英文)

目的:观察四氢孕酮与苯巴比妥的抗惊厥相互作用。方法:采用小鼠最大电休克惊厥(MES)试验,测定四氢孕酮和/或苯巴比妥的保护作用;并采用小鼠大脑皮质膜制备,用氚标氟硝安定检测四氢孕酮和/或苯巴比妥对GABA_A受体复合物的调节。结果:苯巴比妥(0.5-50mg·kg~(-1))对小鼠最大电休克惊厥具剂量依赖性的保护作用,其ED_(50)为2.61mg·kg~(-1),95％可信限为1.59-4.26mg·kg~(-1)。同样,四氢孕酮(0.01-1.0mg·kg~(-1))也有剂量依赖性的保护作用,其ED_(50)为0.11(0.06-0.18)mg·kg~(-1)。四氢孕酮和苯巴比妥联合用药(1:20)的ED_(50)为0.73(0.44-1.21)mg·kg~(-1),Q值小于1。测定四氢孕酮和/或苯巴比妥增加氚标氟硝安定的结合,其浓度效应曲线与功能性协同作用的理论曲线相符。结论:四氢孕酮和苯巴比妥对抗小鼠最大电休克惊厥有协同作用;两者对增加氚标氟硝安定与GABA_A受体复合物的结合也有功能性协同作用。     

Mating Stimuli Influence Endogenous Variations in the Neurosteroids 3α,5α-THP and 3α-Diol

Progesterone facilitates and 5alpha-dihydrotestosterone (DHT) inhibits female sexual behaviour in rodents; their metabolites, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) and 5alpha-androstane-3alpha-17beta-Diol (3alpha-Diol), may influence the onset and termination of lordosis. Changes in these and related steroids in hormonal states associated with differences in receptivity were investigated. Rats were assigned to oestrus, metoestrus, dioestrus, pro-oestrus, mated, gestational days 5-7, 12-14, 18-20, or post-partum conditions; rats 9+ months of age were considered older. Pro-oestrus rats were exposed to the mating arena, sight and smell of a male with no tactile contact, artificial vaginocervical stimulation, standard mating, or no mating. Progesterone, 5alpha-pregnane-3,20-dione, 3alpha,5alpha-THP, oestradiol, testosterone, DHT, 3alpha-Diol, dehydroepiandrosterone, and corticosterone were measured in plasma and whole brain, midbrain, hypothalamus, cortex, amygdala, hippocampus. 3alpha,5alpha-THP and 3alpha-Diol changed with reproductive state and mating stimuli. Plasma and whole brain 3alpha,5alpha-THP and 3alpha-Diol were significantly increased in pro-oestrus versus dioestrus rats; plasma 3alpha,5alpha-THP was decreased and 3alpha-Diol increased in mated versus pro-oestrus rats. The midbrain and hypothalamus had the most evident changes in 3alpha,5alpha-THP and 3alpha-Diol between dioestrus versus pro-oestrus and pro-oestrus versus mated rats. 3alpha,5alpha-THP and 3alpha-Diol were altered differently in response to mating stimuli. 3alpha,5alpha-THP was greater in the midbrain of mated versus pro-oestrus rats; other mating-relevant stimuli decreased 3alpha,5alpha-THP. Midbrain 3alpha-Diol was increased with exposure to a male 相似文献