Efficacy of administration sequence: Sacituzumab Govitecan and Trastuzumab Deruxtecan in HER2-low metastatic breast cancer.

BACKGROUND: Current guidelines recommend that patients with HER2-low metastatic breast cancer (MBC) receive sequentially two antibody-drug conjugates (ADCs): Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd), despite a similar payload. However, the effectiveness of one after another is unknown. METHODS: ADC-Low is a multicentre, retrospective study evaluating the efficacy of SG and T-DXd, one after another, with or without intermediary lines of chemotherapy, in patients with HER2-low MBC. RESULTS: One hundred and seventy-nine patients were included: the majority with HR-negative tumours received SG first (ADC1) (n = 100/108) while most with HR-positive tumours received T-DXd first (n = 56/71). Median progression-free survival 2 was short: 2.7 months (95% CI: 2.4-3.3) in the whole population, respectively, 3.1 (95% CI: 2.6-3.6) and 2.2 months (95% CI: 1.9-2.7) for patients receiving T-DXd or SG second (ADC2). Intermediary lines of chemotherapy between ADC1 and ADC2 had no impact. Primary resistance to ADC2 occurred in 54.4% of patients. Certain patients showed initial response to ADC2. CONCLUSIONS: Clinical benefit of sequentially administered SG and T-DXd is limited for most patients. Nevertheless, a subset of patients might benefit-on the short term-from a second ADC. Additional studies are needed to identify patients who could benefit from two ADCs with similar payloads.

Inhibin-mediated feedback control of follicle-stimulating hormone secretion in the female rat.

The secretion of follicle-stimulating hormone (FSH) by the anterior pituitary gland is regulated by the interaction of hypothalamic and gonadal hormones. Recently, proteins termed inhibins that selectively suppress FSH secretion have been purified and characterized from the gonadal fluids of several species. Antibodies to a synthetic peptide encompassing the amino terminal 25 residues of the recently characterized porcine inhibin were used to develop a specific radioimmunoassay (RIA) for inhibin and to neutralize endogenous inhibin during the estrous cycle of the rat. The administration of 20 international units of pregnant mare serum gonadotropin (PMSG) stimulated the secretion of inhibin in intact immature female rats, whereas ovariectomy caused an abrupt decrease in plasma inhibin concentrations that were not prevented by the injection of PMSG. The infusion of a polyclonal antiserum to inhibin, from 12 noon on proestrus to 1 a.m. on the morning of estrus, as well as its acute intravenous injection during diestrus I or II, caused an increase in plasma FSH (but not luteinizing hormone) concentrations. These results support the hypothesis of a feedback loop between the release of ovarian inhibin and FSH in the female rat.

Stress-induced inhibition of reproductive functions: role of endogenous corticotropin-releasing factor.

In the adult castrated male rat, exposure to inescapable, intermittent electroshocks inhibited the pulsatile pattern of luteinizing hormone release and markedly lowered its plasma concentrations. The central administration of the corticotropin-releasing factor (CRF) antagonist alpha-helical ovine CRF residues 9 to 41 reversed the inhibitory action of stress. Neither its peripheral injection, nor the intraventricular injection of the inactive CRF analog des-Glu to Arg ovine CRF was effective. These results suggest that endogenous CRF may mediate some deleterious effects of noxious stimuli on reproduction.

Inhibition of adrenocorticotropic hormone secretion in the rat by immunoneutralization of corticotropin-releasing factor.

Intravenous administration of rabbit antiserum to ovine corticotropin-releasing factor (CRF) markedly reduced the CRF-induced rise of plasma adrenocorticotropic hormone (ACTH) in intact nonstressed adult male rats while blocking more than 75 percent of the ACTH release observed in rats exposed to ether stress. Furthermore, antiserum to CRF significantly lowered ACTH levels in adrenalectomized animals. These results suggest that endogenous CRF plays a physiological role in regulating ACTH secretion.

Antireproductive effects of a potent gonadotropin-releasing hormone antagonist in the male rat.

Administration of a potent antagonist of gondadotropin-releasing hormone (GnRH) antagonist [Ac-dehydro-Pro1, pCl-D-Phe2, D-Trp3,6]-N alpha-MeLeu7-GnRH to adult male rats for 2 weeks resulted in decreased testosterone production and sexual organ weights and in disrupted spermatogenesis. The results demonstrate the essential role of gonadotropin-releasing hormone in the maintenance of reproductive functions and have implications for the regulation of male fertility.

