Neurosteroid synthesis

Neurosteroid synthesis by cytochrome p450-contain-ing systems localized in the rat brain hippocampal neurons N-methyl-D-aspartate and calcium-dependent synthesis. Endocrinology 142 3578-3589. 

Jung-Testas 1, Do Thi A, Koenig H, Desamaud F, Shazand K, Schumacher M, Baulieu EE (1999) Progesterone as a neurosteroid synthesis and actions in rat gjial cells. J Steroid Biochem Mol Biol 69 97-107... 

Fig. 9.1 Lipid systems affected in CNS disorders (shaded) and injuries (clear). Neurosteroid synthesis in the brain is affected in various brain disorders and injuries and treatment with neurosteroids (pregnenolone, dehydroepiandrosterone and allopregnanolone) showed positive trend in these brain pathologies (Fig. 9.3)...

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. 

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). 

Rose KA, Stapleton G, Dott K, Kieny MP, Best R, et al. 1997. Cyp7b, a novel brain cytochrome P450, catalyzes the synthesis of neurosteroids 7alpha-hydroxydehydroepian-drosterone and 7alpha-hydroxypregnenolone. Proc Natl Acad Sd USA 94 4925-4930. 

The primary function of the pBz receptor is in the regulation of cholesterol uptake and the synthesis of neurosteroids. The latter compounds have an affinity for the GABA-A receptors which provide an indirect coupling between the pBz and the GABA receptors in the brain. 

Maayan, R., Fisch, B., Galdor, M., Kaplan, B., Shinnar, N., Kinor, N., Zeldich, E., Valevski, A., and Weizman, A. (2004). Influence of 17beta-estradiol on the synthesis of reduced neurosteroids in the brain [in vivo) and in glioma cells (in vitro) Possible relevance to mental disorders in women. Brain Res. 1020, 167-172. 

Activation of PTBRs in the brain in liver failure results in increased synthesis of a novel class of compounds known as neurosteroids that are synthesized in the brain mainly by astrocytes independent of peripheral steroidal sources (adrenals and gonads). Neurosteroids bind and modulate different types of neural receptors effects on the GABA-A receptor complex are the most extensively studied. For example, the neurosteroid tetrahydroprogesterone (allopregnanolone), and tetrahydrodeoxy-corticosterone (THDOC) are potent positive allosteric modulators of the GABA-A receptor complex (Fig. 9.7). As a consequence, neurosteroids stimulate inhibitory neurotransmission in the CNS, and it has been suggested that neuroinhibitory... 

Fig. 9.7 (a) Activation of the astrocytic mitochondrial PTBR results in the synthesis of neurosteroids such as allopregnanolone with potent agonist actions at the GABA-A receptor complex, (b) Allopregnanolone levels are increased in autopsied brain tissue from cirrhotic patients who died in hepatic coma (HE) but not in non-encephalopathic cirrhotic patients (LD), or in a patient who died in uremic coma (UC). Modified from Ahboucha et al., 2005)... 

Scheme 8.10 Removal of a formyl group in the total synthesis of a neurosteroid analog.

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