Hypothalamus-pituitary-adrenal Gland Research Articles

Glucocorticoid receptor response and glucocorticoid-induced leucine zipper expression in neutrophils of critically ill patients with traumatic and non-traumatic brain injury.

Critically ill patients, including those with brain injuries (BI), are frequently hospitalized in an intensive care unit (ICU). As with other critical states, an adequate stress response is essential for survival. Research on the hypothalamic-pituitary-adrenal gland (HPA) axis function in BI has primarily focused on assessing ACTH and cortisol levels. However, the immunological, metabolic, and hemodynamic effects of glucocorticoids (GCs) are mediated through the glucocorticoid receptor (GCR), a ubiquitously distributed intracellular receptor protein. Data on GCR-α expression and its signaling in acute BI injury are lacking. We designed a prospective observational study, carried out in one academic multi-disciplinary ICU. Forty-two critically ill patients with acute (BI)were included. These patients suffered from traumatic BI (N= 20), subarachnoid hemorrhage (N= 12), intracranial hemorrhage (N= 7), or ischemic stroke (N= 3). All patients were steroid-free. Twenty-four age and sex-matched healthy controls were used for comparison. Expression of GCR-α and the glucocorticoid-inducible leucine zipper (GILZ), serum cortisol, interleukins (IL) 6, 8, 10 and TNF- α, and the BI biomarkers glial fibrillary acidic protein (GFAP) and total Tau were measured on ICU admission (within 48 hours) and 5-7 days from admission. Compared to healthy controls, in the critically ill patients with BI, GCR-α mRNA expression was significantly downregulated on admission, and after 5-7 days in the ICU (2.3-fold, p<0.05 and 2.6-fold, p<0.01, respectively). Even though GCR-α was downregulated, its downstream gene, GILZ, was expressed at the same levels as in normal controls on admission and was significantly upregulated 5-7 days following admission (2-fold, p<0.001). TNF-α levels were undetectable at both time-points. GCR-α expression levels inversely correlated with IL-6. The levels of cortisol and the BI biomarkers did not differ between the 2 time-points. We provide novel evidence on the downregulated expression and upregulated signaling of the ligand-binding and functionally active GCR-α isoform in the polymorphonuclear neutrophils (PMNs) of critically ill patients with BI. The increased GILZ expression indicates an increased GC sensitivity in the PMNs of BI critically ill patients.

Effect of Maternal High Fat Diet on the Hypothalamus-Pituitary-Adrenal Gland (HPA) Axis of the Offspring in Sheep

Maternal consumption of a high fat diet (HFD) during pregnancy is associated with metabolic dysfunction and altered HPA axis function in the offspring. These effects are well established in species with short gestation length (e.g., rodents), but less established in species with longer gestation periods more comparable with humans. The objective of the study was to determine the effect of maternal HFD on basal and stimulated cortisol secretion in the offspring at 16 weeks of age in sheep. All experiments were approved by the Institutional Animal Care and Use Committee at Cal Poly Pomona. Pregnant ewes were assigned to control (n=3) and HFD (n=3) groups. The control group was fed farmers best complete ewe and ram pellets. The HFD group was fed the same diet with an additional 30% rumen protected fat (Megalac, Volac Wilmar Feed Ingredients Ltd). After birth lambs were weaned at 12 weeks of age and given free access to control pellet diet with grains. To assess adrenal cortisol secretion at 16 weeks, lambs were infused intravenously with adrenocorticotropic hormone (ACTH; 2 ug/kg cortrosyn in 1 mL saline). Blood samples (1 mL) were taken through the jugular catheter at −30, −15, and 0 min (immediately before) and 5, 15, 30, 60, 90, and 120 min after ACTH administration for measurement of plasma cortisol by ELISA. Data were analyzed by two-way repeated measures ANOVA with a Tukey posthoc test. Basal plasma cortisol tended to be higher in HFD (32±8 ng/mL) than control (13±3 ng/mL) lambs, but this did not reach statistical significance. Plasma cortisol was higher than baseline from 15 to 90 minutes after ACTH administration in all lambs (p&lt;0.05). The increment in plasma cortisol was higher in HFD than control lambs from 15-90 minutes (p&lt;0.05). Accordingly, the maximum increase in plasma cortisol at 60 minutes and was higher in HFD (245±8 ng/mL) than control lambs (121±50 ng/mL p&lt;0.05). These preliminary data suggest that maternal consumption of a high fat diet during pregnancy may increase basal and stimulated activity of the HPA axis in sheep. The study was funded by a Strategic Interdisciplinary Research Grant (SIRG) at California State Polytechnic University, Pomona. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Стрес і гіпертензія за умов війни та COVID-19

