[Interaction between central nervous system and immune system after ischemic stroke and its therapeutic significance of traditional Chinese medicine].

Ischemic stroke is divided into acute phase, subacute phase, and recovery phase, with different pathological and physiological characteristics manifested at each stage. Among them, immune and inflammatory reactions persist for several days and weeks after ischemia. Ischemic stroke not only triggers local inflammation in damaged brain regions but also induces a disorder in the immune system, thereby promoting neuroinflammation and exacerbating brain damage. Therefore, conducting an in-depth analysis of the interaction between the central nervous system and the immune system after ischemic stroke, intervening in the main factors of the interaction between them, blocking pathological cascades, and thereby reducing brain inflammation have become the treatment strategies for ischemic stroke. This study summarizes and sorts out the interaction pathways between the central nervous system and the immune system. The impact of the central nervous system on the immune system can be analyzed from the perspective of the autonomic nervous system, the hypothalamic-pituitary-adrenal axis(HPA), and local inflammatory stimulation. The impact of the immune system on the central nervous system can be analyzed from the dynamic changes of immune cells. At the same time, the relevant progress in the prevention and treatment of traditional Chinese medicine(TCM) is summarized, so as to provide new insights for the analysis of complex mechanisms of TCM in preventing and treating ischemic stroke.

The hypothalamic-pituitary-adrenal and -thyroid axes activation lasting one year after an earthquake swarm: results from a big data analysis.

PURPOSE: To cope physical and/or psychological threats, the human body activates multiple processes, mediated by a close interconnection among brain, endocrine and inflammatory systems. The aim of the study was to assess the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes involvement after an acute stressful event (Emilia Romagna earthquake swarm) with a big data approach. METHODS: A retrospective, observational trial was performed, collecting all biochemical examinations regarding HPA and HPT axes performed in the same laboratory the year before and the year after the earthquake swarm (20-29 May 2012). RESULTS: Comparing 2576 pre-earthquake to 3021 post-earthquake measurements, a cortisol serum level increase was observed (p < 0.001). Similar increase was evident for urinary free cortisol (p = 0.016), but not for adrenocorticotropic hormone (p = 0.222). The biochemical hypercortisolism incidence increased from 7.6 to 10.3% after earthquakes (p = 0.001). Comparing 68,456 pre-earthquake to 116,521 post-earthquake measurements, a reduction in thyroid-stimulating hormone (TSH) levels was evident (p = 0.018), together with an increase in free triiodothyronine and free thyroxine levels (p < 0.001 and p < 0.001). Moreover, a significant increase in altered TSH after earthquakes was registered considering the epicenter-nearest measurements (p < 0.001). No clinically relevant alterations were observed considering thyroid-specific autoantibodies. CONCLUSION: A long-term HPA axis activation in the inhabitants of the earthquake-affected areas was highlighted for the first time. Moreover, an increased incidence of biochemical hypercortisolism emerged after earthquakes. We confirmed a recruitment of HPT axis after stressful events, together with increased incidence of altered TSH in the. Our big data study allowed to increase knowledge about the connection between external stressors and endocrine regulation.

Acute Mono-Arthritis Activates the Neurohypophysial System and Hypothalamo-Pituitary Adrenal Axis in Rats.

