Abstract
Neurosteroids are steroids made by brain cells independently of peripheral steroidogenic sources. The biosynthesis of most neurosteroids is mediated by proteins and enzymes similar to those identified in the steroidogenic pathway of adrenal and gonadal cells. Dehydroepiandrosterone (DHEA) is a major neurosteroid identified in the brain. Over the years we have reported that, unlike other neurosteroids, DHEA biosynthesis in rat, bovine, and human brain is mediated by an oxidative stress-mediated mechanism, independent of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) enzyme activity found in the periphery. This alternative pathway is induced by pro-oxidant agents, such as Fe2+ and β-amyloid peptide. Neurosteroids are involved in many aspects of brain function, and as such, are involved in various neuropathologies, including Alzheimer’s disease (AD). AD is a progressive, yet irreversible neurodegenerative disease for which there are limited means for ante-mortem diagnosis. Using brain tissue specimens from control and AD patients, we provided evidence that DHEA is formed in the AD brain by the oxidative stress-mediated metabolism of an unidentified precursor, thus depleting levels of the precursor in the blood stream. We tested for the presence of this DHEA precursor in human serum using a Fe2+-based reaction and determined the amounts of DHEA formed. Fe2+ treatment of the serum resulted in a dramatic increase in DHEA levels in control patients, whereas only a moderate or no increase was observed in AD patients. The DHEA variation after oxidation correlated with the patients’ cognitive and mental status. In this review, we present the cumulative evidence for oxidative stress as a natural regulator of DHEA formation and the use of this concept to develop a blood-based diagnostic tool for neurodegenerative diseases linked to oxidative stress, such as AD.
Highlights
The crucial roles of steroid hormones in the development and function of the central nervous system (CNS) have been well established (Compagnone and Mellon, 1998; Baulieu et al, 1999; Karishma and Herbert, 2002; Suzuki et al, 2004; Wang et al, 2005)
Whereas many steroids originate from peripheral steroidogenic organs, such as adrenals and gonads, recent research has shown that some steroids are synthesized in the nervous system and display beneficial neuroprotective properties, which may be of particular importance in treating diseases in which neurodegeneration is predominant, including age-dependent dementia, stroke, epilepsy, spinal cord injury, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Niemann–Pick type C disease (NP-C)
These results suggested a model for neurosteroid biosynthesis in the CNS
Summary
The crucial roles of steroid hormones in the development and function of the central nervous system (CNS) have been well established (Compagnone and Mellon, 1998; Baulieu et al, 1999; Karishma and Herbert, 2002; Suzuki et al, 2004; Wang et al, 2005). The higher levels of DHEA present in the hypothalamus and hippocampus of the AD brain before FeSO4 treatment suggest that the precursor of the alternative pathway has already been converted to DHEA by endogenous oxidative stress due to the disease process (Brown et al, 2003). A larger sampling is required to validate the results of Brown et al (2003), we speculated that by measuring DHEA levels in the serum and CSF of aging patients, and looking for evidence of alternative pathway activity in these compartments, it may be possible to determine early changes in the levels of oxidative stress in the brain. Such an assay could be used to diagnose AD at a very early stage and to monitor the effect of therapeutic modalities on disease evolution
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