Common mechanisms of the development of the body’s stress response under the conditions of war and the COVID-19 pandemic relate to its acute and chronic course, post-traumatic stress disorder, the role of the hypothalamus-pituitaryadrenal gland, the sympathetic nervous system, and the renin-angiotensin-aldosterone system, and deficiency of α-1- antitrypsin. The development of stress-induced hypertensive changes is characterized by the activity of enzymes independent of the angiotensin-converting enzyme pathway of the renin-angiotensin system, expression of miRNA, damage to the endothelial cells of blood vessels, changes in the content of neutrophils and lymphocytes, and the soluble receptor for glycosylation end products. The considered stress-induced hypertensive changes under the conditions of the COVID-19 pandemic relate to chronic hyperinflammation, emotional response, effects of catecholamines, chymase activity, redox imbalance, DNA damage, endoplasmic reticulum stress. The interaction between ACE/ACE2 and miRNA may increase the probability of SARS-CoV-2 infection in patients with hypertension. A factor in the severity of COVID-19 is considered to be clinical depression and low immunity, and the possibility of a negative effect of antidepressants is highlighted. A more aggressive course of COVID-19 in hypertensive patients is associated with low levels of nitric oxide (NO). Stress-induced hypertensive changes under the conditions of war are associated with adaptation disorders, increased randomness of heart rate changes, post-traumatic stress disorder, the development of hypertension partly of psychological origin against the background of changes in the central nervous system, immunity, and the polymorphism of the ACEI/D gene as an indicator of endurance.

The neurocircuitry of fasting-induced glucocorticoid release

Activation of the hypothalamus-pituitary-adrenal gland (HPA) axis confers adaptations to homeostatic perturbations including food scarcity. A comprehensive new study by Douglass etal. disentangled how agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus (ARC) trigger rapid HPA-axis activation in response to fasting, which is mediated by repression of a tonic, inhibitory neuro circuit.

Evidence for progesterone acting as an inhibitor of stress axis via stimulating pituitary neuropeptide B/W receptor 2 (NPBWR2) expression in chickens

In vertebrates, the hypothalamus-pituitary-adrenal gland (HPA) axis is the main endocrine pathway regulating the stress response, thus also called the stress axis. It has been well-accepted that the stress axis is tightly controlled by both hypothalamic stimulators and inhibitors [e.g. corticotropin (ACTH)-releasing inhibitory factor (CRIF)]. However, the identity of authentic CRIF remains unclear for decades. Recently, neuropeptide W (NPW) was proved to be the physiological CRIF in chickens. Together with its functional receptor (NPBWR2), they play critical roles in attenuating the activity of the chicken stress axis. Because increasing pieces of evidence suggested that sex steroids could regulate the stress axis, using chicken as a model, we investigated whether the newly identified CRIF and its receptor are under the control of sex steroids in this study. Our results showed that: (1) expression of NPW-NPBWR2 in the hypothalamus-pituitary axis was sexually dimorphic and developmental stage-dependent; (2) progesterone (P4), rather than 17β-estradiol (E2) and dihydrotestosterone (DHT), could dose- and time-dependently upregulate NPBWR2 expression, which was accompanied with the decrease of ACTH synthesis and secretion, in cultured pituitary cells; (3) intraperitoneal injection of P4 could elevate the mRNA level of pituitary NPBWR2; (4) P4-stimulated NPBWR2 expression was relevant to both nPR-mediated genomic action and mPRs-triggered nongenomic route associated with MEK/ERK, PI3K/AKT cascade, and calcium influx. To our knowledge, our results discover a novel route of sex steroids in modulating the stress axis of chickens, which lays a foundation to reveal the complicated interaction network between reproduction and stress axes in chickens.

