Astrocyte-derived growth factors and estrogen neuroprotection: Role of transforming growth factor-α in estrogen-induced upregulation of glutamate transporters in astrocytes

Abstract

Extensive studies from the past decade have completely revolutionized our understanding about the role of astrocytes in the brain from merely supportive cells to an active role in various physiological functions including synaptic transmission via cross-talk with neurons and neuroprotection via releasing neurotrophic factors. Particularly, numerous studies have reported that astrocytes mediate the neuroprotective effects of 17β-estradiol (E2) and selective estrogen receptor modulators (SERMs) in various clinical and experimental models of neuronal injury. Astrocytes contain two main glutamate transporters, glutamate aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), that play a key role in preventing excitotoxic neuronal death, a process associated with most neurodegenerative diseases. E2 has shown to increase expression of both GLAST and GLT-1 mRNA and protein and glutamate uptake in astrocytes. Growth factors such as transforming growth factor α (TGF-α) appear to mediate E2-induced enhancement of these transporters. These findings suggest that E2 exerts neuroprotection against excitotoxic neuronal injuries, at least in part, by enhancing astrocytic glutamate transporter levels and function. Therefore, the present review will discuss proposed mechanisms involved in astrocyte-mediated E2 neuroprotection, with a focus on glutamate transporters.

A Quantification of the Injury‐Induced Changes in Central Aromatase, Oestrogenic Milieu and Steroid Receptor Expression in the Zebra Finch

“…The interaction of oestradiol with these receptors or proteins could induce a multitude of neuroprotective cascades and mechanisms, including but not limited to the attenuation of proinflammatory mediators, promotion of protective neurotrophic/growth factors, increased clearance of excitotoxic glutamate via up-regulation of glial glutamate transporters, and/or prevention of blood-brain barrier disruption (45). Numerous studies suggest that E 2 stimulates astrocytes to release neuroprotective growth factors, including nerve growth factor, insulin-like growth factor, brain-derived neurotrophic factor, transforming growth factors a and b and glial cell line-derived neurotrophic factor (46)(47)(48)(49).…”

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

“…That astrocytes may be direct targets of estrogenic compounds is also suggested by the finding that they express ERs both in vitro [181, 183-188] and in vivo, in particular after brain injury [14, 128, 151, 164, 189-195]. In addition, there is evidence that estradiol anti-inflammatory and protective effects in experimental autoimmune encephalomyelitis is dependent on the expression of ERα in astrocytes [196-198], indicating that these cells may mediate neuroprotective actions of estrogenic compounds. In the next subsections, we review the mechanisms regulated by estrogenic compounds in astrocytes that may mediate neuroprotection after TBI (Table 4).…”

“…Estradiol and tamoxifen increase the expression of the glutamate transporters glutamate aspartate transporter (GLAST) and glutamate transporter-1, increasing glutamate uptake by astrocytes [181, 196, 197]. This estrogenic action is mediated by ERs, including G-protein coupled ER, and the PI3K and Mitogen-activated protein kinase signalling pathways [185, 196, 197, 210]. The phytoestrogen resveratrol increases glutamate uptake and glutamine synthetase activity in primary cortical astrocytes [211].…”

Disruption of the Glutamate–Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females

“…Animal studies show that dysfunction of GLT-1 can induce some depressive-like behaviors, and drugs that upregulate GLT-1 ameliorate such deficits (Banasr and Duman, 2008; Banasr et al, 2010). In addition, cell culture studies show that estrogens enhance GLT-1 activity and accelerate glutamate uptake by facilitating GLT-1 promotor activity (Pawlak et al, 2005b; Lee et al, 2013; Karki et al, 2014). Taken together, the Glu–Gln cycle involving astrocytes may play a role in mediating depressive-like deficits when exposed to stress repeatedly.…”