Estrogen and tamoxifen reverse manganese‐induced glutamate transporter impairment in astrocytes

Abstract

Chronic exposure to manganese (Mn) can cause manganism, a neurodegenerative disorder similar to Parkinson's disease. The toxicity of Mn includes impairment of astrocytic glutamate transporters. 17β-Estradiol (E2) has been shown to be neuroprotective in various neurodegenerative diseases including Parkinson's disease and Alzheimer's disease, and some selective estrogen receptor modulators, including tamoxifen (TX), also possess neuroprotective properties. We have tested our hypothesis that E2 and TX reverse Mn-induced glutamate transporter impairment in astrocytes. The results established that E2 and TX increased glutamate transporter function and reversed Mn-induced glutamate uptake inhibition, primarily via the up-regulation of glutamate/aspartate transporter (GLAST). E2 and TX also increased astrocytic GLAST mRNA levels and attenuated the Mn-induced inhibition of GLAST mRNA expression. In addition, E2 and TX effectively increased the expression of transforming growth factor β1, a potential modulator of the stimulatory effects of E2/TX on glutamate transporter function. This effect was mediated by the activation of MAPK/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways. These novel findings suggest, for the first time, that E2 and TX enhance astrocytic glutamate transporter expression via increased transforming growth factor β1 expression. Furthermore, the present study is the first to show that both E2 and TX effectively reverse Mn-induced glutamate transport inhibition by restoring its expression and activity, thus offering a potential therapeutic modality in neurodegenerative disorders characterized by altered glutamate homeostasis.

Yin Yang 1 Is a Repressor of Glutamate Transporter EAAT2, and It Mediates Manganese-Induced Decrease of EAAT2 Expression in Astrocytes

“…1C 1 ). Our earlier studies established that Mn reduced glutamate uptake by decreasing GLAST and GLT-1 mRNA and protein levels (13,23,24). Herein, we corroborated the Mn-induced decrease in astrocytic EAAT2 promoter activity in a time-dependent manner (Fig.…”

“…9). This is interesting because reduction of EAAT2 expression is observed in both excitotoxic neuronal injury and glioblastoma (24). A classical HDACi, trichostatin A, has been shown to enhance GLT-1 mRNA levels in C6 glioma cells (27).…”

cAMP Response Element-binding Protein (CREB) and Nuclear Factor κB Mediate the Tamoxifen-induced Up-regulation of Glutamate Transporter 1 (GLT-1) in Rat Astrocytes

“…Similarly, estrogen increases GLT-1 and glutamate aspartate transporter expression, thereby enhancing astrocytic glutamate uptake (31,32). Our previous study established that both estrogen-and TX-induced astrocytic GLT-1 expression was mediated by TGF-␣ signaling upon 24 h exposure (26).…”

Impairment of glutamine/glutamate-γ-aminobutyric acid cycle in manganese toxicity in the central nervous system

“…Impaired uptake of glutamate by astrocytes medi ates excitotoxicity, slows the synthesis of gluta thione and leaves the brain vulnerable to oxidative damage [24]. Several studies have demonstrated the propensity of Mn to disrupt the Glu transport system and other components of the GGC, leading to both a reduction in Glu uptake and elevation of extra cellular Glu level [23]. Manganese has been widely reported to mediate the impairment of glutamate transporters, GLAST and GLT1 expression and func tion [12,27].…”