G-protein coupled estrogen receptor 1 mediated estrogenic neuroprotection against spinal cord injury*

Hu, Rong; Sun, Haodong; Zhang, Qian; Chen, Jingyu; Wu, Nan; Meng, Hui; Cui, Gaoyu; Hu, S. Jack; Li, Fēi; Lin, Jiangkai; Wan, Qi; Feng, Hua

doi:10.1097/ccm.0b013e3182657560

Cited by 38 publications

(35 citation statements)

References 55 publications

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“…Some researchers have raised the possibility that some modifiers that reside on the X chromosome may affect the phenotype [36]. The high level of oestrogenic hormone in women was also speculated to be associated with neuroprotection [37,38,39]. Further studies on the mechanism of gender difference in SPG4 may provide a clue for HSP treatment.…”

Section: Discussionmentioning

confidence: 99%

Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Luo¹,

Chen²,

Zhan³

et al. 2014

Neurodegener Dis

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Background: Hereditary spastic paraplegias constitute a heterogeneous group of inherited neurodegenerative disorders. To date, there has been no systematic mutation and clinical analysis for a large group of autosomal-dominant hereditary spastic paraplegias in China. Objective: The purpose of this study was to investigate the mutation frequencies and the clinical phenotypes of Chinese spastic paraplegia patients. Methods: Direct sequencing and a multiplex ligation-dependent probe amplification assay were applied to detect the mutations of SPAST and ATL1 in 54 autosomal-dominant hereditary spastic paraplegia probands and 66 isolated cases. Next, mutations in NIPA1, KIF5A, REEP1 and SLC33A1 were detected in the negative patients. Subsets of spastic paraplegia patients were genotyped for the modifying variants. Further, detailed clinical data regarding the genetically diagnosed families were analysed. Results: Altogether, 27 families were diagnosed as SPG4, 3 as SPG3A and 1 as SPG6. No mutations in KIF5A, REEP1 or SLC33A1 were found; 9 SPAST mutations were novel. There was no p.S44L or p.P45Q variant in SPAST and no p.G563A variant in HSPD1 in either the 120 spastic paraplegia patients or the 500 controls. There was a remarkable clinical difference between the SPG4 and non-SPG4 patients and even between genders among the SPG4 patients. Non-penetrance and remarkable gender difference were observed in some SPG4 and SPG3A families. Conclusions: Our data confirm that hereditary spastic paraplegias in China represent a heterogeneous group of genetic neurodegenerative disorders in autosomal-dominant and apparently sporadic forms. Novel genotype-phenotype correlations were established.

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Section: Discussionmentioning

confidence: 99%

Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Luo¹,

Chen²,

Zhan³

et al. 2014

Neurodegener Dis

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“…In contrast, GPR30 is mainly distributed in the motoneurons of the ventral horn and white matter of the spinal cord [17], both of which are directly associated with motor function. The tissue distribution characteristics of GPR30 led to the hypothesis that GPR30 might be a candidate for promoting recovery of SCI-induced motor dysfunction.…”

Section: Introductionmentioning

confidence: 99%

G-1 exerts neuroprotective effects through G protein-coupled estrogen receptor 1 following spinal cord injury in mice

et al. 2016

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Spinal cord injury (SCI) always occurs accidently and leads to motor dysfunction because of biochemical and pathological events. Estrogen has been shown to be neuroprotective against SCI through estrogen receptors (ERs), but the underlying mechanisms have not been fully elucidated. In the present study, we investigated the role of a newly found membrane ER, G protein-coupled estrogen receptor 1 (GPR30 or GPER1), and discussed the feasibility of a GPR30 agonist as an estrogen replacement. Forty adult female C57BL/6J mice (10–12 weeks old) were divided randomly into vehicle, G-1, E2, G-1 + G-15 and E2 + G-15 groups. All mice were subjected to SCI using a crushing injury approach. The specific GPR30 agonist, G-1, mimicked the effects of E2 treatment by preventing SCI-induced apoptotic cell death and enhancing motor functional recovery after injury. GPR30 activation regulated phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK/extracellular signal-regulated kinase (ERK) signalling pathways, increased GPR30 and anti-apoptosis proteins Bcl-2 and brain derived neurotrophic factor (BDNF), but decreased the pro-apoptosis factor Bax and cleaved caspase-3. However, the neuroprotective effects of G-1 and E2 were blocked by the specific GPR30 antagonist, G-15. Thus, GPR30 rather than classic ERs is required to induce estrogenic neuroprotective effects. Given that estrogen replacement therapy may cause unexpected side effects, especially on the reproductive system, GPR30 agonists may represent a potential therapeutic approach for treating SCI.

