Jan Bugajski

Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is accepted as one of the fundamental biological mechanisms that underlie major depression. This hyperactivity is caused by diminished feedback inhibition of glucocorticoid (GC)-induced reduction of HPA axis signaling and increased corticotrophin-releasing hormone (CRH) secretion from the hypothalamic paraventricular nucleus (PVN) and extra-hypothalamic neurons. During chronic stress-induced inhibition of systemic feedback, cytosolic glucocorticoid receptor (GR) levels were significantly changed in the prefrontal cortex (PFC) and hippocampus, both structures known to be deeply involved in the pathogenesis of depression. Cytokines secreted by both immune and non-immune cells can markedly affect neurotransmission within regulatory brain circuits related to the expression of emotions; cytokines may also induce hormonal changes similar to those observed following exposure to stress. Proinflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are implicated in the etiologies of clinical depression and anxiety disorders. Prolonged stress responses and cytokines impair neuronal plasticity and stimulation of neurotransmission. Exposure to acute stress and IL-1β markedly increased IL-1β levels in the PFC, hippocampus and hypothalamus, as well as overall HPA axis activity. Repeated stress sensitized the HPA axis response to IL-1β. Inflammatory responses in the brain contribute to cellular damage associated with neuropsychiatric diseases related to stress. Physical, psychological or combined-stress conditions evoke a proinflammatory response in the brain and other systems, characterized by a complex release of several inflammatory mediators including cytokines, prostanoids, nitric oxide (NO) and transcription factors. Induced CRH release involves IL-1, IL-6 and TNF-α, for stimulation adrenocorticotropic hormone (ACTH) release from the anterior pituitary. NO also participates in signal transduction pathways that result in the release of corticosterone from the adrenal gland. NO participates in multiple interactions between neuroendocrine and neuroimmune systems in physiological and pathological processes. Neuronal NO synthase (nNOS) modulates learning and memory and is involved in development of neuropsychiatric diseases, including depression. Nitric oxide generated in response to stress exposure is associated with depression-like and anxiety-like behaviors. In the central nervous system (CNS), prostaglandins (PG) generated by the cyclooxygenase (COX) enzyme are involved in the regulation of HPA axis activity. Prior exposure to chronic stress alters constitutive (COX-1) and inducible (COX-2) cyclooxygenase responses to homotypic stress differently in the PFC, hippocampus and hypothalamus. Both PG and NO generated within the PVN participate in this modulation. Acute stress affects the functionality of COX/PG and NOS/NO systems in brain structures. The complex responses of central and peripheral pathways to acute and chronic stress involve cytokines, NO and PG systems that regulate and turn off responses that would be potentially harmful for cellular homeostasis and overall health.

Central H1- and H2-Histaminergic Stimulation of Pituitary-Adrenocortical Response under Stress in Rats

In rats subjected to a mild stress of immobilization histamine, H1-receptor agonist 2-pyridylethylamine (PEA), and H2-receptor agonists, 4-methylhistamine (4-MHA) and dimaprit, given intraventricularly 60 min prior to stress, intensified the stress-induced increase of hypophyseal-adrenocortical response, evaluated indirectly through corticosterone concentration in blood serum. The effects were dose dependent and on a molar basis histamine and PEA were the most potent and 4-MHA and dimaprit were less effective, in this respect. The effect of histamine was almost totally blocked by both H1-receptor antagonists, mepyramine or chloropyramine, and by H2-receptor antagonists, metiamide or cimetidine. The corticosterone response to PEA was abolished by mepyramine, and the responses to 4-MHA or dimaprit were antagonized by cimetidine and metiamide. The response to the H1 agonist was not substantially altered by pretreatment with cimetidine, and the responses to the H2 agonists were not changed by mepyramine. These results suggest that in stressed rats the corticosterone response to histamine is mediated by both H1 and H2 central histamine receptors.

Interleukin-1 (IL-1) in stress-induced activation of limbic-hypothalamic-pituitary adrenal axis

Proinflammatory cytokine interleukin-1 (IL-1) produced during psychological and immunological stress, plays a significant role in the neuroendocrine and stress responses. Brain IL-1 is an important mediator in stress-induced stimulation of the limbic-hypothalamic-pituitary-adrenal axis and secretion of ACTH and corticosterone. This review aims to describe some signaling pathways between the limbic-hypothalamic-pituitary structures during prolonged stress responses including their sensitization and adaptation. Interleukin-1 represents an important central component operating in neurochemical and immune network for efficient coping in preventing stress-associated psycho- and neuropathology.

