Neurosteroids

Steroid Hormones and Neurosteroids. Steroids (qv) can affect neuroendocrine function, stress responses, and behavioral sexual dimorphism (78,79) (see Steroids). Mineralocorticoid, glucocorticoid, androgen, estrogen, and progesterone receptors are localized in the brain and spinal cord. In addition to genomic actions, the neurosteroid can act more acutely to modulate the actions of other receptors or ion channels (80). Pregnenolone [145-13-17, ( ) dehydroepiandosterone [53-43-0] C H2 02 (319) are excitatory neurosteroids found in rat brain, independent of adrenal... 

Neurosteroids prolong the mean open time of recombinant GABAa receptor channels. Whereas, at least in recombinant systems, the identity of the a and (3 subunits has little or no effect on neurosteroid action, substitution of the y subunit by a 8 subunit suppresses the GABA-modulatory activity of the neurosteroids. 

Mice lacking the 8 subunit, which is mainly expressed in cerebellum and thalamus, display an attenuation of ssatrighting reflex time following the administration of the neurosteroids, alphaxalone and pregnanolone, while the responses to propofol, etomindate, ketamine and the benzodiazepine midazolam were unaffected. This demonstrates the role of GABAa receptors containing the 8 subunit for neurosteroid action. 

Neurosteroids are neuroactive steroids, which are synthesized in the brain. Neurosteroids can bind to and modulate the activity of y-aminobuty tie acidA(GABA A) receptors. 

CYP7A1 catalyzes the 7a-hydroxylation of cholesterol, the first and rate limiting step of bile acid synthesis. This is also the principal way to eliminate cholesterol. CYP7B1 is primarily expressed in brain and catalyzes the synthesis of various neurosteroids and also the 7a-hydroxylation of oxysterols. 

Neurosteroids Progesterone, dexamethasone, dehydroepiandrosterone Study findings have been negative. 

Wang JM, Johnston PB, Ball BG, Brinton RD. The neurosteroid allopregnano-lone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J Neurosci 2005 25 4706-18. 

Neurosteroids differ from nearly all the other transmitters and mediators in that they are lipid-soluble and can easily cross the blood-brain barrier. Thus it is necessary to distinguish those steroids that are produced in the brain from those that find their way there from the circulation after being released from the adrenal cortex or gonads. There are many natural and synthetic steroids that have some effect on neuronal function and can be considered neuroactive but few are actually produced in the brain to act on neurons, i.e. the true neurosteroids. 

The neurosteroids of most interest are DHEA, PREG, PREGS, PROG and 3a5aThPROG. 

These observations, while implicating steroids in brain function and behaviour, cannot be taken as a reliable indicator of their actual effect on neuronal function. Nevertheless, some neurosteroids produce CNS depression with a rapid inhibition of neuronal excitability and one progesterone derivative, alphaxalone (3a-hydroxy-5a pregnane-11, 20 dione, see Fig. 13.5) has been used effectively as an intravenous anaesthetic in humans. 

With so many different neurosteroids with differing and even opposing neuronal effects, much will depend on their relative concentrations at any time and any evaluation of their function must take this into consideration. Hopefully the synthesis and use of appropriate antagonists will throw more light on the physiological role of steroids in the CNS and facilitate the development and clinical use of new neuroactive steroids (see Gasior et al. 1999). 

Baulieu, EE (1997) Neurosteroids of the nervous system, by the nervous system, for the nervous system. Recent Prog. Hormone Res. 52 1-32. 

Shingai, R, Sutherland, ML and Barnard, EA (1991) Effects of subunit types of the cloned GABAa receptor on the response to a neurosteroid. Eur. J. Pharmacol. 206 77-80. 

Do Rego, JL, Mensah-Nyagan, AG, Feuilloley, M, Ferrara, P, Pelletier, G and Vaudry, H (1998) The endozepine triakontatetraneuropeptide diazepam-binding inhibitor [17-50] stimulates neurosteroid biosynthesis in the frog hypothalamus. Neuroscience 83 555-570. 

Reddy, DS and Kulkarni, SK (1998) The role of GABA-A and mitochondrial diazepam-binding inhibitor receptors on the effects of neurosteroids on food intake in mice. Psychopharmacology 137 391-100. 

Mellon, S. H. Griffin, L. D. (2002). Neurosteroids biochemistry and clinical significance. Trends Endocrinol. Metab. 13, 35 43. 

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