Interaction Between Glucocorticoid Receptors and FKBP5 in Regulating Neurotransmission of the Hippocampus

FK501 binding protein 51 (FKBP5) is a stress response prolyl isomerase that inhibits the translocation of the glucocorticoid receptor (GR) heterocomplex to the nucleus. Previous studies have shown that the expression levels of FKBP5 are positively correlated with psychiatric disorders, including depression and post-traumatic stress disorder. In rodents, FKBP5 deletion in the brain leads to be resilient to stress-induced depression. The hippocampus is known to be one of the primary locations mediating stress responses in the brain by providing negative feedback signals to the hypothalamus–pituitary-adrenal gland axis. Therefore, we aimed to investigate the role of FKBP5 and its interaction with GRs in the hippocampus. We observed that FKBP5 deletion in the hippocampus resulted in a minimal change in synaptic transmission. In the hippocampus, GR activation alters the release probability in inhibitory synapses as well as the postsynaptic contribution of glutamate receptors in excitatory synapses; however, no such alterations were induced in the absence of FKBP5. FKBP5 deficiency causes insensitivity to activated GRs in the hippocampus suggesting that FKBP5 mediates synaptic changes caused by GR activation. Our study provides electrophysiological evidence of stress resilience observed in FKBP5-deficient mice.

The Type of Fat in the Diet Influences Regulatory Aminopeptidases of the Renin-Angiotensin System and Stress in the Hypothalamic-Pituitary-Adrenal Axis in Adult Wistar Rats.

(1) Background: Prolonged feeding with a high-fat diet (HFD) acts as a stressor by activating the functions of the hypothalamic-pituitary-adrenal gland (HPA) stress axis, accompanied of hypertension by inducing the renin-angiotensin-aldosterone system. Angiotensinases enzymes are regulatory aminopeptidases of angiotensin metabolism, which together with the dipeptidyl peptidase IV (DPP-IV), pyroglutamyl- and tyrosyl-aminopeptidase (pGluAP, TyrAP), participate in cognitive, stress, metabolic and cardiovascular functions. These functions appear to be modulated by the type of fat used in the diet. (2) Methods: To analyze a possible coordinated response of aminopeptidases, their activities were simultaneously determined in the hypothalamus, adenohypophysis and adrenal gland of adult male rats fed diets enriched with monounsaturated (standard diet (S diet) supplemented with 20% virgin olive oil; VOO diet) or saturated fatty acids (diet S supplemented with 20% butter and 0.1% cholesterol; Bch diet). Aminopeptidase activities were measured by fluorimetry using 2-Naphthylamine as substrates. (3) Results: the hypothalamus did not show differences in any of the experimental diets. In the pituitary, the Bch diet stimulated the renin-angiotensin system (RAS) by increasing certain angiotensinase activities (alanyl-, arginyl- and cystinyl-aminopeptidase) with respect to the S and VOO diets. DPP-IV activity was increased with the Bch diet, and TyrAP activity decrease with the VOO diet, having both a crucial role on stress and eating behavior. In the adrenal gland, both HFDs showed an increase in angiotensinase aspartyl-aminopeptidase. The interrelation of angiotensinases activities in the tissues were depending on the type of diet. In addition, correlations were shown between angiotensinases and aminopeptidases that regulate stress and eating behavior. (4) Conclusions: Taken together, these results support that the source of fat in the diet affects several peptidases activities in the HPA axis, which could be related to alterations in RAS, stress and feeding behavior.