Synthetic competitive antagonists of corticotropin-releasing factor: effect on ACTH secretion in the rat.

Polypeptide analogs of the known members of the corticotropin-releasing factor (CRF) family were synthesized and tested in vitro and in vivo for enhanced potency or competitive antagonism. Predictive methods and physicochemical measurements had suggested an internal secondary alpha-helical conformation spanning about 25 residues for at least three members of the CRF family. Maximization of alpha-helix-forming potential by amino acid substitutions from the native known sequences (rat/human and ovine CRF, sauvagine, and carp and sucker urotensin 1) led to the synthesis of an analog that was found to be more than twice as potent as either of the parent peptides in vitro. In contrast, certain amino-terminally shortened fragments, such as alpha-helical CRF or ovine CRF residues 8 to 41, 9 to 41, and 10 to 41, were found to be competitive inhibitors in vitro. Selected antagonists were examined and also found to be active in vivo.

Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor.

There is now evidence that the immune system, during times of infectious challenge, can stimulate the secretion of glucocorticoids, the adrenal steroids that mediate important aspects of the response to stress. Specifically, secretion of interleukin-1 (IL-1), a monocyte lymphokine secreted after infection, appears at least in part responsible for this effect. Glucocorticoids are secreted in response to a neuroendocrine cascade involving, first, the brain, then the pituitary, and finally the adrenal gland. In this report, human IL-1 is shown to activate the adrenocortical axis at the level of the brain, stimulating the release of the controlling hormone corticotropin-releasing factor (CRF) from the hypothalamus. Infusion of IL-1 induced a significant secretion of CRF into the circulation exiting the hypothalamus, whereas immunoneutralization of CRF blocked the stimulatory effect of IL-1 on glucocorticoid secretion. IL-1 appeared to have no acute direct stimulatory effects on the pituitary or adrenal components of this system. Furthermore, IL-1 did not cause a nonspecific release of other hypothalamic hormones. Thus, the lymphokine acts in a specific manner to activate the adrenocortical axis at the level of the brain; this effect appears to be unrelated to the known pyrogenic effects of IL-1 within the hypothalamus.

beta-Endorphin and adrenocorticotropin are selected concomitantly by the pituitary gland.

The opiate-like peptide beta-endorphin and adrenocorticotropin are concomitantly secreted in increased amounts by the adenohypophysis in response to acute stress or long-term adrenalectomy as well as in vitro in response to purified corticotropin releasing factor and other secretagogues. Conversely, administration of the synthetic glucocorticoid dexamethasone inhibits the secretion of both adrenocorticotropin and beta-endorphin. Thus, both hormones possess common and identical regulatory mechanisms and there may be a functional role for circulating beta-endorphin.

Novel role of adrenergic neurons in the brain stem in mediating the hypothalamic-pituitary axis hyperactivity caused by prenatal alcohol exposure.

Exposure to alcohol during embryonic development leads to changes in the hypothalamic-pituitary-adrenal (HPA) axis such that adult offspring release more adrenocorticotrophic hormone (ACTH) than controls when exposed to stress. In the present work, we tested the hypothesis that changes in the activity of the catecholaminergic system modulate, at least in part, this upregulation of the HPA axis. Pregnant Sprague-Dawley rats were exposed to alcohol 6 h daily during gestation days 7-18 using the vapor chamber model, which generated mean blood alcohol levels of 188.6+/-10 mg/dl. All experiments were performed on 2 to 3-month-old offspring. We first measured the ACTH response to i.c.v. injection of adrenergic receptor agonists. In rats exposed to footshocks, we then investigated the activity of corticotrophin-releasing factor (CRF) as well as indexes of catecholamine ir, namely tyrosine hydroxylase (TH) immunopositive neurons in the paraventricular nucleus (PVN), TH immunopositive neurons in the locus coeruleus, and phenylethanolamine N-methyltransferase (PNMT) immunopositive neurons in the brain stem. While adult females exposed to alcohol during fetal development (FAE) displayed the expected enhanced ACTH response to stress, there were no significant differences in response to adrenergic receptor agonists or in shock-induced CRF/TH ir and neuronal activity, as determined by c-fos colocalization. In contrast, FAE female offspring exposed to footshocks showed a significant increase in the activity of adrenergic neurons in the C1 region of the brain stem, a population of cells that project to the PVN. Collectively, these results suggest that while FAE-induced hyperactivity of the HPA axis is not accompanied by significant changes in PVN CRF or TH-ir neurons, it is characterized by an upregulation of C1 adrenergic neurons of the brain stem. This novel finding should lead to the functional characterization of this brain region in the FAE model.