Influence of chronic stress on brain corticosteroid receptors and HPA axis activity

BACKGROUND Disruption of the glucocorticoid negative feedback system evoked in animals by chronic stress can be induced by downregulation of glucocorticoid receptors (GRs) in several brain regions. In the present study, the dynamics of the changes in GRs, in brain structures involved in stress reactions, prefrontal cortex, hippocampus and hypothalamus was compared with the peripheral hypothalamo-pituitary-adrenocortical (HPA) axis hormones response to chronic stress. METHODS Rats were exposed to 10 min restraint or restrained twice a day for 3, 7 or 14 days, and 24 h after the last stress session exposed to homotypic stress for 10 min. Control rats were not restrained. After rapid decapitation at 0, 1, 2, and 3 h after stress termination, trunk blood for plasma adrenocorticotropic hormone (ACTH) and corticosterone determinations was collected and prefrontal cortex, hippocampus and hypothalamus were excised and frozen. Plasma hormones were determined using commercially available kits and glucocorticoids and mineralocorticoids protein levels in brain structure samples were determined by western blot procedure. RESULTS Restraint stress alone significantly decreased glucocorticoid receptor (GR) level in prefrontal cortex and hippocampus, and increased mineralocorticoid receptor (MR) level in hypothalamus. Prior repeated stress for 3 days significantly increased GR protein level in hippocampus and diminished that level in hypothalamus in 7 days stressed rats. Acute stress-induced strong increase in plasma ACTH and corticosterone levels decreased to control level after 1 or 2 h, respectively. Prior repeated stress for 3 days markedly diminished the fall in plasma ACTH level and repeated stress for 7 days moderately deepened this decrease. Plasma ACTH level induced by homotypic stress in rats exposed to restraint for 3, 7, and 14 days did not markedly differ from its control level, whereas plasma corticosterone response was significantly diminished. The fast decrease of stress-induced high plasma ACTH and corticosterone levels was accompanied by a parallel decline of GR level only in prefrontal cortex but not in the hippocampus or hypothalamus. CONCLUSIONS Comparison of the dynamics of changes in plasma ACTH and corticosterone level with respective alterations in GR and MR in brain structures suggests that the buffering effect of repeated stress depends on the period of habituation to stress and the brain structure involved in regulation of these stress response.

Central histaminergic stimulation of pituitary-adrenocortical response in the rat

In conscious rats histamine, the H1-receptor agonist 2-pyridylethylamine (PEA), and the H2-receptor agonists dimaprit and impromidine given intracerebroventriculary (i.c.v.) increased the hypophyseal-adrenocortical response, evaluated indirectly through the corticosterone concentration in the blood serum. On a molar basis histamine was the most potent drug whereas its agonists were less potent in inducing an increased corticosterone response. Impromidine however, was far more active than dimaprit and PEA. The effect of histamine was significantly yet not totally antagonized by either mepyramine, a H1-receptor antagonist, or cimetidine, a H2-receptor blocker. The combination of mepyramine and cimetidine caused a considerably stronger inhibition than that induced by either antagonist given separately. Mepyramine impaired the corticosterone response to PEA, and the responses to impromidine and dimaprit were significantly diminished by cimetidine. The results suggest that i.c.v. histamine increases the pituitary-adrenocortical activity via both H1- and H2-receptors, and there seems to be no significant prevalence of either of these receptors in mediating this action of histamine.

Lipolytic responses induced by intracerebroventricular administration of histamine in the rat

Histamine (10–50 μg) administered intraventricularly in conscious rats induced an increase in serum-free fatty acids. The maximum, significant increase appeared 30–60 min after administration. Histamine H1-receptor antagonists, mepyramine and chloropyramine, when injected 2 h prior to histamine, abolished considerably hyperlipaemic responses to histamine. H2-Receptor antagonists, metiamide and cimetidine, given i.c.v. only moderately diminished the histamine-induced hyperlipaemia. Histamine injected i.c.v. also increased serum corticosterone levels considerably. This elevation was prevented significantly by the H1-receptor antagonist, mepyramine, but not by the H2-receptor blocker, cimetidine. It seems likely that histamine given i.c.v. induces lipolysis through the release of ACTH, one of the known lipid-mobilizing hormones. The central lipid-mobilizing mechanism after histamine depends more on activation of H1- than H2-receptors.

