Effect of Mycoplasma fermentans on brain PGE(2): role of glucocorticoids and their receptors.

OBJECTIVES: Mycoplasmas are a group of eubacteria, which cause various diseases in animals and in humans, and can contribute to diseases produced by other infectious agents, particularly HIV. We have recently reported that intracerebral administration of Mycoplasma fermentans (MF) produces both neuroendocrine and behavioral alterations. Some of these responses were mediated by MF-induced production of prostaglandin E(2 )(PGE(2)). The aim of this study was to examine the role of glucocorticoids (GC) in regulating MF-induced brain prostaglandin production. METHODS: Male rats were injected intracerebroventricularly with various doses of heat-inactivated MF, LPS or IL-1 beta and the following parameters were measured: (1) ex vivo production of hippocampal PGE(2), (2) serum levels of ACTH and corticosterone, and (3) binding capacity of [(3)H]-dexamethasone (DEX) to hippocampal cytosol. RESULTS: MF caused a small increase in hippocampal PGE(2) production, but higher doses failed to produce a further increase. In contrast, the effects of LPS or IL-1 beta on PGE(2) were dose-dependent. Removal of circulating GC by bilateral adrenalectomy significantly enhanced MF-induced brain PGE(2) production. The three immune stimulators increased serum levels of ACTH and corticosterone to the same extent. Finally, MF, but not IL-1 beta increased the specific binding of [(3)H]-DEX to hippocampal cytosol. CONCLUSIONS: Brain PGE(2) induced by MF is regulated by endogenous GC. These hormones have an attenuating effect on PGE(2 )production, probably through an MF-induced increase in GC binding by brain tissue. This mechanism may be important in the pathological effect of MF within the brain of AIDS patients.

The role of brain cytokines in mediating the behavioral and neuroendocrine effects of intracerebral mycoplasma fermentans.

Intracerebral administration of Mycoplasma fermentans (MF), a small microorganism that has been found in the brain of some AIDS patients, induces behavioral and neuroendocrine alterations in rats. To examine the role of tumor necrosis factor-alpha (TNFalpha) and interleukin-1 (IL-1) in mediating these effects we measured MF-induced expression of TNFalpha and IL-1beta mRNA in various brain regions, and the effects of TNFalpha synthesis blockers and IL-1 receptor antagonist (IL-1ra) on MF-induced sickness behavior and adrenocortical activation. Intracerebroventricular (i.c.v.) administration of heat-inactivated MF induced the expression of both TNFalpha and IL-1beta mRNA in the cortex, dorsal hippocampus, amygdala, and hypothalamus. Pre-treatment of rats with either TNFalpha synthesis blockers, pentoxifylline or rolipram, or with IL-1ra did not attenuate MF-induced anorexia, body weight loss, and suppression of social behavior. However, simultaneous administration of both pentoxifylline and IL-1ra markedly attenuated MF-induced anorexia and body weight loss, but had no effect on the suppression of social behavior. Pre-treatment with pentoxifylline, but not with IL-1ra, significantly attenuated MF-induced corticosterone (CS) secretion. Together, these findings indicate that both TNFalpha and IL-1 participate, in a complementary manner, in mediating some of the behavioral effects of MF, whereas only TNFalpha, but not IL-1, is involved in mediating MF-induced adrenocortical activation. We suggest that cytokines within the brain are involved in mediating at least some of the neurobehavioral and neuroendocrine abnormalities that may be produced by MF in AIDS patients.

Characterization of the effect of Mycoplasma fermentans on the hypothalamo-pituitary-adrenal axis.

The mechanisms involved in the activation of the hypothalamus-pituitary-adrenal axis after administration of Mycoplasma fermentans were examined. Male rats were injected intracerebroventricularly (i.c.v.) with heat-inactivated M. fermentas (6 micrograms protein/10 microliters/rat) or vehicle and were killed 2 h later. M. fermentans caused a significant depletion of corticotropin releasing hormone (CRH-41) content in the median eminence (ME), and elevation of serum ACTH and corticosterone (CS) levels, compared to control levels. Pretreatment with dexamethasone (DEX, 40 micrograms/kg) markedly inhibited M. fermentans-induced depletion of ME CRH-41 and the increase in serum ACTH and CS. Injection of the type II corticosteroid receptor antagonist RU-38486, but not the type 1 antagonist RU-28318, enhanced the adrenocortical response and completely abolished the inhibitory effect of DEX following M. fermentans. Injection of the catecholamine neurotoxin 6-hydroxydopamine into the ventral noradrenergic bundle, which significantly depleted hypothalamic norepinephrine content, or i.c.v. injection of the specific alpha 1-adrenergic receptor antagonist prazosin failed to affect the adrenocortical response to M. fermentans. In contrast, these agents markedly inhibited the adrenocortical response following i.c.v. injection of interleukin-1. I.c.v. administration of M. fermentans caused a significant elevation of hypothalamic levels of tumor necrosis factor-alpha (TNF alpha), determined by both bioassay and immunoassay. In rats treated with pentoxifylline, an inhibitor of TNF alpha synthesis, the adrenocortical response to M. fermentans was markedly inhibited. These findings suggest that: (1) M. fermentans-induced activation of the pituitary-adrenal axis, and the inhibitory effect of DEX on this response, are mediated by a reduction of CRH-41 release from the ME. (2) The feedback exerted by glucocorticoids is mediated by type II corticosteroid receptors. (3) In contrast to the adrenocortical response to interleukin-1 beta, the central noradrenergic system does not have an important role in mediating the adrenocortical response to M. fermentans. (4) Hypothalamic TNF alpha production is probably involved in mediating the adrenocortical activation following M. fermentans.

