Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the γ-amino-butyric type A (GABAA) receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases. Neuroactive steroids regulate many physiological functions such as stress response, puberty, ovarian cycle, pregnancy and reward. Their levels are altered in several neuropsychiatric and neurologic diseases and both preclinical and clinical studies emphasise a therapeutic potential of neuroactive steroids for these diseases, whereby symptomatology ameliorates upon restoration of neuroactive steroid concentrations. However, direct administration of neuroactive steroids has several challenges, including pharmacokinetics, low bioavailability, addiction potential, safety and tolerability that limit its therapeutic use. Therefore, modulation of neurosteroidogenesis to restore the altered endogenous neuroactive steroid tone may represent a better therapeutic approach. This review summarizes recent approaches that target the neuroactive steroid biosynthetic pathway at different levels in order to promote neurosteroidogenesis. These include modulation of neurosteroidogenesis through ligands of the translocator protein 18 kDa (TSPO), and the pregnane xenobiotic receptor (PXR), as well as targeting of specific neurosteroidogenic enzymes like 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) or P450 side chain cleavage (P450scc). Enhanced neurosteroidogenesis through these targets may be beneficial for neurodegenerative diseases such as Alzheimer's disease and age-related dementia, but also for neuropsychiatric diseases, including alcohol use disorders.

A novel L-3-hydroxyacyl-CoA dehydrogenase from human brain has been cloned, expressed, purified, and characterized. This enzyme is a homotetramer with a molecular mass of 108 kDa. Its subunit consists of 261 amino acid residues and has structural features characteristic of short chain dehydrogenases. It was found that the amino acid sequence of this human brain enzyme is identical to that of an endoplasmic reticulum amyloid ␤-peptide-binding protein (ERAB), which mediates neurotoxicity in Alzheimer's disease (Yan, S. D., Fu, J., Soto, C., Chen, X., Zhu, H., Al-Mohanna, F., Collison, K., Zhu, A., Stern, E., Saido, T., Tohyama, M., Ogawa, S., Roher, A., and Stern, D. (1997) Nature 389, 689 -695). The purification of human brain short chain L-3-hydroxyacyl-CoA dehydrogenase made it possible to characterize the structural and catalytic properties of ERAB. This NAD ؉ -dependent dehydrogenase catalyzes the reversible oxidation of L-3-hydroxyacyl-CoAs to form 3-ketoacyl-CoAs, but it does not act on the D-isomers. The catalytic rate constant of the purified enzyme was estimated to be 37 s ؊1 with apparent K m values of 89 and 20 M for acetoacetyl-CoA and NADH, respectively. The activity ratio of this enzyme for substrates with chain lengths of C 4 , C 8 , and C 16 was ϳ1:2:2. The human short chain L-3-hydroxyacyl-CoA dehydrogenase gene is organized into six exons and five introns and maps to chromosome Xp11.2. The amino-terminal NAD-binding region of the dehydrogenase is encoded by the first three exons, whereas the other exons code for the carboxyl-terminal substratebinding region harboring putative catalytic residues. The results of this study lead to the conclusion that ERAB involved in neuronal dysfunction is encoded by the human short chain L-3-hydroxyacyl-CoA dehydrogenase gene.L-3-Hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35) catalyzes the third step of the fatty acid ␤-oxidation pathway: L-3-hydroxyacyl-CoA ϩ NAD ϩ i 3-ketoacyl-CoA ϩ NADH ϩ H ϩ (1). This reaction is known to be catalyzed by mitochondrial monofunctional L-3-hydroxyacyl-CoA dehydrogenase and by prokaryotic and eukaryotic multifunctional ␤-oxidation enzymes that possess an L-3-hydroxyacyl-CoA dehydrogenase functional domain (2, 3). The catalytic residue of this kind of dehydrogenase was recently identified to be a conserved histidine (4), and a conserved glutamate residue is also required for high catalytic efficiency (5). The catalytic residue of L-3-hydroxyacyl-CoA dehydrogenase was proposed to interact with the conserved glutamate, and this electrostatic interaction seemed to be strengthened by the binding of substrate (5). However, we were surprised to see that a catalytic His-Glu pair is not present in the newly isolated bovine liver type II dehydrogenase (6, 7), which is not homologous to any of the known L-3-hydroxyacylCoA dehydrogenases. More interestingly, it was reported that this new type of L-3-hydroxyacyl-CoA dehydrogenase was not found in human liver by either Northern blot or immunoblot analysis (6, 7). As a result, several important q...

Human brain short chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) was found to catalyze the oxidation of 17␤-estradiol and dihydroandrosterone as well as alcohols. Mitochondria have been demonstrated to be the proper location of this NAD ؉ -dependent dehydrogenase in cells, although its primary structure is identical to an amyloid ␤-peptide binding protein reportedly associated with the endoplasmic reticulum (ERAB). This fatty acid ␤-oxidation enzyme was identified as a novel 17␤-hydroxysteroid dehydrogenase responsible for the inactivation of sex steroid hormones. The catalytic rate constant of the purified enzyme was estimated to be 0.66 min ؊1 with apparent K m values of 43 and 50 M for 17␤-estradiol and NAD ؉ , respectively. The catalytic efficiency of this enzyme for the oxidation of 17␤-estradiol was comparable with that of peroxisomal 17␤-hydroxysteroid dehydrogenase type 4. As a result, the human SCHAD gene product, a single-domain multifunctional enzyme, appears to function in two different pathways of lipid metabolism. Because the catalytic functions of human brain short chain L-3-hydroxyacyl-CoA dehydrogenase could weaken the protective effects of estrogen and generate aldehydes in neurons, it is proposed that a high concentration of this enzyme in brain is a potential risk factor for Alzheimer's disease.

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17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10) is encoded by the HSD17B10 gene mapping at Xp11.2. This homotetrameric mitochondrial multifunctional enzyme catalyzes the oxidation of neuroactive steroids and the degradation of isoleucine. This enzyme is capable of binding to other peptides, such as estrogen receptor α, amyloid-β, and tRNA methyltransferase 10C. Missense mutations of the HSD17B10 gene result in 17β-HSD10 deficiency, an infantile neurodegeneration characterized by progressive psychomotor regression and alteration of mitochondria morphology. 17β-HSD10 exhibits only a negligible alcohol dehydrogenase activity, and is not localized in the endoplasmic reticulum or plasma membrane. Its alternate name - Aβ binding alcohol dehydrogenase (ABAD) - is a misnomer predicated on the mistaken belief that this enzyme is an alcohol dehydrogenase. Misconceptions about the localization and function of 17β-HSD10 abound. 17β-HSD10's proven location and function must be accurately identified to properly assess this enzyme's important role in brain metabolism, especially the metabolism of allopregnanolone. The brains of individuals with Alzheimer's disease (AD) and of animals in an AD mouse model exhibit abnormally elevated levels of 17β-HSD10. Abnormal expression, as well as mutations of the HSD17B10 gene leads to impairment of the structure, function, and dynamics of mitochondria. This may underlie the pathogenesis of the synaptic and neuronal deficiency exhibited in 17β-HSD10 related diseases, including 17β-HSD10 deficiency and AD. Restoration of steroid homeostasis could be achieved by the supplementation of neuroactive steroids with a proper dosing and treatment regimen or by the adjustment of 17β-HSD10 activity to protect neurons. The discovery of this enzyme's true function has opened a new therapeutic avenue for treating AD.