School commute time, chronotype, and altered HPA axis functioning during adolescence

Hypothalamic pituitary adrenal gland (HPA) axis functioning has been linked with daily demands during adolescence. A ubiquitous, yet understudied daily demand in the lives of youth is the commute to school, which may be associated with the diurnal rhythm of cortisol as demonstrated in prior research among adults. The current study hypothesized that longer school commute times would be associated with altered HPA axis functioning as demonstrated by a heightened cortisol awakening response (CAR) and flatter diurnal slope. Additionally, given that the HPA axis follows a diurnal rhythm and adolescence is marked by changes in the circadian rhythm, adolescents with a more evening chronotype were hypothesized to evince even more altered HPA axis functioning in the face of long school commute times. A total of 269 adolescents (M = 16.38 years, SD = 0.74) provided saliva samples at wake, 15-min. post-wake, and 30-min. post-wake for the calculation of CAR and at dinnertime and bedtime for the calculation of diurnal slope, completed up to 8 nights of sleep actigraphy, and self-reported school commute time. Results suggest that more evening chronotype youth with longer school commute times evince a higher CAR, but not an altered diurnal slope. The present findings may have implications for adolescent mental health as higher CAR has been associated poor mental health and heightened stress.

Effects of alkylphenols mixture on the adrenal gland of the lizard Podarcis sicula

Alkylphenols (AP) are widespread environmental compounds belonging to the large family of substances known as Endocrine Disrupting Chemicals (EDCs). The present study was carried out to assess the effects of Octylphenol (OP) alone and in combination with Nonylphenol (NP) on the hypothalamus-pituitary-adrenal gland (HPA) axis of the lizard Podarcis sicula. Lizards are good bioindicators due to their features such as wide distribution, large population and good sensitivity to contaminants. Results obtained showed a time and dose-dependent stimulation of the HPA together with a high variation of both catecholamine plasma levels and greater vascularization and hypertrophy of steroidogenic cord of adrenal gland after both OP and OP + NP treatments. Interestingly, the OP + NP mixture treatment has provoked a state of stress of the adrenal gland which in fact appeared to be characterized by the presence of a marked macrophage infiltration which can be seen especially close to the connective capsule surrounding the gland. This macrophage infiltration could be an evidence of a particularly pronounced inflammatory state to indicate, probably, an animal’s response to a non-physiological situation.

Corticosterone Production during Repeated Social Defeat Causes Monocyte Mobilization from the Bone Marrow, Glucocorticoid Resistance, and Neurovascular Adhesion Molecule Expression.

Repeated social defeat (RSD) stress promotes the release of bone marrow-derived monocytes into circulation that are recruited to the brain, where they augment neuroinflammation and cause prolonged anxiety-like behavior. Physiological stress activates the sympathetic nervous system and hypothalamic-pituitary-adrenal gland (HPA) axis, and both of these systems play a role in the physiological, immunological, and behavioral responses to stress. The purpose of this study was to delineate the role of HPA activation and corticosterone production in the immunological responses to stress in male C57BL/6 mice. Here, surgical (adrenalectomy) and pharmacological (metyrapone) interventions were used to abrogate corticosterone signaling during stress. We report that both adrenalectomy and metyrapone attenuated the stress-induced release of monocytes into circulation. Neither intervention altered the production of monocytes during stress, but both interventions enhanced retention of these cells in the bone marrow. Consistent with this observation, adrenalectomy and metyrapone also prevented the stress-induced reduction of a key retention factor, CXCL12, in the bone marrow. Corticosterone depletion with metyrapone also abrogated the stress-induced glucocorticoid resistance of myeloid cells. In the brain, these corticosterone-associated interventions attenuated stress-induced microglial remodeling, neurovascular expression of the adhesion molecule intercellular cell adhesion molecule-1, prevented monocyte accumulation and neuroinflammatory signaling. Overall, these results indicate that HPA activation and corticosterone production during repeated social defeat stress are critical for monocyte release into circulation, glucocorticoid resistance of myeloid cells, and enhanced neurovascular cell adhesion molecule expression.SIGNIFICANCE STATEMENT Recent studies of stress have identified the presence of monocytes that show an exaggerated inflammatory response to immune challenge and are resistant to the suppressive effects of glucocorticoids. Increased presence of these proinflammatory monocytes has been implicated in neuropsychiatric symptoms and the development of chronic cardiovascular, autoimmune, and metabolic disorders. In the current study, we show novel evidence that corticosterone produced during stress enhances the release of proinflammatory monocytes from the bone marrow into circulation, augments their recruitment to the brain and the induction of a neuroinflammatory profile. Overproduction of corticosterone during stress is also the direct cause of glucocorticoid resistance, a key phenotype in individuals exposed to chronic stress. Inhibiting excess corticosterone production attenuates these inflammatory responses to stress.