Various types of acute/chronic nociceptive stimuli cause neuroendocrine responses such as activation of the hypothalamo-neurohypophysial [oxytocin (OXT) and arginine vasopressin (AVP)] system and hypothalamo-pituitary adrenal (HPA) axis. Chronic multiple-arthritis activates the OXT/AVP system, but the effects of acute mono-arthritis on the OXT/AVP system in the same animals has not been simultaneously evaluated. Further, AVP, not corticotropin-releasing hormone (CRH), predominantly activates the HPA axis in chronic multiple-arthritis, but the participation of AVP in HPA axis activation in acute mono-arthritis remains unknown. Therefore, we aimed to simultaneously evaluate the effects of acute mono-arthritis on the activity of the OXT/AVP system and the HPA axis. In the present study, we used an acute mono-arthritic model induced by intra-articular injection of carrageenan in a single knee joint of adult male Wistar rats. Acute mono-arthritis was confirmed by a significant increase in knee diameter in the carrageenan-injected knee and a significant decrease in the mechanical nociceptive threshold in the ipsilateral hind paw. Immunohistochemical analysis revealed that the number of Fos-immunoreactive (ir) cells in the ipsilateral lamina I-II of the dorsal horn was significantly increased, and the percentage of OXT-ir and AVP-ir neurons expressing Fos-ir in both sides of the supraoptic (SON) and paraventricular nuclei (PVN) was increased in acute mono-arthritic rats. in situ hybridization histochemistry revealed that levels of OXT mRNA and AVP hnRNA in the SON and PVN, CRH mRNA in the PVN, and proopiomelanocortin mRNA in the anterior pituitary were also significantly increased in acute mono-arthritic rats. Further, plasma OXT, AVP, and corticosterone levels were significantly increased in acute mono-arthritic rats. These results suggest that acute mono-arthritis activates ipsilateral nociceptive afferent pathways at the spinal level and causes simultaneous and integrative activation of the OXT/AVP system. In addition, the HPA axis is activated by both AVP and CRH in acute mono-arthritis with a distinct pattern compared to that in chronic multiple-arthritis.

Comparison of Protective Effects of Electroacupuncture at ST 36 and LU 5 on Pulmonary and Hypothalamic Pituitary Adrenal Axis Changes in Perinatal Nicotine-Exposed Rats.

BACKGROUND: Maternal smoking and/or exposure to environmental tobacco smoke continue to be significant factors in fetal and childhood morbidity and are a serious public health issue worldwide. Nicotine passes through the placenta easily with minimal biotransformation, entering fetal circulation, where it results in many harmful effects on the developing offspring, especially on the developing respiratory system. OBJECTIVES: Recently, in a rat model, electroacupuncture (EA) at maternal acupoints ST 36 has been shown to block perinatal nicotine-induced pulmonary damage; however, the underlying mechanism and the specificity of ST 36 acupoints for this effect are unknown. Here, we tested the hypothesis that compared with EA at ST 36, EA at LU 5 acupoints, which are on lung-specific meridian, will be equally or more effective in preventing perinatal nicotine-induced pulmonary changes. METHODS: Twenty-four pregnant rat dams were randomly divided into 4 groups: saline ("S"), nicotine ("N"), nicotine + ST 36 (N + ST 36), and nicotine + LU 5 (N + LU 5) groups. Nicotine (1 mg/kg, subcutaneously) and EA (at ST 36 or LU 5 acupoints, bilaterally) were administered from embryonic day 6 to postnatal day 21 once daily. The "S" group was injected saline. As needed, using ELISA, western analysis, q-RT-PCR, lung histopathology, maternal and offspring hypothalamic pituitary adrenal axes, offspring key lung developmental markers, and lung morphometry were determined. RESULTS: With nicotine exposure, alveolar count decreased, but mean linear intercept and septal thickness increased. It also led to a decrease in pulmonary function and PPARγ and an increase of ß-catenin and glucocorticoid receptor expression in lung tissue and corticosterone in the serum of offspring rats. Electroacupuncture at ST 36 normalized all of these changes, whereas EA at LU 5 had no obvious effect. CONCLUSION: Electroacupuncture applied to ST 36 acupoints provided effective protection against perinatal nicotine-induced lung changes, whereas EA applied at LU 5 acupoints was ineffective, suggesting mechanistic specificity and HPA axis' involvement in mediating EA at ST 36 acupoints' effects in mitigating perinatal nicotine-induced pulmonary phenotype. This opens the possibility that other acupoints, besides ST 36, can have similar or even more robust beneficial effects on the developing lung against the harmful effect of perinatal nicotine exposure. The approach proposed by us is simple, cheap, quick, easy to administer, and is devoid of any significant side effects.

Effects of the Ethanol Extract of Dipterocarpus alatus Leaf on the Unpredictable Chronic Mild Stress-Induced Depression in ICR Mice and Its Possible Mechanism of Action.

