Neurosteroids in learning and memory processes.
ABSTRACT The discovery that neurosteroids could be synthesized de novo in the brain independent from the periphery and display neuronal actions led to great enthusiasm for the study of their physiological role. Pharmacological studies suggest that neurosteroids may be involved in several physiological processes, such as learning and memory. This chapter summarizes the effects of the administration of neurosteroids on learning and memory capabilities in rodents and in models of amnesia. We address the central mechanisms involved in mediating the modulation of learning and memory processes by neurosteroids. In this regard, the neurosteroid-modulated neurotransmitter systems, such as gamma-aminobutyric acid type A, N-methyl-D-aspartate, and cholinergic and sigma opioid systems, appear to be potential targets for the rapid memory alteration actions of neurosteroids. Moreover, given that some neurosteroids affect neuronal plasticity, this neuronal change could be involved in the long-term modulation of learning and memory processes. To understand the role of endogeneous neurosteroids in learning and memory processes, we present some physiological studies in rodents and humans. However, the latter do not successfully prove a role of endogenous neurosteroids in age-related memory impairments. Finally, we discuss the relative implication of a given neurosteroid vs its metabolites. For this question, a new approach using the quantitative determination of traces of neurosteroids by mass spectrometry seems to have potential for examining the role of each neurosteroid in discrete brain areas in learning and memory alterations, as observed during aging.
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ABSTRACT: Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated. The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.Science 01/2014; 343(6166):94-8. · 31.20 Impact Factor
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ABSTRACT: Oxysterols and neurosteroids are important signaling molecules produced by monooxygenases of the cytochrome P450 family that realize their effect through the nuclear receptors. CYP7B1 catalyzes the 6- or 7-hydroxylation of both steroids and oxysterols and thus is involved in metabolism of neurosteroids and bile acid synthesis, respectively. The dual physiological role of CYP7B1 is evidenced from different diseases, liver failure and progressive neuropathy, caused by enzyme malfunction. Here we present biochemical characterization of CYP7B1 at the molecular level to understand substrate specificity and susceptibility to azole drugs. Based on our experiments with purified enzyme substrate, the requirements for CYP7B1 hydroxylation of steroid molecules are as follows: C5 hydrogen in the α-configuration (or double bond at C5), a polar group at C17, a hydroxyl group at C3, and the absence of the hydroxyl-group at C20-C24 in the C27-sterol side chain. 21-hydroxypregnenolone was identified as a new substrate, and overall low activity toward pregnanes could be related to the increased potency of 7-hydroxyderivatives produced by CYP7B1. Metabolic conversion (deactivation) of oxysterols by CYP7B1 in a reconstituted system proceeds via two sequential hydroxylations. Two mutations that are found in patients with diseases, Gly57Arg and Phe216Ser, result in apo-P450 (devoid of heme) protein formation. Our CYP7B1 homology model provides a rationale for understanding clinical mutations and relatively broad substrate specificity for steroid hydroxylase. This article is protected by copyright. All rights reserved.FEBS Journal 02/2014; · 4.25 Impact Factor
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ABSTRACT: New research findings in the field of neuroactive steroids strongly suggest that to understand their role in physiopathology, it is essential to accurately measure their tissue levels. Through his broad chemical expertise and extensive knowledge of steroids, Dr. Robert H. Purdy pioneered structure-activity relationship studies on these compounds and developed innovative detection assays that are essential to assess their function in biological tissues. The goal of the present paper is to point out the specific contributions of Dr. Purdy and his collaborators to the current knowledge on the role of neuroactive steroids in the modulation of memory and alcohol- and stress-related effects with particular emphasis on the detection assays he developed to assess their endogenous levels. Reviewed here are the major results as well as the original and valuable methodological strategies issued by the long-term collaboration between Dr Purdy and many scientists worldwide on the investigation of the structure-activity relationship of neuroactive steroids. Altogether, the data presented herein put forward the original notion that knowledge of the chemical structure of steroids is essential for their detection and the understanding of their role in physiological and pathological conditions, including the stress response. The current challenge is to identify and quantify using appropriate methods neuroactive steroids in the context of both animal and clinical studies in order to reveal how their levels change under physiological and disease states. Dr. Purdy passed away in September 2012, but scientists all over the world will always be grateful for his pioneering work on steroid chemistry and for his great enthusiasm in research.Psychopharmacology 04/2014; · 4.06 Impact Factor