The intracerebroventricularly administered mast cells degranulator compound 48/80 increases the pituitary-adrenocortical activity in rats

The effect of brain mast cells degranulation by compound 48/80 on the pituitary-adrenocortical activity, measured indirectly through corticosterone secretion, and the involvement of a histaminergic mechanism in that stimulation was investigated in conscious rats. All the drugs were given intracerebroventricularly (icv), histamine antagonists 15 min prior to compound 48/80. Compound 48/80 induced a significant dose- and time-related increase in the serum corticosterone levels. That increase, measured 1 h after adminstration of compound 48/80, was moderately diminished by icv pretreatment of rats with mepyramine and cimetidine, histamine H1- and H2-receptor antagonists. Three hours after administration of compound 48/80 mast cells of the thalamus and the hypothalamus were completely degranulated. At the same time the thalamus and the whole brain histamine levels were substantially higher than in the saline-treated control rats.The above results suggest that histamine liberated from the brain mast cells and central histamine receptors play a moderate role in increasing the pituitary-adrenocortical activity by compound 48/80.

Effect of metiamide, a histamine H2-receptor antagonist, on the development of gastric stress ulcers and acid secretion

Abstract In normal and stressed rats with chronic gastric fistula small doses of metiamide (0.001–0.01 μM/kg) increased and doses of over 20 μM/kg decreased gastric acid secretion. In both these dose ranges of dosage metiamide suppressed the development of stress ulcers, most markedly in doses of 0.005 and 100 μM/kg. Intermediate doses had no such action. Only the anti-ulcer action of large doses of metiamide ran parallel to a reduction in acid secretion. Small doses of metiamide increased gastric secretion, but like larger doses, had a weak adrenergic action.

The role of central histamine H1- and H2-receptors in hypothermia induced by histamine in the rat.

Histamine administered intraventricularly or into the anterior hypothalamic preoptic region induced dosedependent hypothermia in rats with chronic i.c.v. cannula. This hypothermia was almost totally abolished by both the histamine H1-and H2-receptor antagonists, mepyramine or chloropyramine and metiamide or cimetidine, respectively, given i.c.v. prior to histamine. In behavioural thermoregulation studies histamine considerably diminished the mean duration of dwelling of the rat under the heat lamp. This effect was abolished by histamine H1- but not by H2-receptor antagonists. It is concluded that histamine induces hypothermia by lowering the set point of the hypothalamic thermostat by means of H1-receptors. Histamine H2-receptor blockers antagonized the increase in tail skin temperature after histamine administration, suggesting that H2-receptors are involved in a heat loss mechanism.

Degranulation and decrease in histamine levels of thalamic mast cells coincides with corticosterone secretion induced by compound 48/80

Mast cells (MC) synthesize and secrete numerous powerful mediators such as histamine (HA), serotonin and prostaglandins (PGs), which are known to have significant physiological effects on vascular and neuronal tissues. In the rat brain, H A is located in at least two different cell types: neurons and MC [1]. The quantitative importance of each of these two pools is still controversial. While there is a large body of evidence suggesting that neuronal H A is a neurotransmitter in the central nervous system, the specific functions carried out by HA of the MC present in brain structures remain speculative. Compound 48/80 a standard MC degranulating agent and H A releaser administered intracerebroventricularly (icv) decreased both the number of MC and the H A content of the crude nuclear fraction but not H A of the neuronal fraction [2]. HA is considered to be the hallmark mediator of MC activation. It is present in significant quantities in all MC so far examined and is stored in the cells cytoplasmic granules and released upon cell activation. Other MC mediators such as PGs are not stored but produced and secreted upon appropriate stimulation of the cells. Eicosanoid synthesis originates not only from phospholipid of damaged membranes but may also be the result of receptor-mediated granule exocytosis [3, 4]. The activation of MC granules triggers the arachidonic acid cascades resulting in PGs production and HA release [5]. The purpose of the present experiment was to determine and compare the extent of MC degranulation and changes in H A levels in the thalamus and hypothalamus with changes in the hypothalamicpituitary-adrenocorticol (HPA) activity after central administration of compound 48/80. A possible involvement of PGs induced by compound 48/80 on the HPA activation was also examined.