GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy.

Hepatic encephalopathy (HE) is one of the primary complications of liver cirrhosis. Current treatments for HE, mainly directed to reduction of ammonia levels, are not effective enough because they cannot completely eliminate hyperammonemia and inflammation, which induce the neurological alterations. Studies in animal models show that overactivation of GABAA receptors is involved in cognitive and motor impairment in HE and that reducing this activation restores these functions. We have developed a new compound, GR3027, that selectively antagonizes the enhanced activation of GABAA receptors by neurosteroids such as allopregnanolone and 3α,21-dihydroxy-5α-pregnan-20-one (THDOC). This work aimed to assess whether GR3027 improves motor incoordination, spatial learning, and circadian rhythms of activity in rats with HE. GR3027 was administered subcutaneously to two main models of HE: rats with chronic hyperammonemia due to ammonia feeding and rats with portacaval shunts (PCS). Motor coordination was assessed in beam walking and spatial learning and memory in the Morris water maze and the radial maze. Circadian rhythms of ambulatory and vertical activity were also assessed. In both hyperammonemic and PCS rats, GR3027 restores motor coordination, spatial memory in the Morris water maze, and spatial learning in the radial maze. GR3027 also partially restores circadian rhythms of ambulatory and vertical activity in PCS rats. GR3027 is a novel approach to treatment of HE that would normalize neurological functions altered because of enhanced GABAergic tone, affording more complete normalization of cognitive and motor function than current treatments for HE.

Hormonal changes associated with Danazol therapy.

During a 6-month course of treatment of endometriosis with Danazol, a synthetic derivative of 17alpha-ethinyl testosterone, the following hormonal changes were found. Plasma LH remained essentially unchanged but FSH concentration was consistently in the low normal range. Plasma estradiol, especially after the fourth week of therapy, dropped to levels that did not exceed 30 pg/ml throughout the 6-month period of therapy. Plasma progesterone concentration was consistent with follicular phase levels. In the months after discontinuation of Danazol, all hormone parameters were strongly suggestive of normal ovulatory cycles. Danazol did not displace estradiol bound by endometrial cytosol.

Prevention by polyhydroxysteroids and saponins of Asterina pectinifera of the desquamation of stratum corneum cells.

Two polyhydroxysteroids and three steroidal saponins (pectiniosides A, B and C) were isolated as bioactive substances from Asterina pectinifera. These compounds inhibited the release of guinea-pig skin stratum corneum cells by 48-67% (control, 0%) at 2 mg/ml. It is suggested that the bioactivity of these compounds is connected with the remedial and preventive effects of an aqueous extract of A. pectinifera on rough human skin.

7-Hydroxylated epiandrosterone (7-OH-EPIA) reduces ischaemia-induced neuronal damage both in vivo and in vitro.

Recent evidence suggests that steroids such as oestradiol reduce ischaemia-induced neurodegeneration in both in vitro and in vivo models. A cytochrome P450 enzyme termed cyp7b that 7-hydroxylates many steroids is expressed at high levels in brain, although the role of 7-hydroxylated steroids is unknown. We have tested the hypothesis that the steroid-mediated neuroprotection is dependent on the formation of 7-hydroxy metabolites. Organotypic hippocampal slice cultures were prepared from Wistar rat pups and maintained in vitro for 14 days. Cultures were then exposed to 3 h hypoxia and neuronal damage assessed 24 h later using propidium iodide fluorescence as a marker of cell damage. Neurodegeneration occurred primarily in the CA1 pyramidal cell layer. The steroids oestradiol, dehydroepiandrosterone and epiandrosterone (EPIA) were devoid of neuroprotective efficacy when present at 100 nM pre-, during and post-hypoxia. The 7-hydroxy metabolites of EPIA, 7alpha-OH-EPIA and 7beta-OH-EPIA significantly reduced neurotoxicity at 100 nM and 10 nM. 7beta-OH-EPIA was also neuroprotective in two in vivo rat models of cerebral ischaemia: 0.1 mg/kg 7beta-OH-EPIA significantly reduced hippocampal cell loss in a model of global forebrain ischaemia, whereas 0.03 mg/kg was neuroprotective in a model of focal ischaemia even when administration was delayed until 6 h after the onset of ischaemia. Taken together, these data demonstrate that 7-hydroxylation of steroids confers neuroprotective efficacy, and that 7beta-OH-epiandrosterone represents a novel class of neuroprotective compounds with potential for use in acute neurodegenerative diseases.