Enzyme activities of lactic acid bacteria from a pearl millet fermented gruel (ben-saalga) of functional interest in nutrition.

Lactic acid bacteria responsible for the fermentation of a pearl-millet based fermented gruel, ben-saalga, were investigated for enzyme activity in relation with the nutritional characteristics of gruels used as complementary foods for young children. Thirty pre-selected LAB from a set of 155 isolates were characterized principally for their ability to produce amylase, phytase and alpha-galactosidase. Two Lactobacillus plantarum strains (4.4 and 6.1) and three Lactobacillus fermentum strains (11.11.2, 3.7, 7.4) able to produce one or more of these enzymes were selected. Only weak amylase activity was found in the two Lactobacillus plantarum strains. alpha-amylase activity was associated with cells and was lower than 0.05 Ceralpha Units/ml. Phytase activity was detected in all five strains and was linked to the cell. The highest phytase activity was found in Lb. plantarum 4.4 and 6.1 (348.7 +/- 17.4U/ml and 276.3 +/- 51.4U/ml, respectively) and Lb. fermentum 7.4. (276.3 +/- 13.2U/ml). All strains displayed a cell-linked alpha-galactosidase activity. In a medium containing 2% glucose, the highest cellular activity was found in Lb. fermentum 3.7 (1441.1 +/- 133.7U/ml) and Lb. plantarum 4.4 (1223.1 +/- 148.3U/ml) after 6h of fermentation in the presence of stachyose, and in Lb. plantarum 4.4 (763.3 +/- 23.5U/ml) and Lb. fermentum 7.4 (346.7 +/- 14.8U/ml) after 24h of fermentation with raffinose. These results are consistent with previous observations showing that phytates and alpha-galactooligosaccharides decreased during the natural lactic acid fermentation of pearl millet slurries, and that partial starch hydrolysis can be performed by endogenous microflora provided a pre-gelatinisation step is included in the process.

Effect of the long-term administration of corticotropin-releasing factor on the pituitary-adrenal and pituitary-gonadal axis in the male rat.

The effect of the continuous exposure to ovine corticotropin-releasing factor (oCRF) was measured in adult male rats. The intravenous infusion of 0.75 nmol oCRF/h to intact rats over a 24-h period was accompanied by a peak of ACTH and corticosterone secretion that occurred during the first 90 min of administration of the releasing factor, followed by a decrease to lower, but still above control, values. Additionally, corticotropin-releasing factor (CRF)-treated rats had decreased plasma testosterone levels. The subcutaneous administration of 0.075 or 0.75 nmol oCRF/h to intact rats for 7 d also resulted in elevations of both plasma ACTH and corticosterone levels comparable to those measured after a 24-h exposure to the releasing factor, as well as dose-related hypertrophy of the adrenals and increases in pituitary ACTH content. In these animals, CRF markedly inhibited luteinizing hormone (LH) (but not follicle-stimulating hormone [FSH] ), testosterone, and PRL secretion and decreased seminal vesicle weights. All the effects of CRF were mimicked by exogenously administered ACTH. By contrast, with the exception of FSH secretion, which was slightly elevated by CRF, neither CRF nor ACTH were able to significantly modify reproductive parameters in adrenalectomized animals, which suggests that the elevation of circulating levels of adrenal steroids induced by peripherally administered CRF represents major mediators of CRF-induced inhibition of fertility. These results indicate that in the rat, the continuous stimulation of the pituitary-adrenal axis by peripherally administered CRF causes some degree of desensitization of the pituitary-adrenal axis, but is still accompanied by persistent elevations of the circulating levels of both ACTH and corticosteroids. The increased secretion of adrenal steroids by CRF-treated rats is believed to participate in the disruption of reproductive parameters observed in these rats.

Effect of synthetic ovine corticotropin-releasing factor. Dose response of plasma adrenocorticotropin and cortisol.

