Dehydroepiandrosterone sulphate improves cholestasis-associated fatigue in bile duct ligated rats.

Fatigue is a common debilitating symptom in patients with primary biliary cirrhosis (PBC). The mechanism of fatigue is still poorly understood. However, it has been reported that levels of the steroid dehydroepiandrosterone sulphate (DHEAS) are reduced in plasma of patients with PBC, and substitutive therapy has been suggested to improve fatigue symptoms experienced during the course of this disease. In this study, we tested the effect of DHEAS on whole body fatigue in rats following bile duct ligation (BDL). Fatigue was estimated by the time spent on an electrified grid as a result of falling off a treadmill and by performance of rats on an infrared beam monitor which allows the assessment of travelled distance and stereotypic movement activities. On day 5 after BDL surgery, cholestatic rats exhibited increased whole body fatigue as reflected by significantly increased time spent on the electrified grid, reduced travelled distance and reduced stereotypic movements. Administration of 5 mg kg(-1) of DHEAS to BDL rats for three consecutive days significantly normalized their behaviour. Fatigue scores were also found to be reduced in cirrhotic rats 4 weeks after BDL surgery, and DHEAS treatment for 3 days reduced fatigue scores at this stage. Dehydroepiandrosterone sulphate treatment was sufficient to increase brain levels of DHEAS in the BDL rats in a manner that is significantly and highly correlated with those of plasma DHEAS and brain dehydroepiandrosterone (DHEA). Substitutive therapies with DHEAS or DHEA could represent novel approaches in the management of fatigue due to cholestasis-induced liver failure.

Indomethacin improves locomotor deficit and reduces brain concentrations of neuroinhibitory steroids in rats following portacaval anastomosis.

Hepatic encephalopathy (HE) is a neuropsychiatric complication of both acute and chronic liver failure characterized by progressive neuronal inhibition. Some neurosteroids are potent positive allosteric modulators of the gamma-aminobutyric acid (GABA)-A receptor complex, and 'increased GABAergic tone' has been proposed to explain the neuroinhibition characteristics of HE. Brain levels of the neurosteroids pregnenolone, allopregnanolone and tetrahydrodesoxycorticosterone (THDOC) and the functional status of the GABA-A receptor complex were assessed in rats following portacaval anastomosis (PCA). Effects of indomethacin, an inhibitor of the 3alpha-hydroxysteroid dehydrogenase enzyme involved in neurosteroid synthesis, on PCA rat locomotor activity and brain neurosteroid levels were also assessed. Significant increases of the neurosteroid pregnenolone (2.6-fold), allopregnanolone (1.7-fold) and THDOC (4.7-fold) were observed in brains of PCA rats. Brain levels of these neurosteroids were in the nanomolar range, sufficient to exert positive allosteric modulatory effects at the GABA-A receptor. Indomethacin (0.1-5 mg kg(-1)) ameliorated dose-dependently the locomotor deficit of PCA rats and concomitantly normalized brain levels of allopregnanolone and THDOC. Increased brain levels of neurosteroids with positive allosteric modulatory actions at the neuronal GABA-A receptor offer a cogent explanation for the notion of 'increased GABAergic tone' in HE. Pharmacological approaches using agents that either reduce neurosteroid synthesis or modulate the neurosteroid site on GABA-A receptor could offer new therapeutic tools for the management and treatment of HE.

Neuroactive steroids and fatigue severity in patients with primary biliary cirrhosis and hepatitis C.

Fatigue is one of the most common non-specific symptoms associated with several disease states including liver diseases. Recently, it was reported that levels of progesterone metabolites such as allopregnanolone (3alpha,5alpha-tetrahydroprogesterone; 3alpha,5alpha-THP) and isopregnanolone (3beta,5alpha-THP) were increased in plasma of patients with chronic fatigue syndrome. We hypothesize that THP metabolites might be associated with fatigue commonly observed in chronic liver diseases. We evaluated fatigue scores and plasma levels of five progesterone metabolites in 16 patients with primary biliary cirrhosis (PBC), 12 patients with chronic hepatitis C (CHC) and 11 age-matched controls. The fatigue impact scale (FIS) ratio was significantly increased (P < 0.01) in patients with PBC and CHC compared to controls. Plasma levels of 3alpha,5alpha-THP and pregnanolone (3alpha,5beta-THP) were significantly increased in PBC and CHC patients. The other progesterone metabolites, i.e. 3beta,5alpha-THP, 3beta,5beta-THP and 3alpha,5alpha-tetrahydrodeoxycorticosterone were either undetectable or detected only in some patients. Plasma levels of 3alpha,5alpha-THP and 3alpha,5beta-THP were found to be significantly higher in patients with fatigue (P < 0.05), while those of patients without fatigue were not significantly different from controls. Both 3alpha,5alpha-THP and 3alpha,5beta-THP are positive allosteric modulators of the gamma-aminobutyric acid type A (GABA-A) receptor and readily cross the blood-brain barrier. The present preliminary findings suggest that increased inhibition through GABA-A receptors due to the accumulation of neuroinhibitory steroids may represent an important pathophysiological mechanism of fatigue in chronic liver diseases.