Mycoplasma fermentans activates the hypothalamo-pituitary adrenal axis in the rat.

Intracerebroventricular administration in rats of heat inactivated Mycoplasma fermentans caused a dose- and time-dependent increase in serum adrenocorticotrophin (ACTH) and corticosterone (CS). In rats with complete deafferentation of the mediobasal hypothalamus, which markedly depleted the median eminence CRF-41, the ACTH and CS responses to M. fermentans were completely inhibited. Pretreatment with dexamethasone abolished the adrenocortical response to M. fermentans. In lipopolysaccharide (LPS) unresponsive C3H/HeJ mice LPS failed to induce the adrenocortical response while administration of M. fermentans elicited a normal CS response. These results suggest that: M. fermentans can activate the hypothalamo-pituitary-adrenal axis via a central mechanism which involves hypothalamic ACTH secretagogue(s), and this effect is sensitive to the negative feedback of glucocorticoids. It is possible that the elevated glucocorticoid levels resulting from mycoplasma infection may be involved in the pathogenesis of mycoplasma-associated diseases.

Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens.

In the present study we have characterized the hypothermic effect of the psychoactive cannabinoid HU-210, by investigating its interaction with the endogenous pyrogens, IL-1 and PGE2. We also studied the involvement of the adrenergic system in mediation of this hypothermic effect. Injection of HU-210 directly into the preoptic area caused a dose dependent reduction of rectal temperature from 37 to 32.1 degrees C. Injection of the non-psychoactive analog, HU-211 which does not bind to brain cannabinoid receptor, did not affect body temperature. Injection of the adrenergic agonists, CGP-12177 and clonidine (beta, and alpha adrenergic agonists, respectively) abrogated the hypothermia induced by HU-210. Injection of the adrenergic antagonists, prazosin (alpha 1) and propranolol (beta) enhanced the hypothermic effect of HU-210. Intracerebral administration of IL-1 or PGE2 to rats pretreated with HU-210 caused a transient inhibition of the hypothermia. The ex vivo rate of basal or bacterial endotoxin-induced synthesis of PGE2 by different brain regions, including the preoptic area was not affected by HU-210 administration. These results suggest that the synthetic cannabinoid HU-210 acts in the preoptic area, probably via the brain cannabinoid receptor to induce hypothermia. The hypothermic effect can be antagonized by adrenergic agonists and enhanced by adrenergic antagonists. HU-210 does not interfere with the pyrogenic effect of IL-1 or PGE2.

Characterization of the 2-deoxyglucose effect on the adrenocortical axis.

In the present study we examined the mechanisms involved in the activation of the hypothalamo-pituitary-adrenal (HPA) axis after administration of the glucose analog 2-deoxyglucose (2-DG), which inhibits intracellular glucose use. Adult male rats were injected with either 2-DG (400 mg/kg body wt ip) or vehicle and were killed 60 min later. 2-DG increased serum ACTH and corticosterone (CS) by 3- and 7-fold, respectively, as compared to vehicle-treated rats. Bilateral lesions of the lateral hypothalamic area completely inhibited the 2-DG-induced HPA axis activation. Administration of 2-DG caused a significant depletion in the CRF-41 content of the median eminence (ME). Pretreatment with dexamethasone (80 micrograms/kg body wt ip) inhibited the 2-DG-induced depletion of ME CRF-41 and the increase in serum ACTH and CS. To investigate the role of type I and type II corticosteroid receptors in mediating the feedback effect of endogenous glucocorticoids on the responses to 2-DG, specific type I (RU-28318) or type II (RU-38486) receptor antagonists were injected intracerebroventricularly (icv) (1 microgram/kg body wt). In rats pretreated with these antagonists, the recovery of serum ACTH and CS to basal levels after 2-DG was markedly inhibited. Injection of the serotonin (5-HT) neurotoxin, 5,7-dihydroxy-tryptamine, either into the raphe nuclei or icv, which caused a 50 and 70% depletion of the hypothalamic 5-HT content, respectively, did not affect the HPA axis responses to 2-DG. In contrast, icv injection of ketanserin, a 5-HT2 receptor antagonist, completely inhibited the 2-DG-induced activation of the HPA axis. The results suggest that: 1) the lateral hypothalamic area is involved in the mediation of the HPA axis responses to 2-DG; 2) CRF-41 released from the ME plays a dynamic role in mediating the 2-DG-induced adrenocortical response; 3) the effect of 2-DG is sensitive to inhibition by dexamethasone, and the feedback effect exerted by endogenous glucocorticoids is mediated by both type I and type II corticosteroid receptors; and 4) 5-HT is involved in the activation of the HPA axis after 2-DG via its interactions with 5-HT2 receptors.