Synthetic ovine corticotropin-releasing factor (CRF) was administered to normal male volunteer subjects as an intravenous bolus or 30-s infusion. Doses of CRF ranging from 0.001 to 30 micrograms/kg body wt were administered, and plasma immunoreactive (IR)-ACTH and IR-cortisol concentrations were measured. The threshold dose appeared to be 0.01-0.03 micrograms/kg, the half-maximal dose 0.3-1 micrograms/kg, and the maximally effective dose 3-10 micrograms/kg. Basal concentrations of IR-ACTH and IR-cortisol were 14 +/- 7.6 pg/ml (mean +/- SD) and 5.6 +/- 2.2 micrograms/dl, respectively. IR-ACTH rose as early as 2 min after CRF injection, reached peak levels in 10-15 min, and declined slowly thereafter. IR-cortisol rose at 10 min or later and reached peak levels in 30-60 min. At a dose of 30 micrograms/kg, neither IR-ACTH nor IR-cortisol fell from peak levels of 82 +/- 21 pg/ml (mean +/- SE) and 23 +/- 1.4 micrograms/dl, respectively, during the 2-h course of the experiment, indicating that CRF has a sustained effect on ACTH release and/or a prolonged circulating plasma half-life. There was little or no increase in the levels of other anterior pituitary hormones. At doses of 1 microgram/kg and higher, facial flushing, tachycardia, and, in some subjects, a 15-29-mmHg decline in systemic arterial blood pressure were observed, even though blood volume was replaced and the subjects remained supine. These data indicate that synthetic ovine CRF is a very potent and specific ACTH secretagogue in man. Administered with caution until its vasomotor effects are more fully defined, CRF promises to be a safe and very useful investigative, diagnostic, and, possibly, therapeutic agent in man.

Study through surveys and fermentation kinetics of the traditional processing of pearl millet (Pennisetum glaucum) into ben-saalga, a fermented gruel from Burkina Faso.

Traditional cereal-based fermented foods are frequently used as complementary foods for infants and young children in Africa. This is the case for ben-saalga, a popular fermented gruel produced from pearl millet (Pennisetum glaucum) in Burkina Faso. Detailed knowledge of traditional processing is a prerequisite for investigating ways to improve both the nutritional and sanitary qualities of the corresponding foodstuff. In this work, the traditional processing of pearl millet into ben-saalga was investigated in 24 production units, and fermentation kinetics were studied in pilot scale experiments. Processing steps include: washing (optional), soaking of the grains (first fermentation step), grinding and sieving of the wet flour, settling (second fermentation step), and cooking. The soaking step was mainly characterized by alcoholic fermentation whereas lactic acid fermentation occurred during the settling step. Fermentation kinetics during settling indicates a temporal variation of metabolic activity. Initially, both homofermentative and heterofermentative pathways were simultaneously active, and later only a homofermentative pathway was active. The paste produced at the end of settling had a low pH (4.0+/-0.4) and its microflora was dominated by lactic acid bacteria (LAB) with an amylolytic LAB/LAB ratio of 12%. Sucrose disappeared in the grains during soaking but was not detected in the soaking water, whereas glucose, fructose and maltose appeared transiently. Glucose and fructose were the main substrates observed for lactic acid fermentation during the settling step; however unbalanced fermentation led to the hypothesis that starch hydrolysis products may also serve as substrates for lactic acid formation. At the end of the processing, a 75% and 83% decrease was observed in phytate (IP6) and raffinose, respectively. The sour gruel ben-saalga resulting from cooking the sour paste had inadequate nutritional characteristics with respect to infants' and young children's requirements; it was characterized by fluid consistency (Bostwick flow: 137 mm/30 s) and low energy density (about 30 kcal/100 g of gruel).

The type of fortificant and the leaf matrix both influence iron and zinc bioaccessibility in iron-fortified green leafy vegetable sauces from Burkina Faso.

Leafy vegetable sauces from Burkina Faso were assessed as a potential vehicle for food fortification. First, iron and zinc bioaccessibility were measured by dialysability method in amaranth and Jew's mallow sauces and in traditional whole dishes consisting of maize paste plus leafy vegetable sauces. Iron dialysability and solubility were higher in amaranth than in Jew's mallow sauce, pointing to a marked effect of the matrix. Iron dialysability was hardly affected by the maize paste contrary to zinc dialysability, which was reduced. Second, iron and zinc bioaccessibility was assessed in the same sauces fortified with NaFeEDTA or iron sulfate. Added iron, i.e. iron supplied by fortification, represented 60% of total iron at the low fortification level and 80% at high level. In amaranth sauces with the high level of fortification using NaFeEDTA and iron sulfate, fractional dialysable iron reached respectively 66% and 26% compared to only 8.1% in the unfortified sauce. Similarly, in Jew's mallow sauces, fractional dialysable iron was 57% and 5% respectively with NaFeEDTA and iron sulfate and less than 1% in the unfortified sauce. Concomitantly, fractional dialysable zinc increased by respectively 20% and 40% in amaranth and Jew's mallow sauces fortified with NaFeEDTA whereas it remained unchanged with iron sulfate. Iron fortification could be an efficient way to greatly increase the available iron content of green leafy vegetable sauces and for this purpose NaFeEDTA is more effective than iron sulfate whatever the food matrix.