Postnatal secretion of the subcommissural organ of the Meriones shawi: control of serotonin innervation.

The postnatal development of the subcommissural organ (SCO) glycoprotein secretion in form of Reissner's fiber and the putative control of the serotonin innervation upon the SCO activity were examined by immunohistochemistry in the semi-desert rodent, Meriones shawi. Abundant SCO secretory material and numerous serotoninergic fibers reaching the SCO were observed in newborns meriones. An increase of both secretory material and serotonin fibres density inside the SCO was observed during postnatal period and into adulthood. Neurotoxic destruction with 5,7-dihydroxytryptamine of the SCO serotonin input in the adult or the inhibition of serotonin synthesis by para-chlorophenylalanine at different postnatal ages, resulted in a decrease of the intensity of SCO Reissner's fiber immunolabelling suggesting a reduction in the SCO secretory material. This result might reflect either an inhibition of the synthesis or a stimulation of release of secretory material. These data suggest that serotonin innervation could be precociously involved in the regulation of the merione SCO secretion.

Differences in protein expression in the subcommissural organ of normal and lordotic lizards (Agama impalearis).

Lordosis, a skeletal malformation, is characterized by abnormal curvature of the vertebral column. Involvement of the subcommissural organ (SCO) in the correct development of the axial skeleton via the thread-like Reissner's fiber (RF) has been suggested. However, the functional significance of the SCO and RF in these mechanisms remains, to date, little understood. To detect eventual changes in the SCO of reptiles bearing a naturally occurring skeletal malformation, we aimed here at investigating with immunohistochemistry RF glycoprotein and immediate early gene expression in the SCO of normal and lordotic lizards. In normal lizards, RF immunoreactivity was evident in the apical and basal domains of SCO cells. In specimens derived from lordotic animals, RF-immunoreactive material filled all SCO cell portions, and numerous large droplets were observed in the basal part of the organ. Cell nuclei exhibiting immunoreactivity to the protein product of the gene c-fos were evident in basal SCO cells of lordotic animals, whereas Fos immunoreactivity was absent in the SCO of normal lizards. The changes detected in RF immunoreactivity and Fos induction in SCO cells of lordotic animals favor the occurrence of changes in the secretory activity and gene expression of SCO cells. The present data further demonstrate modifications occurring in the SCO secretory material in skeletal malformed vertebrates, and support a relationship of such changes with the malformed state of these animals.

Secretory activity and serotonin innervation of lizard's subcommissural organ.

We investigated immunohistochemically the subcommissural organ (SCO) glycoprotein secretion, its serotoninergic (5-HT) innervation and the possible control of this innervation upon the SCO activity in lizards (Agama impalearis, Saurodactylus mauritanicus and Eumeces algeriensis). Inside the SCO, interspecific differences in the intensity and the distribution of both secretory product and 5-HT nerve fibers were observed. Compared with Agama and Eumeces, the SCO of Saurodactylus displayed intense secretory products and several 5-HT fibers. In Saurodactylus, i.p. injection of parachlorophenylalanine, a potent inhibitor of 5-HT synthesis, produced a marked decrease of SCO secretory product. We report in this study species differences of the lizard SCO secretory activity and its possible physiological control by 5-HT innervation, as previously demonstrated in mammals.

Secretory activity and serotonin innervation of subcommissural organ.

We investigated immunohistochemically the subcommissural organ (SCO) glycoprotein secretion, its serotoninergic (5-HT) innervation and the possible control of this innervation upon the SCO activity in lizards (Agama impalearis, Saurodactylus mauritanicus and Eumeces algeriensis). Inside the SCO, interspecific differences in the intensity and the distribution of both secretary product and 5-HT nerve fibers were observed. Compared with Agama and Eumeces, the SCO of Saurodactylus displayed intense secretory products and several 5-HT fibers. In Saurodactylus, i.p. injection of parachlorophenylalanine, a potent inhibitor of 5-HT synthesis, produced a marked decrease of SCO secretory product. We report in this study species differences of the lizard SCO secretory activity and its possible physiological control by 5-HT innervation, as previously demonstrated in mammals.