Treatment of the unpredictable chronic mild stress (UCMS) mice with the ethanol extract of Dipterocarpus alatus leaf attenuated anhedonia (increased sucrose preference) and behavioral despair (decreased immobility time in tail suspension test (TST) and forced swimming test (FST)). The extract not only decreased the elevation of serum corticosterone level and the index of over-activation of the hypothalamic-pituitary-adrenal (HPA) axis, caused by UCMS, but also ameliorated UCMS-induced up-regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) mRNA expression and down-regulation of cyclic AMP-responsive element binding (CREB) and brain-derived neurotrophic factor (BDNF) mRNAs in frontal cortex and hippocampus. In vitro monoamine oxidase (MAO) inhibition assays showed that the extract exhibited the partial selective inhibition on MAO-A. HPLC analysis of the extract showed the presence of flavonoids (luteolin-7-O-glucoside, kaempferol-3-glucoside, rutin) and phenolic acids (gallic acid, ferulic acid, and caffeic acid) as major constituents.

Periconceptional ethanol exposure alters the stress axis in adult female but not male rat offspring.

Ethanol consumption during pregnancy alters offspring hypothalamus-pituitary-adrenal (HPA) axis regulation. However, little is known about the outcomes of alcohol consumption confined to the periconceptional period. This study investigated the effects of periconceptional ethanol (PC:EtOH) exposure on corticosterone concentrations, response to restraint stress and gene expression of adrenal, hypothalamic, and hippocampal glucocorticoid-related pathways in rat offspring. Female Sprague-Dawley rats were treated with PC:EtOH (12.5% v/v EtOH liquid diet) or a control diet from four days before conception, until embryonic day 4. At 6 (adult) and 12-14 (aged) months of age, basal corticosterone concentrations were measured, while in a separate cohort of aged rats, blood pressure, heart rate, and plasma corticosterone concentrations were measured during a 30-minute restraint stress. Adrenal gland, hypothalamic and hippocampal tissue from aged rats were subjected to transcriptomic analysis. PC:EtOH exposure reduced basal plasma corticosterone concentrations in adult and aged female but not male offspring (p < .05). The corticosterone and pressor response were significantly reduced in aged PC:EtOH female offspring following restraint (p < .05). Expression of adrenal steroidogenesis genes (Mc2r, Cyp11a1, Cyp21a1, 11bhsd2, and Nr3c1) and hypothalamic genes (Crh, Crh-r1, Nr3c1, and Hsp90a1) was not affected by PC:EtOH. In aged female offspring exposed to PC:EtOH, adrenal mRNA expression of Hsp90a1 was significantly elevated, and within the hippocampus, mRNAs for glucocorticoid receptor (Nr3c1) and Hsp90a1 were increased (p < .05). This study supports the hypothesis that prenatal alcohol exposure programs sex-specific alterations in the HPA axis and provides the first evidence that the periconceptional period is a critical window for programing of this axis. Lay summary This study investigated the impact of alcohol consumption around the time of conception on offspring stress reactivity in a rat model. Offspring exposed to alcohol displayed altered cardiovascular responses to stress and had reduced circulating concentrations of the stress hormone corticosterone both under basal conditions and following a stressful challenge. This study also identified altered expression of key genes in an important part of the brain known to be involved in stress responsiveness; the hippocampus. If similar outcomes occur in humans, these results would suggest that alcohol consumption, even before a woman knows she is pregnant, may significantly impact stress-related outcomes in children.

Agarwood Essential Oil Ameliorates Restrain Stress-Induced Anxiety and Depression by Inhibiting HPA Axis Hyperactivity.