Nitric oxide stimulates ACTH secretion and the transcription of the genes encoding for NGFI-B, corticotropin-releasing factor, corticotropin-releasing factor receptor type 1, and vasopressin in the hypothalamus of the intact rat.

We investigated the effect of the intracerebroventricular injection of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1) on the release of adrenocorticotropin hormone (ACTH) and the neuronal response of hypothalamic neurons responsible for this release. Rats that were administered SIN-1 showed significant elevations in plasma ACTH levels, a response that was virtually abolished by antibodies against corticotropin-releasing factor (CRF) and significantly blunted by vasopressin (VP) antiserum. SIN-1 also upregulated heteronuclear (hn) transcripts for CRF and VP and messenger RNA (mRNA) levels for the immediate early gene NGFI-B and for CRF receptor type 1 (CRF-R(1)) in the parvocellular portion of the paraventricular nucleus (PVN) of the hypothalamus. Blockade of prostaglandin synthesis with ibuprofen did not alter the ACTH or the PVN response to SIN-1. The central nucleus of the amygdala and the supraoptic nucleus, regions that are involved in autonomic adjustments to altered cardiovascular activity, also responded to SIN-1 with elevated NGFI-B mRNA levels. However, the only change in mean arterial blood pressure caused by this NO donor was a transient and modest increase. To our knowledge, this is the first demonstration that in the intact rat NO stimulates the activity of PVN neurons that control the hypothalamic-pituitary-adrenal axis. It must be noted, however, that our results do not allow us to determine whether this effect was direct or mediated through PVN afferents. This study should help resolve the controversy generated by the use of isolated brain tissues to investigate the net effect of NO on hypothalamic peptide production.

Corticotropin-releasing factor activates c-fos, NGFI-B, and corticotropin-releasing factor gene expression within the paraventricular nucleus of the rat hypothalamus.

Studies examining the regulation of hypothalamic CRF biosynthesis have provided substantial information regarding the relevance of this peptide in neuroendocrine homeostasis. However, the consequences of elevated CRF levels within the mammalian central nervous system on regulation of CRF production within the paraventricular nucleus (PVN) of the hypothalamus remain unclear. The expression of the immediate early gene c-fos has been used and validated as a marker for neural systems activated by a variety of extracellular stimuli and has been especially useful when examining activation of central neuroendocrine systems such as those involved in the response to stressful stimuli. The present study investigates the effects of injecting CRF into the lateral ventricle of conscious rats, firstly on the expression of two separate immediate early genes, c-fos and NGFI-B within the hypothalamic PVN, and secondly on the expression of CRF mRNA itself, as determined by quantitative in situ hybridization. Expression of Fos protein was also examined by immunohistochemical techniques. Intracerebroventricular (icv) injection of CRF increased the gene expression of both c-fos and NGFI-B in the parvocellular division of the PVN 30 min after injection. Fos immunoreactivity increased in this same region between 30-60 min, whereas expression of the CRF gene itself increased 2-fold 60 min after injection and remained elevated 2 h after treatment. A positive hybridization signal for CRF was observed over Fos-immunoreactive neurons within the parvocellular division of the PVN. Finally, we observed that all CRF-induced changes in gene expression were abolished by pretreatment with the competitive CRF antagonist alpha-helical CRF-(9-41). The time-related changes in expression of the genes measured imply that the expression of both c-fos and NGFI-B occurs before a significant increase in the expression of CRF. The results also suggest that CRF may act in a positive manner to regulate its own biosynthesis.

Rapid changes in the expression of inhibin alpha-, beta A-, and beta B-subunits in ovarian cell types during the rat estrous cycle.

