Preclinical development of neurosteroids as neuroprotective agents for the treatment of neurodegenerative diseases.

Recent literature has emphasized the unique role that the neurosteroid subclass of steroids, which includes dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), play in the developing and adult central nervous system (CNS). Both DHEA and DHEAS are found in abundance in the CNS (Majewska, 1995), and both can be synthesized and metabolized in the brain of many species (Baulieu, 1981, 1998; Corpéchot et al., 1981, 1983; Zwain and Yen, 1999). DHEA and DHEAS have been implicated as potential signaling molecules for neocortical organization during neuronal development, suggesting that they have trophic factor-like activity (neurotrophic or neurotropic) or can interact with various neurotransmitter systems to promote neuronal remodeling (Compagnone and Mellon, 1998; Mao and Barger, 1998). Consistent with a neurotrophic role for these steroids, studies have shown that DHEAS protects certain neuronal populations against neurotoxic insults inflicted by the excitatory amino acid glutamate (Kimonides et al., 1998; Mao and Barger, 1998). This finding suggests that DHEAS may be useful in treating neurodegenerative diseases in which excitotoxicity is believed to be the underlying cause or a major contributor to cell death. Moreover, because DHEA and DHEAS are multifunctional and exhibit a variety of properties in the CNS, including memory consolidation, neuroprotection, and reduction of neurodegeneration (Majewska, 1992, 1995; Lapchak et al., 2000), their potential therapeutic benefits may be extended to include the treatment of other neurodegenerative diseases not directly linked to excitotoxicity.