Astrocytic aromatization and consequent increases in estradiol are neuroprotective in the injured brain. In zebra finches, cyclooxygenase-activity is necessary for injury-induced aromatase expression, and increased central estradiol lowers neuroinflammation. The mechanisms underlying these influences are unknown. Here, we document injury-induced, cyclooxygenase-dependent increases in glial aromatase expression and replicate previous work in our lab showing increases in central prostaglandin E2 and estradiol following brain damage. Further, we describe injury-dependent changes in E-prostanoid and estrogen receptor expression and reveal the necessity of E-prostanoid and estrogen receptors in the injury-dependent, reciprocal interactions of neuroinflammatory and neurosteroidogenic pathways.
Adult male and female birds were shams or received bilateral injections of the appropriate drug or vehicle into contralateral telencephalic lobes.
Injuries sustained in the presence of indomethacin (a cyclooxygenase inhibitor) had fewer aromatase-expressing reactive astrocytes relative to injuries injected with vehicle suggesting that cyclooxygenase activity is necessary for the induction of glial aromatase around the site of damage. Injured hemispheres had higher prostaglandin E2 and estradiol content relative to shams. Importantly, injured hemispheres injected with E-prostanoid- or estrogen receptor-antagonists showed elevated prostaglandin E2 and estradiol, respectively, but lower prostaglandin E2 or estradiol-dependent downstream activity (protein kinase A or phosphoinositide-3-kinase mRNA) suggesting that receptor antagonism did not affect injury-induced prostaglandin E2 or estradiol, but inhibited the effects of these ligands. Antagonism of E-prostanoid receptors 3 or 4 prevented injury-induced increases in neural estradiol in males and females, respectively, albeit this apparent sex-difference needs to be tested more stringently. Further, estrogen receptor-α, but not estrogen receptor-β antagonism, exaggerated neural prostaglandin E2 levels relative to the contralateral lobe in both sexes.
These data suggest injury-induced, sex-specific prostaglandin E2-dependent estradiol synthesis, and estrogen receptor-α dependent decreases in neuroinflammation in the vertebrate brain.
Foy MR, Henderson VW, Berger TW, Thompson RF. Estrogen and neural plasticity. Curr Dir Psychol Sci. 2000;9:148–52. CrossRef
Sohrabji F, Welsh C, Reddy D. Sex differences in neurological diseases. 2015.
Pike CJ, Carroll JC, Rosario ER, Barron A. Protective actions of sex steroid hormones in Alzheimer’ s disease. Front Neuroendocrinol. 2010;30:239–58. CrossRef
Garcia-Segura LM, Azcoitia I, DonCarlos LL. Neuroprotection by estradiol. 2001.
Peterson RS, Saldanha CJ, Schlinger BA. Rapid upregulation of aromatase mRNA and protein following neural injury in the zebra finch (Taeniopygia guttata). J Neuroendocrinol. 2001;13:317–23. https://doi.org/10.1046/j.1365-2826.2001.00647.x. CrossRefPubMed
Rau SW, Dubal DB, Böttner M, Gerhold LM, Wise PM, Bottner M, et al. Estradiol attenuates programmed cell death after stroke-like injury. J Neurosci. 2003;23:11420–6. PubMed
Saldanha CJ, Burstein SR, Duncan K A. Induced synthesis of oestrogens by glia in the songbird brain.: EBSCOhost J Neuroendocrinol. 2013;25:1032–1038.
Mehos CJ, Nelson LH, Saldanha CJ. A quantification of the injury-induced changes in central aromatase, estrogenic milieu and steroid receptor expression in the zebra finch. J Neuroendocrinol. 2015;8(2):12348. doi: 10.1111/jne.12348.
Pedersen AL, Brownrout JL, Saldanha CJ. Central administration of indomethacin mitigates the injury-induced upregulation of aromatase expression and estradiol content in the zebra finch brain. Endocrinology. 2017; doi: 10.1210/en.2017-00346.
Subbaramaiah K, Howe LR, Bhardwaj P, Du B, Gravaghi C, Yantiss RK, et al. Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland 3539. Cancer PrevRes(Phila). 2011;4:329–46.
Liu N-J, Chakrabarti S, Schnell S, Wessendorf M, Gintzler AR. Spinal synthesis of estrogen and concomitant signaling by membrane estrogen receptors regulate spinal κ- and μ-opioid receptor heterodimerization and female-specific spinal morphine antinociception. J Neurosci. 2011;31:11836–45. CrossRefPubMedPubMedCentral
Li T-F, Zuscik MJ, Ionescu AM, Zhang X, Rosier RN, Schwarz EM, et al. PGE2 inhibits chondrocyte differentiation through PKA and PKC signaling. 2004.
Acarregui MJ, Brown JJ, Penisten ST. Cyclic AMP-dependent protein kinase (PKA) gene expression is developmentally regulated in fetal lung. Biochim Biophys Acta - Mol Cell Res. 1998;1402:303–12. CrossRef
Saldanha CJ, Duncan KA, Walters BJ. Neuroprotective actions of brain aromatase. Front Neuroendocrinol. 2010;30:106–18. CrossRef
Geary GG, McNeill AM, Ospina JA, Krause DN, Korach KS, Duckles SP. Selected contribution: cerebrovascular nos and cyclooxygenase are unaffected by estrogen in mice lacking estrogen receptor-alpha. J Appl Physiol. 2001;91:2391-2399-2390.
Vegeto E, Bonincontro C, Pollio G, Sala A, Viappiani S, Nardi F, et al. Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia. J Neurosci. 2001;21:1809–18. PubMed
W AEBVMB and JJ. Estrogen modulates microglial inflammatory mediator production via interactions with estrogen receptor β. 2004.
Minghetti L. Role of COX-2 in inflammatory and degenerative brain diseases. In: Inflammation in the pathogenesis of chronic diseases. Dordrecht: Springer Netherlands; 2007. p. 127–41. CrossRef
- Reciprocal interactions between prostaglandin E2- and estradiol-dependent signaling pathways in the injured zebra finch brain
Alyssa L. Pedersen
Colin J. Saldanha
- BioMed Central