Distributions of inhibin alpha-, beta A-, and beta B-subunits in different ovarian compartments were studied in cycling female rats by in situ hybridization with complementary RNA probes and using immunohistochemical localization with antibodies selective for each inhibin subunit. Consistent with earlier studies showing inhibin production by granulosa cells of maturing follicles, we also detected mRNAs for inhibin alpha-, beta A-, and beta B-subunits in granulosa cells of these follicles. However, based on immunohistochemistry and in situ hybridization, we found that inhibin alpha- is not only expressed in granulosa cells of mature follicles but in follicles at all stages of maturation, including primary to tertiary follicles. A number of primordial follicles also contained alpha mRNA and immunodetectable alpha-subunit. Interestingly, theca interna and interstitial gland cells contained inhibin alpha mRNA and alpha-subunit. Low levels of inhibin alpha immunoreactivity as well as specific hybridization to the complementary inhibin alpha mRNA probe were observed in newly formed luteal tissue. beta-Subunits, on the other hand, were detected exclusively in granulosa cells of healthy tertiary follicles. The changes in expression of inhibin alpha-, beta A-, and beta B-subunits were more pronounced during the follicular phase of the cycle: inhibin alpha reached its highest level in granulosa cells, theca interna, and interstitial gland cells a few hours after the LH/FSH surge, while at the same time the beta-subunits decreased dramatically in granulosa cells of mature follicles. Immediately before ovulation (estrus 0200 h), the alpha-subunit sharply declined in preovulatory follicles and was present mainly in granulosa cells from nonovulatory follicles at various stages of maturation. At that time, the beta A- and beta B-subunits could not be detected in preovulatory follicles but were localized mainly in small tertiary follicles (less than 300 microns). Unlike for the alpha- and beta B-subunits, beta A mRNA and immunoreactivity was present in large tertiary follicles (approximately 600 microns) immediately before ovulation. The present findings support the hypothesis that a decrease in inhibin production could be responsible for the secondary FSH surge observed early on estrus. This could be initiated by a change in the ratios of activin-inhibin production by decreasing first, the levels of beta-subunits, second, the levels of alpha-subunit, and third, by a resurgence of activin A produced mainly by granulosa cells from large tertiary follicles.(ABSTRACT TRUNCATED AT 400 WORDS)

Blockade of nitric oxide formation augments adrenocorticotropin released by blood-borne interleukin-1 beta: role of vasopressin, prostaglandins, and alpha 1-adrenergic receptors.

Blockade of nitric oxide (NO) formation with the arginine derivative L-N omega nitro-L-arginine-methylester (L-NAME) produces a dramatic increase in ACTH released by the iv injection of interleukin-1 beta (IL-1 beta). The present work investigated the potential role of three mechanisms in this effect: the activation of adrenergic receptors and/or the release of vasopressin (VP) or prostaglandins (PG). As previously observed, blockade of adrenergic receptors with prazosin and propranolol did not alter the stimulatory effect of IL-1 beta. We show here that this treatment did not significantly interfere with the potentiating influence of L-NAME 30 min after IL-1 injection, but blunted this effect at 60 min. Immunoneutralization of endogenous VP did not consistently decrease the ACTH response to IL-1 beta regardless of whether NO was present. Finally, as expected, blockade of PG synthesis with ibuprofen totally abolished IL-1 beta-induced ACTH secretion; in addition, it prevented the interaction between L-NAME and the pituitary response. In contrast to results obtained after the injection of IL-1 beta, neither the adrenergic antagonists nor ibuprofen significantly altered the ability of L-NAME to potentiate the stimulatory effect of VP. Collectively, these results indicate that the influence of NO on ACTH released by blood-borne IL-1 beta (an effect thought to be primarily exerted on nerve terminals in the median eminence) is not primarily mediated by endogenous VP. The inability of L-NAME to augment the stimulatory effect of the cytokine on ACTH secretion in the presence of ibuprofen suggests that PG play an obligatory role in the response of the hypothalamic-pituitary axis to systemic cytokine administration that cannot be compensated for by removing the restraining influence of NO. Finally, removal of the inhibitory effect of NO either unmasks the participation of adrenergic receptors in modulating the response of the hypothalamic-pituitary axis to IL-1 beta or stimulates catecholamine secretion, which, in turn, acts on CRF nerve terminals and/or synergizes with IL-1 beta-induced CRF release.

Stimulatory effect of interleukin-1 on adrenocorticotropin secretion in the rat: is it modulated by prostaglandins?