Effect of central and peripheral injection of prostaglandin E2 and F2α on feeding and the crop-emptying rate in chicks

Prostaglandins (PGs) have been shown to cause several physiological changes in mammals including anorexia, awakening and sleeping, change in digestive function, and activation of the hypothalamus-pituitary-adrenal gland (HPA) axis. However, there is a paucity of information about the effect of PGs on physiological parameters in birds. The purpose of the present study was to clarify whether intracerebroventricular (ICV) and intraperitoneal (IP) injections of prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) affect feeding, voluntary movement, crop-emptying rate, and corticosterone release in chicks (Gallus gallus). ICV injection of either PGE2 or PGF2α (2 and 4μg) significantly decreased food intake in chicks. The anorexigenic effect was also observed after IP injection of the PGs. Voluntary movement was significantly suppressed by ICV injection of PGE2 or PGF2α, although the time-course change was different between the two. In contrast, IP injection of the PGs had no or less effect on voluntary movement. Both ICV and IP injection of PGE2 significantly retarded the crop-emptying rate, whereas PGF2α significantly lowered the crop-emptying rate only after IP injection. The plasma corticosterone concentration significantly increased after ICV and IP injection of PGE2, whereas PGF2α had no effect. These results suggest that central and peripheral PGs are involved in the regulation of appetite, voluntary movement, food passage in the digestive tract, and activation of the HPA axis in chicks, although the effects depend on the site of action and type of PGs.

Microbiota, the immune system, black moods and the brain—melancholia updated

There is now abundant evidence that the immune system and the brain have close functional interactions in both directions. This review focuses on the influence of the microbiota (the bacteria resident in the gut) on brain function in major depressive disorder (MDD) and related syndromes. The gut and the central nervous system communicate partly through the autonomic nervous system (ANS), consisting of the sympathetic (i.e., the splanchnic nerves) and the parasympathetic (i.e., the vagus nerve and the sacral parasympathetic pelvic nerves) nervous system. The brain integrates inputs from the digestive tract by a central autonomic network that includes the hypothalamus, limbic system and cerebral cortex with output to the ANS and hypothalamic-pituitary-adrenal gland (HPA) stress axis (Bonaz, 2013). There are also extensive chemical signaling systems via the blood.

Nonylphenol effects on the HPA axis of the bioindicator vertebrate, Podarcis sicula lizard