In our previous investigation, we found that agarwood essential oil (AEO) has a sedative-hypnotic effect. Sedative-hypnotic drugs usually have an anxiolytic effect, where concomitant anxiety and depression are a common comorbidity. Therefore, this study further investigated the anxiolytic and antidepressant effects of AEO using a series of animal behavior tests on a restraint stress-induced mice model. The elevated plus maze (EPM) test, the light dark exploration (LDE) test, and the open field (OF) test demonstrated that AEO has a significant anxiolytic effect. Simultaneously, the tail suspension (TS) test and the forced swimming (FS) test illuminated that AEO has an antidepressant effect with the immobility time decreased. Stress can cause cytokine and nitric oxide (NO) elevation, and further lead to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. AEO was shown to dose-dependently inhibit the levels of cytokines, including interleukin 1α (IL-1α), IL-1ß, and IL-6 in serum, significantly decrease the mRNA level of neural nitric oxide synthase (nNOS) in the cerebral cortex and hippocampus, and inhibit the nNOS protein level in the hippocampus. Concomitant measurements of the HPA axis upstream regulator corticotropin releasing factor (CRF) and its receptor CRFR found that AEO significantly decreases the gene expression of CRF, and significantly inhibits the gene transcription and protein expression of CRFR in the cerebral cortex and hippocampus. Additionally, AEO dose-dependently reduces the concentrations of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) downstream of the HPA axis, as measured by ELISA kits. These results together demonstrate that AEO exerts anxiolytic and antidepressant effects which are related to the inhibition of CRF and hyperactivity of the HPA axis.

Endocannabinoid system, stress and HPA axis.

The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana's psychoactive ingredient ∆9-tetrahydrocannabinol (∆9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors. In addition to its recreational actions, some of the earliest reports regarding the effects of Cannabis use on humans were related to endocrine system changes. Accordingly, the ∆9-THC and later on, the ECS signalling have long been known to regulate the hypothalamic-pituitary-adrenocortical (HPA) axis, which is the major neuroendocrine stress response system of mammals. However, how the ECS could modify the stress hormone secretion is not fully understood. Thus, the present article reviews current available knowledge on the role of the ECS signalling as important mediator of interaction between HPA axis activity and stressful conditions, which, in turn could be involved in the development of psychiatric disorders.

Early life programming of pain: focus on neuroimmune to endocrine communication.

Chronic pain constitutes a challenge for the scientific community and a significant economic and social cost for modern societies. Given the failure of current drugs to effectively treat chronic pain, which are based on suppressing aberrant neuronal excitability, we propose in this review an integrated approach that views pain not solely originating from neuronal activation but also the result of a complex interaction between the nervous, immune, and endocrine systems. Pain assessment must also extend beyond measures of behavioural responses to noxious stimuli to a more developmentally informed assessment given the significant plasticity of the nociceptive system during the neonatal period. Finally integrating the concept of perinatal programming into the pain management field is a necessary step to develop and target interventions to reduce the suffering associated with chronic pain. We present clinical and animal findings from our laboratory (and others) demonstrating the importance of the microbial and relational environment in programming pain responsiveness later in life via action on hypothalamo-pituitary adrenal (HPA) axis activity, peripheral and central immune system, spinal and supraspinal mechanisms, and the autonomic nervous system.

Catalpol regulates function of hypothalamic-pituitary-adrenocortical-axis in an Alzheimer's disease rat model.

AIMS: To investigate the regulating effects of catalpol on the hypothalamic-pituitary- adrenocortical-axis (HPA) in an Alzheimer's disease (AD) rat model. METHODS: Healthy male Wistar Rats were selected. The AD model was generated by orthotopic injection of beta-amyloid 25-35 (Abeta25-35) into the right lateral ventricle. The animals were divided into five study groups: Catalpol at low dose (5 mg/kg), Catalpol at high dose (10 mg/kg), model control group and sham surgery control group, n = 9 respectively. The serum concentration of hydrocortisone (HYD), adrenocorticotropin (ACTH) and corticotropin releasing hormone (CRH) determined by Enzyme-Linked Immunosorbent Assay (ELISA). Structural alterations of the hypothalamus were examined by H&E stain and electron microscope. The CRH receptor 1 (CRHR1) positive neurons were detected with immunohistochemistry. RESULTS: Serum HYD level was significantly increased (p < 0.01), and both ACTH and CRH were dramatically decreased (p < 0.01) in the AD model group rats compared with normal control rats at day 7. Catalpol treatment was able to improve the hormone secretion disorder in AD model group rats compared with the model group (p < 0.01 or p < 0.05) in particular at 21 days. Structure damage of hypothalamus in the AD rat as evidenced less CRHR1 positive neurons, rough endoplasmic reticulum dilation and degranulation, and mitochondrial swelling under electron microscope. Catalpol treatment at both high and low doses was able to alleviate the structure damage of the hypothalamus in the AD rats. CONCLUSIONS: Catalpol could improve the endocrine function of the HPA and alleviate the structural damage of hypothalamus in AD rats.