The in vivo release of ACTH by interleukin-1 alpha (II-1 alpha) is reportedly blocked by acute treatment with indomethacin (indo), suggesting an involvement of endogenous prostaglandins in the effect of cytokines on the hypothalamic-pituitary-adrenal axis. However, indo also increases plasma corticosterone levels, raising the possibility that inhibition of ACTH release is due to suppressive effects of hypercorticolemia rather than to blockade of the stimulatory effects of II-1 alpha. We observed that the iv administration of indo (10 mg/kg) 15 min before II-1 alpha completely abolished the rise in plasma ACTH levels caused by the peripheral injection of this lymphokine to intact rats. At the time of II-1 alpha injection, plasma corticosterone levels were 39 +/- 12 ng/ml in controls and 121 +/- 22 ng/ml in indo-treated animals (P less than or equal to 0.01). In contrast, implantation of intact rats with indo pellets (which delivered 30 micrograms drug/h) 28 h before II-1 only partially interfered with II-1-induced ACTH secretion. In these rats plasma corticosterone levels before II-1 alpha injection were 29 +/- 14 ng/ml in controls and 66 +/- 18 ng/ml in rats implanted with indo pellets (P less than or equal to 0.05). To determine whether the effect of indo was due to corticosteroid feedback or represented a modulating action of prostaglandins themselves, a similar series of experiments was carried out in adrenalectomized rats. In the absence of corticoid replacement therapy, acute treatment with indo did not measurably interfere with the stimulatory effect of II-1 alpha. In contrast, indo blunted, but did not abolish, the effect of II-1a in ADX rats pretreated with corticosterone or dexamethasone to normalize basal ACTH levels. We conclude that the acute ability of indomethacin to totally block II-1-induced ACTH secretion by intact rats appears to be primarily mediated through corticosteroid feedback. However, results obtained when a similar experiment was carried out in adrenalectomized/corticosteroid-treated rats suggest, although they do not prove, that the ability of II-1 alpha to activate the hypothalamic-pituitary-adrenal axis may be partially dependent on the release of prostaglandins.

Influence of the paraventricular nucleus of the hypothalamus in the alteration of neuroendocrine functions induced by intermittent footshock or interleukin.

The documented ability of physical stress and cytokines to increase the secretion of corticotropin-releasing factor CRF by the paraventricular nucleus of the hypothalamus (PVN), coupled with our earlier demonstration that CRF acts within the brain to interfere with reproductive functions, led us to investigate the effect of lesions of the PVN on LH, testosterone, ACTH, and corticosterone (CORT) secretion. Bilateral lesions of the PVN were done electrolytically, and 2 weeks later a series of acute and chronic experiments were performed in intact or castrated male rats bearing indwelling jugular and/or intracerebroventricular cannulas. The first study involved a single 2-h exposure of intact male rats to footshocks (2 mA, 2-sec duration, 4 per min). Although PVN lesions did not measurably alter the ability of intermittent footshock to lower plasma testosterone levels, this treatment attenuated the rise in plasma ACTH and CORT. In a second study, which was done in castrated rats, shocks were delivered 2 h daily for 7 days, and circulating hormone levels were measured at the end of the last shock period. Plasma LH levels of stressed rats showed statistically comparable decreases in both sham- and PVN-lesioned animals. Chronic exposure to footshocks induced smaller increases of ACTH and CORT secretion in PVN-lesioned compared to sham-lesioned rats, but the lesions did not completely abolish stress-induced activation of the hypothalamic-pituitary adrenal (HPA) axis. The third experiment involved the central injection of the vehicle or 40 ng interleukin-1 beta (IL-1 beta) to castrated rats. As expected, IL-1 beta dramatically decreased plasma LH values and increased circulating ACTH and CORT levels measured 2 h later. Bilateral PVN lesion did not influence LH secretion after injection of the vehicle or IL-1 beta. In contrast, destruction of the PVN completely blocked the increase of HPA axis activity observed in sham-operated rats 2 h after the intracerebroventricular infusion of IL-1 beta. These results confirm our previous observation that exposure to either footshocks or interleukins alters the activity of the hypothalamic-pituitary gonadal and HPA axis. Additionally, the present studies suggest that the PVN, which represents the predominant hypothalamic nucleus controlling the response of the HPA axis to a number of stimuli, does not appear to be necessary for the antireproductive effects of intermittent footshock or immune activation.