Chronic neuroinflammation contributes to neuropathy and is implicated in a number of serious health conditions such as Stroke, Parkinson's and Alzheimer's disease. Emerging evidence strongly supports an anti-inflammatory role for circulating estrogens (E) since removal and replacement of this steroid dramatically exacerbates and mitigates several indices of inflammation respectively. Indeed, E-administration decreases the expression and secretion of several pro-inflammatory cytokines including IL1, IL6 and TNF?. The vertebrate brain responds to mechanical perturbation or endotoxin with a rapid increase in cytokine expression in microglia and aromatase (E- synthase) expression in reactive astrocytes. Importantly, microglial cytokine induction occurs prior to astrocytic aromatase expression suggesting that cytokines may induce the expression of aromatase in reactive glia. Given the well-studied anti-inflammatory role of peripheral E, we propose that neural E, via glial aromatization, may serve as a rapidly induced and potent anti-inflammatory signal in the vertebrate brain. More specifically, we hypothesize that cytokines rapidly induce sustained glial aromatase expression and consequent E synthesis, which in turn, causes a decrease in cytokines. This down-regulation prevents chronic exposure of neural tissue to the deleterious effects of prolonged cytokine secretion. To elucidate and hone this model we will use a molecular approach and behavioral assays to test the role of specific pro-inflammatory cytokines in the induction of aromatase transcription following central or peripheral endotoxin administration. Next, using a pharmacological inhibitor of aromatase, we will test the role of aromatization in the mitigation of cytokine expression and sickness behavior following central endotoxin administration. Taken together these experiments will explore an exciting new role for pro-inflammatory cytokines in the induction of encephalic, glial aromatization and further, a mechanism whereby cytokine activity is curtailed by neural E-provision. These data are necessary for the development of therapies that target and prevent inflammatory processes, thereby reducing the severity of neurodegenerative disease.
Chronic inflammation may contribute to devastating neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, Huntington's chorea and Stroke. Prolonged exposure to inflammatory secretions such as cytokines can result in autophagy and the destruction of important and necessary cells, tissues and organs including the brain. Preventing chronic inflammation may be one strategy towards mitigating neural degeneration and promoting the preservation of neural circuits. Notably, several peripheral hormones, including the estrogens (E) are potent anti-inflammatory agents with established roles in the dampening of cytokine secretion and other inflammatory events. This proposal will explore an exciting, novel mechanism of E-provision directly within the brain. Specifically, while the up-regulation of aromatase (E-synthase) in reactive astrocytes following brain damage and/or the exposure to inflammagens is well established, what signals responsible for the initiation of aromatase transcription is completely unknown. Further, the physiological consequences of glial-derived E are only beginning to be revealed. We propose that pro- inflammatory cytokines may initiate aromatase expression and this induction is necessary to quell prolonged cytokine expression and sickness behavior. This reduction in the chronic exposure of brain tissue to cytokines may prevent degeneration and/or other deleterious effects of sustained neuroinflammation.
| Bailey, David J; Makeyeva, Yekaterina V; Paitel, Elizabeth R et al. (2017) Hippocampal Aromatization Modulates Spatial Memory and Characteristics of the Synaptic Membrane in the Male Zebra Finch. Endocrinology 158:852-859 |
| Mehos, C J; Nelson, L H; Saldanha, C J (2016) A Quantification of the Injury-Induced Changes in Central Aromatase, Oestrogenic Milieu and Steroid Receptor Expression in the Zebra Finch. J Neuroendocrinol 28:12348 |
| Bailey, David J; Saldanha, Colin J (2015) The importance of neural aromatization in the acquisition, recall, and integration of song and spatial memories in passerines. Horm Behav 74:116-24 |