Nutritional omega-3 modulates neuronal morphology in the prefrontal cortex along with depression-related behaviour through corticosterone secretion.

Understanding how malnutrition contributes to depression is building momentum. In the present study we unravel molecular and cellular mechanisms by which nutritional disturbances lead to impaired emotional behaviour in mice. Here we report that nutritional n-3 polyunsaturated fatty acids (PUFA) deficiency induces a chronic stress state reflected by disrupted glucocorticoid receptor (GR)-mediated signalling pathway along with hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. This hyperactivity in turn resulted in neuronal atrophy in the dorsolateral (dl)- and dorsomedial (dm)- prefrontal cortex (PFC) and subsequent mood-related behaviour alterations, similarly to chronic social defeat stress. Supplementation of n-3 PUFA prevented detrimental chronic social defeat stress-induced emotional and neuronal impairments by impeding HPA axis hyperactivity. These results indicate a role for dietary n-3 PUFA in the prevention of HPA axis dysfunction associated with the development of some neuropsychiatric disorders including depression.

Acupuncture for posttraumatic stress disorder: conceptual, clinical, and biological data support further research.

Posttraumatic stress disorder (PTSD) is common, debilitating, and has highly heterogeneous clinical and biological features. With the exception of one published preliminary clinical trial, rationale in support of the efficacy of acupuncture, a modality of Chinese medicine (CM), for PTSD has not been well described. This is a focused review of conceptual and clinical features of PTSD shared by modern western medicine (MWM) and CM, and of biological mechanisms of acupuncture that parallel known PTSD pathology. MWM and CM both recognize individual developmental variables and interactions between external conditions and internal responses in the genesis of PTSD. There is one published and one unpublished clinical trial that preliminarily support the efficacy of acupuncture for PTSD. Although there have been no mechanistic studies of acupuncture in human PTSD, extant research shows that acupuncture has biological effects that are relevant to PTSD pathology. Conceptual, clinical, and biological data support possible efficacy of acupuncture for PTSD. However, further definitive research about simultaneous clinical and biological effects is needed to support the use of acupuncture for PTSD in health care systems.

Central NPY-Y5 receptors activation plays a major role in fasting-induced pituitary-thyroid axis suppression in adult rat.

Neuropeptide Y (NPY) inhibits TRH neurons in fed state, and hypothalamic NPY higher expression during fasting has been proposed to be involved in fasting-induced suppression of the hypothalamus-pituitary-thyroid (HPT) axis. We investigated the role of central Y5 receptors in the control of thyrotropin (TSH) and thyroid hormone (TH) secretion. Fed and fasting rats received twice daily central injections (3rd ventricle) of Y5 receptor antagonist (CGP71683; 15nmol/rat) for 72h. Fasted rats also received a single central injection of CGP71683 (15nmol/rat) at the end of 72h of fasting. In fed rats, Y5 receptor blockade reduced total food intake by 32% and body mass by almost 10% (p<0.01), corroborating the role of this receptor in food intake control. 72h-fasted rats exhibited a 4-fold increase in serum TSH (p<0.001), 1h after a single injection of Y5 antagonist. Also with multiple injections during 72h of fasting, Y5 blockade resulted in activation of thyroid axis, as demonstrated by a 3-times rise in serum T4 (p<0.001), accompanied by unchanged TSH and T3. In fed rats, the chronic central administration of CGP71683 resulted in reduced total serum T4 without changes in free T4 and TSH. Serum leptin and PYY were not altered by the NPY central blockade in both fed and fasted rats, suggesting no role of these hormones in the alterations observed. Therefore, the inhibition of central Y5 neurotransmission resulted in activation of thyroid axis during fasting suggesting that NPY-Y5 receptors contribute to fasting-induced TSH and TH suppression.

Gender differences in the long-term effects of chronic prenatal stress on the HPA axis and hypothalamic structure in rats.

