Abstract
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.
Highlights
Numerous studies have verified that estrogen exhibits clear neuroprotective effects following stroke and cerebral ischemia [1,2,3], and estrogen replacement therapy (ERT) is a well-established method of managing climacteric symptoms in women after menopause [4]
Estrogen has been widely reported to be neuroprotective against neurodegenerative diseases [29,30], it is identified that estrogen exerts effects by activating estrogen receptor (ER), but the underlying mechanisms are not fully understood
Classic ERs are expressed in the superficial laminae of the dorsal horn of the spinal cord, which is mainly involved with sensory and nociceptive modulation [31,32]
Summary
Numerous studies have verified that estrogen exhibits clear neuroprotective effects following stroke and cerebral ischemia [1,2,3], and estrogen replacement therapy (ERT) is a well-established method of managing climacteric symptoms in women after menopause [4]. Most studies have demonstrated that classic ERs play an indispensable role in estrogenic neuroprotection [8]. GPR30 knockout attenuates estrogen-induced neuroprotection and activation of a rapid kinase signal pathway in global cerebral ischemia [9]. It has been reported that classic ERs are mainly distributed in the superficial layer of the dorsal horn of the spinal cord [15,16]. 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 present study aimed to explore the effects of GPR30 activation on SCI and its underlying molecular mechanisms, which may provide a new strategy for treatment of SCI
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