Nonylphenol (NP) is an endocrine disruptor widely distributed in the environment. It accumulates in the lipids of living organisms and enters the human food chain. The main source of human exposure is expected to be food, drinking water and foodstuff contaminated through leaching from packaging or pesticide formulation applications. NP acts as an estrogenic compound and it is able to mimic the action of estradiol 17β (E2) by binding to the estrogen receptor (ER). The aim of the present study was to investigate the NP effects on the hypothalamic–pituitary–adrenal gland (HPA) axis of the bioindicator Podarcis sicula lizard. A time-dependent stimulation of the HPA axis and variations of both catecholamine plasma levels were showed. Moreover, NP effects on adrenal gland morphology were evaluated by light and transmission electron microscopy. Clear morphological signs of adrenal gland stimulation such as an increase of steroidogenic cord diameter and vascularization, a strong escalation of adrenaline cell number and a decrease of noradrenaline cells were observed. The notably elevated levels of adrenal hormones suggested a permanent turning on of hypothalamic corticotropin releasing factor (CRF) secretion together with a lack of the negative feedback of HPA axis, perturbing systemic responses of the organism. Our data may help to predict the biological alterations induced by NP and to extend its impact upon adrenal function.

Repeated Short-term (2h×14d) Emotional Stress Induces Lasting Depression-like Behavior in Mice

Chronic behavioral stress is a risk factor for depression. To understand chronic stress effects and the mechanism underlying stress-induced emotional changes, various animals model have been developed. We recently reported that mice treated with restraints for 2 h daily for 14 consecutive days (2h-14d or 2h×14d) show lasting depression-like behavior. Restraint provokes emotional stress in the body, but the nature of stress induced by restraints is presumably more complex than emotional stress. So a question remains unsolved whether a similar procedure with "emotional" stress is sufficient to cause depression-like behavior. To address this, we examined whether "emotional" constraints in mice treated for 2h×14d by enforcing them to individually stand on a small stepping platform placed in a water bucket with a quarter full of water, and the stress evoked by this procedure was termed "water-bucket stress". The water-bucket stress activated the hypothalamus-pituitary-adrenal gland (HPA) system in a manner similar to restraint as evidenced by elevation of serum glucocorticoids. After the 2h×14d water-bucket stress, mice showed behavioral changes that were attributed to depression-like behavior, which was stably detected >3 weeks after last water-bucket stress endorsement. Administration of the anti-depressant, imipramine, for 20 days from time after the last emotional constraint completely reversed the stress-induced depression-like behavior. These results suggest that emotional stress evokes for 2h×14d in mice stably induces depression-like behavior in mice, as does the 2h×14d restraint.

Endocrine system dynamics and MS epidemiology

In the kidney there is a co-transport relationship in the nephron between the reabsorption of positive Na(+) ions and the reabsorption of negative ions such as uric acid anions. Uric acid acts as an anti-oxidant and it has been shown to have a sealing effect on the blood-brain barrier. The theory developed here is that chronic neurological vasoconstriction in cool environmental conditions injects an offset into the rennin-angiotensin-aldosterone system (RAAS) blood pressure control loop and reduces demand for angiotensin and aldosterone. (Aldosterone is produced in the adrenal gland and has a direct effect on renal reabsorption of Na(+) ions.) Via co-transport these conditions will reduce the body's ability to reabsorb uric acid and this in turn will weaken the integrity of the blood-brain barrier. Also, in cool environments, where levels of vasopressin (ADH) and aldosterone are lower, the gain of the hypothalamus-pituitary-adrenal gland (HPA) axis is reduced so that the production average levels of ACTH, cortisone and aldosterone will be biased at a lower level and the kidney-local levels of aldosterone in particular will remain lower. This paper develops these ideas and suggests that they can help explain the traditionally-recognized latitudinal gradient in MS epidemiology. Also, acclimatization to heat encourages sweating, which should create a greater demand for the renal reabsorption of Na(+) ions which enables greater reabsorption of uric acid. Therefore people living at low latitudes should have a lower chance of hypouricemia and a lower chance of developing MS. In fact people who spend their first fifteen years in the tropics almost never go onto develop MS. And MS patients in relapse are consistently hypouricemic. This hypothesis can explain both of these facts. The paper goes onto show how the MS condition will tend to progress because of a number of self-sustaining effects: over time the immune system becomes more targeted to myelin, MS patients are unlikely to become acclimatized to heat because they tend to avoid heat since demyelinated nerve function is worsened by elevated temperature, and the normal circadian excitation of the HPA axis gets weaker under the benign environmental conditions typically adopted by MS patients as the disease develops.

