Glial Aromatization Decreases Neural Injury in the Zebra Finch (Taeniopygia guttata): Influence on Apoptosis

Abstract

Emerging evidence suggests a neuroprotective role for oestrogens following damage to the vertebrate brain. Aromatase (oestrogen synthase) is rapidly transcribed and translated in glial cells around areas of neural damage in several vertebrates. However, the potential neuroprotection afforded by locally up-regulated glial aromatase immediately surrounding the injury remains to be tested. Towards this end, individual birds sustained penetrating mechanical injuries via a needle that contained either vehicle or the aromatase inhibitor fadrozole into contralateral hemispheres. Seventy-two hours later, the size of neural injury (as assessed by the extent of necrotic tissue) and the number of apoptotic cells around the injuries were evaluated. The size of injury in the hemisphere injected with fadrozole was significantly larger than the injury caused by vehicle injection. Furthermore, a greater number of apoptotic nuclei were found around the fadrozole-associated lesion relative to vehicle. Finally, constitutively expressed, neuronal aromatase close to the injury site did not differ between hemispheres. We conclude that local inhibition of glial aromatase immediately around the site of injury plays a neuroprotective role in the songbird brain and this protection involves apoptotic pathways. Local up-regulation of glial aromatase may play a pivotal role in the limitation of secondary damage and/or the acceleration of restorative processes following injury to the vertebrate brain.

A major role for astrocytes in the neuroprotective effect of estrogen

“…This up-regulation has been observed in the brains of both rodents and songbirds, where a rapid and marked increase in aromatase transcription and translation occurs in a restricted area surrounding injury due to neuropil disruption [Peterson et al, 2001]. Interestingly, no change is observed in the levels of constitutively expressed neuronal aromatase in areas surrounding the injury [Wynne and Saldanha, 2004]. This cell-specific aromatase up-regulation is especially noteworthy because, in the zebra finch, enzyme expression is particularly abundant in neuronal populations in different brain areas [Schlinger, 1997;Saldanha et al, 2000], suggesting that estrogen production by aromatase plays a critical role in the control of neuronal function in these species.…”

“…The increased neuronal death in these models can be reversed by administration of estradiol [Azcoitia et al, 2001a;Sierra et al, 2003], thereby confirming that blockade of estrogen synthesis is a key event in reducing endogenous neuroprotection mechanisms . The neuroprotective activity of glial aromatase has also been quantified in the zebra finch brain, where a dramatic increase in the size of injury and in the number of apoptotic nuclei was observed in those brain hemispheres in which fadrozole had been administered [Wynne and Saldanha, 2004]. This effect was counterbalanced by the administration of exogenous estrogen [Saldanha et al, 2005].…”

Role of Protein Phosphatases in Estrogen-Mediated Neuroprotection

“…Similarly, the ability of estrogens to antagonize these glutamate-induced reductions in protein phosphatases suggests that this action is common to estrogen protection in both oxidative stress and excitotoxicity in neurons. In addition, experimental data from various studies have shown not only the ability of estrogen to protect glial cells from various toxins (Bishop and Simpkins, 1994;Haghighat et al, 2004;Takao et al, 2004) but also the mediation of glial cells in estrogen neuroprotection (Sortino et al, 2004;Wynne and Saldanha, 2004). Therefore, it is important to understand the mechanism of estrogen actions in both neurons and glia.…”

Recent advances in behavioral neuroendocrinology: Insights from studies on birds

“…These data suggest that glia switch on the ability to synthesize E 2 in response to neural injury, and indicate a functional role for the glial aromatase expression that was first described in cell cultures of songbird telencephalon . Indeed localized administration of an aromatase inhibitor increases neural damage and increases apoptosis relative to localized saline administration (Wynne & Saldanha, 2004) an effect rescued by replacement with E 2 in the zebra finch (Saldanha et al, in press). These data point to the clinical relevance of avian studies and highlight important similarities between avian and mammalian neurophysiology.…”