Stress during pregnancy can impair biological and behavioral responses in the adult offspring and some of these effects are associated with structural changes in specific brain regions. Furthermore, these outcomes can vary according to strain, gender, and type and duration of the maternal stress. Indeed, early stress can induce sexually dimorphic long-term effects on diverse endocrine axes, including subsequent responses to stress. However, whether hypothalamic structural modifications are associated with these endocrine disruptions has not been reported. Thus, we examined the gender differences in the long-term effects of prenatal and adult immobilization stress on the hypothalamic-pituitary-adrenocortical (HPA) axis and the associated changes in hypothalamic structural proteins. Pregnant Wistar rats were subjected to immobilization stress three times daily (45 min each) during the last week of gestation. One half of the offspring were subjected to the same regimen of stress on 10 consecutive days starting at postnatal day (PND) 90. At sacrifice (PND 180), serum corticosterone levels were significantly higher in females compared to males and increased significantly in females subjected to both stresses with no change in males. Prenatal stress increased pituitary ACTH content in males, with no effect in females. Hypothalamic CRH mRNA levels were significantly increased by prenatal stress in females, but decreased in male rats. In females neither stress affected hypothalamic cell death, as determined by cytoplasmic histone-associated DNA fragment levels or proliferation, determined by proliferating cell nuclear antigen levels (PCNA); however, in males there was a significant decrease in cell death in response to prenatal stress and a decrease in PCNA levels with both prenatal and adult stress. In all groups BrdU immunoreactivity colocalized in glial fibrillary acidic protein (GFAP) positive cells, with few BrdU/NeuN labelled cells found. Furthermore, in males the astrocyte marker S100ß increased with prenatal stress and decreased with adult stress, suggesting affectation of astrocytes. Synapsin-1 levels were increased by adult stress in females and by prenatal stress in males, while, PSD95 levels were increased in females and decreased in males by both prenatal and adult stress. In conclusion, hypothalamic structural rearrangement appears to be involved in the long-term endocrine outcomes observed after both chronic prenatal and adult stresses. Furthermore, many of these changes are not only different between males and females, but opposite, which could underlie the gender differences in the long-term sequelae of chronic stress, including subsequent responses to stress.

Angiotensin II inhibition reduces stress sensitivity of hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats.

Angiotensin II type 1 (AT(1)) receptors are expressed within organs of the hypothalamo-pituitary-adrenal (HPA) axis and seem to be important for its stress responsiveness. Secretion of CRH, ACTH, and corticosterone (CORT) is increased by stimulation of AT(1) receptors. In the present study, we tested whether a blockade of the angiotensin II system attenuates the HPA axis reactivity in spontaneously hypertensive rats. Spontaneously hypertensive rats were treated with candesartan (2 mg/kg), ramipril (1 mg/kg), or mibefradil (12 mg/kg) for 5 wk. In addition to baseline levels, CORT and ACTH responses to injection of CRH (100 microg/kg) were monitored over 4 h. mRNA of CRH, proopiomelanocortin, AT(1A), AT(1B), and AT(2) receptors was quantified by real-time PCR. All treatments induced equivalent reductions of blood pressure and had no effect on baseline levels of CORT and ACTH. However, both candesartan and ramipril significantly reduced CRH-stimulated plasma levels of ACTH (-26 and -15%) and CORT (-36 and -18%) and lowered hypothalamic CRH mRNA (-25 and -29%). Mibefradil did not affect any of these parameters. Gene expression of AT(1A), AT(1B), and AT(2) receptors within the HPA axis was not altered by any drug. We show for the first time that antihypertensive treatment by inhibition of AT(1) receptors or angiotensin-converting enzyme attenuates HPA axis reactivity independently of blood pressure reduction. This action is solely evident after CRH stimulation but not under baseline conditions. Both a reduced pituitary sensitivity to CRH and a down-regulation of hypothalamic CRH expression have the potential to reduce HPA axis activity during chronic AT(1) blockade or angiotensin-converting enzyme inhibition.

Prenatal dexamethasone treatment does not prevent alterations of the hypothalamic pituitary adrenal axis in steroid 21-hydroxylase deficient mice.