Mice lacking adenylyl cyclase‐5 cope badly with repeated restraint stress

Physiological responses to acute stress proceed with the activation of the hypothalamus-pituitary-adrenal gland (HPA) system. Many brain regions are known to modulate the HPA axis activation in stress responses, but the detailed neural circuits and signaling system in the upstream of the HPA axis have to be explored further. Type 5 adenylyl cyclase (AC5) is highly concentrated in the dorsal striatum and nucleus accumbens, which are implicated in reward and stress-related behavior. AC5(-/-) mice exposed to daily 2-hr restraint stress for only 3-5 days showed poor stress-coping responses, including severe body weight loss, poor coat condition, respiratory difficulties, and freezing behavior. Plasma corticosterone levels during 2-hr stress sessions increased in AC5(-/-) mice compared with those of AC5(+/+) mice. However, neither the corticosterone receptor antagonist RU486 nor the CRH receptor antagonist NBI27914 blocked their poor stress coping, whereas the administration of the GABA(A) receptor allosteric modulator diazepam or the D1 dopamine receptor antagonist SCH23390 prior to restraint stress sessions changed their stress-coping response to the stressed AC5(+/+) mouse level. Stress-triggered c-Fos expression was completely blunted in the dorsal striatum of AC5(-/-). These results suggest that the AC5-associated signal system and neural network are involved in the regulation of anxiety and stress-coping response.

Neuropeptide Y regulates catecholamine release evoked by interleukin-1β in mouse chromaffin cells

Activation of the hypothalamic-pituitary–adrenal gland (HPA) axis can modulate the immune system. Cytokines and neuropeptide Y (NPY) are potent regulators of the HPA axis and are both produced by the adrenal medulla. The cytokine interleukin-1β (IL-1β) belongs to the interleukin-1 family along with interleukin-1α and the interleukin receptor antagonist (IL-1ra). The aim of the present study was to determine the interaction between NPY and IL-1β in catecholamine (norepinephrine, NE and epinephrine, EP) release from mouse chromaffin cells in culture. We found that IL-1β increased the constitutive release of NPY, NE and EP from mouse chromaffin cells. This IL-1β stimulatory effect was blocked by IL-1ra. The immunoneutralization of NPY and the use of the NPY Y 1 receptor antagonist (BIBP 3226) inhibited the stimulatory effect of IL-1β on catecholamine release from these cells. The present work shows that IL-1β induces catecholamine release, and in turn this peptide will induce an additional increase in catecholamine release acting through the Y 1 receptor. This work suggests that NPY is involved in the regulatory loop between the immune and the adrenal system in some pathophysiological conditions where plasmatic IL-1β increases, like in sepsis, rheumatoid arthritis, stress or hypertension.

Lithium‐induced gene expression of inducible cyclic adenosine monophosphate early repressor in the rat adrenal gland

Lithium has acute and chronic effects on the hypothalamic-pituitary-adrenal gland (HPA) axis that are important for both therapeutic (e.g., treatment of mood disorders) and experimental (e.g., as the toxin in conditioned taste aversion studies) applications. We visualized lithium-induced activation of the HPA axis in rats by the adrenal expression of inducible cAMP early repressor (ICER), which is activated by elevated intracellular cAMP. We have shown that 1) intraperitoneal lithium chloride (LiCl) induces transient expression of ICER and c-fos mRNAs in the rat adrenal cortex and increases plasma level of corticosterone; 2) the cortical expression of ICER mRNA by LiCl occurs in a dose-dependent manner; 3) adrenal induction of ICER expression is delayed compared with c-fos expression; 4) dexamethasone pretreatment (4 mg/kg) blocks corticosterone release and adrenocortical ICER induction either by systemic LiCl (76 mg/kg) or by restraint stress; and 5) intracerebroventricular LiCl (127 microg/5 microl) is sufficient for adrenocortical, but not medullary, ICER induction. These results suggest that adrenocortical ICER expression could serve as a reliable marker for lithium-induced activation of the HPA axis. Understanding the activation of immediate-early genes such as c-fos or ICER in response to a single LiCl injection is an important first step in understanding the long-term changes in gene expression elicited by lithium that are involved in its therapeutic and toxic effect. The pattern and mechanism by which lithium stimulates ICER transcription in the adrenal gland would serve as a useful model system in future studies of lithium.

