ReviewNeuroprotective actions of brain aromatase
Section snippets
Introduction and general considerations
Steroids have long been studied for their acute, chronic and dramatic influences on the anatomy and physiology of the vertebrate brain [185], [3], [103], [131], [144]. The gamut of structural and functional endpoints affected by steroids has broadened far beyond the early paradigms of study which involved sexual behavior and aggression. It was these very studies, however, that identified 17β-estradiol (E2) as an effector of many targets within the central nervous system (CNS). Perhaps more
Brain aromatization and neuroprotection
There is good reason to consider the neuroprotection afforded by many estrogenic precursors as due to their ultimate aromatization to neuroactive estrogens. The aromatization of androgenic substrates within the brain itself continues to provoke tantalizing questions about the neuroendocrine nature of the vertebrate brain. Recently, a considerable body of evidence strongly supports a neuroprotective role for encephalic estrogen synthesis particularly following brain damage resulting from
Effects on secondary degeneration
There is general agreement that the manner in which upregulated aromatase affects neurodegeneration is via the inhibition of secondary, apoptotic damage. More specifically, TUNEL labeling in the songbird suggested that treatment with the aromatase inhibitor fadrozole increased, and concomitant E2 administration decreased, the number of cells undergoing apoptosis 72 h post primary insult [268], [215]. Interestingly, there was no difference in the degenerating cells labeled by Fluoro-Jade-B, a
Molecular mechanisms of glial aromatase expression
Since the neuroprotective effects of brain aromatase after injury appear dependent upon its expression in reactive glia surrounding the damaged area [13], discovering the mechanism by which aromatase is upregulated after injury is of critical importance. Currently, most of our information about the regulation of aromatase transcription comes from data in human cells or in non-human primates [237]. In humans and other mammals, aromatase transcription in the ovary is initiated by steroidogenic
How is induced astroglial aromatase neuroprotective?
While the mechanisms of aromatase neuroprotection are most likely mediated by local estrogen synthesis, it is important to note that several different isoforms of estrogens can result from aromatization (estradiol, estrone, 2-OH-estradiol, and the 17alpha and beta stereoisomers) many of which have demonstrated neuroprotective properties [25], [67], [153], [250]. Additionally, brain aromatization may also affect the local concentrations of C19 and C21 steroids (androgens and progestins) which
Is constitutive aromatase neuroprotective?
There remains little doubt that injury-induced aromatization in astrocytes and perhaps radial glia, is neuroprotective in mammals and birds. A quick examination of constitutive brain aromatase expression across vertebrate phyla, however, exposes two interesting patterns. Firstly, constitutive neural aromatase expression is extremely high in teleost fish, high in passerine songbirds, and relatively low in mammals. Although it is difficult to directly compare aromatase activities across species,
Summary and future considerations
The neuroprotective actions of brain aromatase are relatively well studied in birds and mammals. Aromatase is induced in glia (radial glia and astrocytes) around the site of brain damage. This induction is quite rapid with increases in aromatase detectable 2 h following mechanical damage in the songbird [269]. In rodents and songbirds, locally produced E2 via astrocytic aromatization dramatically decreases apoptotic secondary damage. The inhibitory effect of E2 on apoptosis has been well
Acknowledgements
The Saldanha laboratory is supported by NIH NS 042767. We thank all members of our laboratory and our collaborators for their assistance in conducting several of the experiments described here.
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2020, General and Comparative EndocrinologyCitation Excerpt :Thus, blocking or decreasing this secondary wave of degeneration has become a target for therapeutics. Steroid hormones, especially estrogens are neuroprotective following TBI by decreasing the secondary wave of degeneration (Acaz-Fonseca et al., 2014; Azcoitia et al., 2001; Dubal et al., 1999; Pedersen et al., 2018; Saldanha et al., 2009). Steroid expression seems to be confined to neuronal populations in the intact homeotherm brain during development and adulthood (Almey et al., 2015; Wynne et al., 2008a), however following injury, non-neuronal cells (microglia, astrocytes/astroglia, and radial glia) represent an additional location for steroid hormone activity and receptor expression (Duncan et al., 2013a,b; Garcia-Segura et al., 2001; Klores et al., 2016; Melcangi et al., 2008; Peterson et al., 2007; Saldanha et al., 2005; Wynne and Saldanha, 2004).
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