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“…A previous study by this group confirmed that estrogen exerts a neuroprotective effect following SCI, via GPR30 (18). It was hypothesized that apoptosis within the spinal cord may increase following SCI, and that estrogen administration may decrease this apoptosis.…”

Section: Discussionmentioning

confidence: 69%

“…In a previous animal study by this group, it was observed that apoptosis in the spinal cord increases in the early stages following SCI (18). It has been reported in a number of previous studies that estrogen may exert an antiapoptotic effect following SCI by enhancing antiapoptotic gene expression, while reducing caspase-3 activity and inhibiting calcium activation (21,35–37).…”

Section: Discussionmentioning

confidence: 89%

“…Previous studies by this group have shown that estrogen improves the motor function of rats with SCI and reduces apoptosis in the spinal cord following SCI, via the membrane receptor, GPR30, rather than the conventional ERs (18). GPR30 receptors are located in the ventral horn of the spinal cord (18), while the classic nuclear ERs are located in the spinal dorsal horn (19). This suggests that the effect of estrogen, mediated by GPR30, on spinal motor neurons may be an important target for neuroprotection following SCI.…”

Section: Introductionmentioning

confidence: 99%

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G-protein-coupled receptor 30-mediated antiapoptotic effect of estrogen on spinal motor neurons following injury and its underlying mechanisms

Chen

et al. 2015

Molecular Medicine Reports

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Spinal cord injury (SCI) may result in severe dysfunction of motor neurons. G-protein-coupled receptor 30 (GPR30) expression in the motor neurons of the ventral horn of the spinal cord mediates neuroprotection through estrogen signaling. The present study explored the antiapoptotic effect of estrogen, mediated by GPR30 following SCI, and the mechanisms underlying this effect. Spinal motor neurons from rats were cultured in vitro in order to establish cell models of oxygen and glucose deprivation (OGD). The effects of estrogen, the estrogen agonist, G1, and the estrogen inhibitor, G15, on motor neurons were observed using MTT assays. The effects of E2, G1 and G15 on spinal motor neuron apoptosis following OGD, were detected using flow cytometry. The role of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) inhibitor, LY294002, was also determined using flow cytometry. Rat SCI models were established. E2, G1 and E2+LY294002 were administered in vivo. Motor function was scored at 3, 7, 14, 21 and 28 d following injury, using Basso-Beattie-Bresnahan (BBB) standards. Cell activity in the estrogen and G1 groups was higher than that in the solvent group, whereas cell activity in the E2+G15 group was lower than that in the E2 group (P<0.05). Following OGD, the proportion of apoptotic cells significantly increased (P<0.05). The proportion in the estrogen group was significantly lower than that in the solvent group, whereas the proportion of apoptotic cells in the E2+G15 and E2+LY294002 groups was higher than that in the E2 group (P<0.05). Treatment with E2 and G1 led to upregulation of P-Akt expression in normal cells and post-OGD cells. The BBB scores of rats in the E2 and G1 groups were higher than those in the placebo group (P<0.05). The BBB scores of the E2+LY294002 group were lower than those of the E2 group (P<0.05). Estrogen thus appears to exert a protective effect on spinal motor neurons following OGD, via GPR30. The PI3K/Akt pathway may be one of those involved in the estrogen-related antiapoptotic effects mediated by GPR30.

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G-protein coupled estrogen receptor 1 mediated estrogenic neuroprotection against spinal cord injury*

Abstract: These results reveal that G-protein coupled estrogen receptor 1 may mediate estrogenic neuroprotection against spinal cord injury, and underline the promising potential of estrogen with its new target G-protein coupled estrogen receptor 1 for the treatment of spinal cord injury patients.

Cited by 38 publications

References 55 publications

Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

G-1 exerts neuroprotective effects through G protein-coupled estrogen receptor 1 following spinal cord injury in mice

G-protein-coupled receptor 30-mediated antiapoptotic effect of estrogen on spinal motor neurons following injury and its underlying mechanisms

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