A major difficulty in the clinical management of congenital adrenal hyperplasia (CAH) is adjustment of glucocorticoid doses to suppress ACTH and androgens without causing iatrogenic hypercortisolism. The possibility that structural alterations of the adrenal or a dysfunction of the hypothalamic pituitary adrenal (HPA) axis caused by glucocorticoid deficiency during fetal life contribute to this problem was studied in 21-hydroxylase deficient mice caused by deletion of the cytochrome P-450 21-hydroxylase gene. Homozygotes showed about 200-fold elevations in plasma progesterone, hyperplastic adrenal cortices lacking zonation, and structural alterations of adrenocortical mitochondria. Histochemical studies showed increases in hypothalamic CRH messenger RNA (mRNA) and immunoreactive (ir) CRH, and pituitary POMC mRNA in homozygous mice. VP mRNA levels in PVN perikarya were normal, but irVP in parvicellular terminals of the median eminence was increased in homozygotes. Prenatal dexamethasone treatment (0.5 to 2 microg/day) prevented the increases in CRH mRNA, whereas dexamethasone only partially decreased POMC mRNA levels, and had no effect on serum progesterone levels. The data suggest that intrauterine glucocorticoid deficiency in CAH causes hyperactivity of the hypothalamic-pituitary-corticotroph axis and insensitivity to glucocorticoid feedback. These studies in 21-hydroxylase deficient mice may provide new insights on the mechanism, clinical manifestations and management of some types of human CAH.

[Experimental study of effect on tonifying kidney herbs in pituitary ovary adrenal gland of androgen sterilized rats].

OBJECTIVE: To observe the effect of tonifying Kidney herbs (TKH) in pituitary, ovary, adrenal gland of androgen sterilized rats(ASR). METHODS: ASR model was established by injecting testosterone propionate subcutaneously to SD female rats of 9 days age. Morphological and hormonal change of pituitary, ovary and adrenal gland in rats of 100-107 days old before and after feeding TKH extract were observed by light and electron microscope, cell culture immunohistochemical studies and radioimmuno-assay. RESULTS: In the ASR groups, there were intracytopiasmic lipid drops, autophagy, vacuole, granulolysis of pituitary gland. There were anovulation apparently and increased the amount of lipid drops in cytoplasm of interstitial glandular cell of ovary. The fatty drops of the reticular zone of adrenal gland decreased, the numbers of AGNOR (P < 0.01) and PCNA (P < 0.01) increased significantly. The levels of FSH, LH (P < 0.05-0.005) lowered, but the levels of DHA, T (P < 0.01, 0.05, 0.001) were raised significantly. Morphological and hormonal change of all RSA returned to normal range after the treatment. CONCLUSIONS: The hyperandrogenemia were disturbed by the function of sex gland axis and adrenal in female rats of 9 days old and played an important role in pathogenesis of ASR, the TKH reduced the levels of androgen and induced ovulation through sex gland axis and adrenal level and multi-organ regulation.

Prenatal stress selectively alters the reactivity of the hypothalamic-pituitary adrenal system in the female rat.

A study was made of the effects of prenatal stress on the reactivity of the hypothalamic-pituitary adrenal (HPA) axis in male and female offspring. Rat dams were subjected to noise and light stress on an unpredictable basis throughout pregnancy. At 28 days of age mRNA for POMC, proenkephalin and prodynorphin were measured in the hypothalamus of the offspring. A marked reduction was found in POMC mRNA in PS females (PSF) but not in males (PSM), but the other mRNA's did not differ from controls (C). At 60 days of age, PSF has 3 times higher resting levels of serum corticosterone (COR) and significantly lower dexamethasone (DEX)3H hippocampal binding sites than CF. Overnight adrenalectomy abolished the difference in DEX binding. After 10 min exposure to open field PS males and females voided more fecal pellets and made fewer center entries than C offspring, testifying to increased emotionality. Open field stress caused a 3-5-fold rise in circulating COR in all groups within 15 min, which returned to baseline by 90 min in all rats except PSF. These data show that prenatal stress can cause permanent alterations in the behavior of both sexes in stressful situations but appears to cause a selective effect on the HPA axis in the female rat.