Toluene inhalation-induced adrenocortical hypertrophy and endocrinological changes in rat

Rats were exposed to toluene (1,500 ppm for 4 hr per day) for 7 days. The body weight of the rats was significantly lower and the weight of the adrenal gland was significantly higher in the toluene inhalation group compared to the controls. Microscopically, there was no obvious change in the medulla, but hypertrophy of the cortex was observed in the toluene inhalation group. And, the size of adrenocortical cells in treated-rats was also significantly enlarged than the control. Immunohistochemical staining did not show a clear difference in localization of aldosterone-positive cells between the control and inhalation groups. Expansion of the corticosterone-positive area consistent with the cortical hypertrophy was recognized in the inhalation group. Enhancement of 72 kD-heat-shock protein (HSP70)-expression in the toluene inhalation group was not observed. Neither stress nor damage to cortical cells due directly to toluene exposure was observed in the cortex. Also, there was no obvious difference in the anti-proliferating cell nucleus antigen (PCNA)-immunostaining between control and inhalation groups. Thus, it is suspected that cortical hypertrophy was the result of cell enlargement due to the stimulation of the cortical cells. Corticotropin-releasing factor (CRF) immunoreactivity in the paraventricular nucleus (PVN) was increased in the inhalation group. Concentration of plasma ACTH was elevated significantly by toluene exposure. The amounts of mRNA of adrenocortical steroid metabolism gene, cytochrome side-chain cleavage (P450scc), was also increased by toluene inhalation. Toluene exposure might induce adrenocortical hypertrophy via the hypothalamus-pituitary-adrenal gland (HPA) axis.

Effect of prolonged exposure to low concentrations of formaldehyde on the corticotropin releasing hormone neurons in the hypothalamus and adrenocorticotropic hormone cells in the pituitary gland in female mice

We examine the effect on the hypothalamus–pituitary–adrenal gland (HPA) axis of prolonged exposure to low levels of formaldehyde in female C3H/He mice, using immunocytochemical and RT-PCR methods. Two groups of female mice were exposed to differing concentrations (0, 80, 400, 2000 ppb) of formaldehyde inhalation for 16 h/day, 5 days/week, for 12 weeks. The corticotropin releasing hormone (CRH)-immunoreactive (ir) neurons in the hypothalamus were then examined, together with the adrenocorticotropin hormone (ACTH)-ir cells and ACTH mRNA in the pituitary. One group comprised sham control mice. The other group was made allergic by injection of ovalbumin (OVA) and alum prior to exposure to formaldehyde, since most sick building syndrome (SBS) sufferers are women with allergic disease. These animals were further exposed to aerosolized OVA as a booster four times during the exposure period. Our results showed a dose-dependent increase in the number of CRH-ir neurons in the non-allergy (NAG) group. A similar pattern was found in ACTH-ir cells and ACTH mRNA. The allergy (AG) model group showed an increase in basal levels of all markers of HPA activity. Moreover, the AG mice appeared to respond to the lowest concentration of formaldehyde, and all indices of HPA activity were reduced at the highest concentrations of formaldehyde. These results relate to an important clinical issue and also have implications in the broader area of HPA regulation. We conclude that our experimental system may be a suitable animal model for SBS and/or multiple chemical sensitivity (MCS).