Central aromatization: A dramatic and responsive defense against threat and trauma to the vertebrate brain

Abstract

Aromatase is the requisite and limiting enzyme in the production of estrogens from androgens. Estrogens synthesized centrally have more recently emerged as potent neuroprotectants in the vertebrate brain. Studies in rodents and songbirds have identified key mechanisms that underlie both; the injury-dependent induction of central aromatization, and the protective effects of centrally synthesized estrogens. Injury-induced aromatase expression in astrocytes occurs following a broad range of traumatic brain damage including excitotoxic, penetrating, and concussive injury. Responses to neural insult such as edema and inflammation involve signaling pathways the components of which are excellent candidates as inducers of this astrocytic response. Finally, estradiol from astrocytes exerts a paracrine neuroprotective influence via the potent inhibition of inflammatory pathways. Taken together, these data suggest a novel role for neural aromatization as a protective mechanism against the threat of inflammation and suggests that central estrogen provision is a wide-ranging neuroprotectant in the vertebrate brain.

Keywords: Estrogen; Inflammation; Neuroprotection; Songbird; Traumatic brain injury.

Figure 1.

Multiple mild concussive traumatic brain injury (mmTBI) were created by briefly anesthetizing subjects with isofluorane. Subjects were then placed on a modified weight drop apparatus (Laboratory weight drop device, Northeast Biomedical) where a 293.19 g rod was raised 1 cm above the head of the subject and dropped. The above procedure was repeated 4 times over 7 days and subjects were collected 10 days after the first injury. In zebra finches (A) mmTBI upregulates glial aromatase in astrocytes (purple) around the site of injury. Following mmTBI in mice (N=3/group), aromatase transcript was significantly upregulated in injured brains when compared to sham tissue following one-way ANOVA analysis. * denotes a significant difference at P <0.05 (one-way ANOVA)

Figure 2.

A single concussive injury was directed to the brain of an anesthetized adult zebra finches as described in Figure 1. 6 hours following injury, a 4mm diameter brain sample was collected and immediately weighed for the wet weight (WW). Brain samples were then placed at 110C for 24 hours and weighed again for the dry weight (DW). Brain water content or edema was calculated as %H2O = (WW - DW) × 100/WW. Edema (as measured by brain water content) is significantly higher in birds that underwent concussive traumatic brain injury (cTBI) relative to shams as measured using a one tailed Mann-Whitney U. * denotes a significant difference at P <0.05

Figure 3.

Adult wild type C57BL/6 (WT) mice and either IL-1 receptor null (IL-1R KO) or TNFα (TNFα KO) were implanted with in-dwelling cannula directed towards the hippocampus. 10 days post-surgery, animals were sacrificed and total RNA was extracted from microdissections immediately adjacent to the cortical needle and the corresponding location in sham animals. Expression of aromatase relative to GAPDH was measured using quantitative PCR using primers specific for the aromatase mRNA sequence. Fold change in aromatase expression 10 days after (A) a unilateral penetrating injury to the hippocampus of male wild type adult mice, and (B) aromatase expression following the same injury in the hippocampus of wild-type, interleukin 1 receptor knockouts (IL-1RKO) and TNFαKO knockouts. Aromatase expression is increased in the hippocampus and also in the distal cerebellum (A). In the hippocampus itself (B) aromatase is upregulated in WT and IL-1RKO, but not in TNFαKO mice. * denotes a significant difference at P <0.05