G protein-coupled estrogen receptor: a new therapeutic target in stroke and traumatic brain/spinal cord injury?
G protein-coupled estrogen receptor: a new therapeutic target in stroke and traumatic brain/spinal cord injury?
复制标题
G蛋白偶联雌激素受体：中风和创伤性脑/脊髓损伤的新治疗靶点？
DOI：
10.1097/ccm.0b013e31826be998
复制
发表时间：
2012
影响因子：
8.8
通讯作者：
Prossnitz,EricR
中科院分区：
文献类型：
--
作者：
Prossnitz,EricR
Traumatic brain and spinal cord injury (SCI), together with stroke, represent the major sources of acute nervous system injury. In the United States alone, approximately 200,000 individuals (the vast majority male) live with SCI, with the predominant age of injury between 16 and 30 (1). A common feature of these injuries is that following the primary damage, a secondary sequence of complex pathophysiological events occurs over a period of hours to days and weeks that leads to the expansion of the initial injury both at the original site of damage and beyond. This continuing tissue damage occurs in large part through apoptosis or programmed cell death, an intricate cellular mechanism that can potentially be regulated or blocked with the appropriate stimuli. Beyond repair of the initial site of injury with treatments such as stem cells, gene therapy, or growth factors, an important goal of clinical care is to limit this secondary phase of tissue injury with neuroprotective agents (2, 3). Ideal pharmacological agents would act both to limit apoptosis of neurons (and supporting cells) and to reduce the subsequent inflammation that produces much of the secondary damage, similar to stroke and myocardial infarction, where tissue reperfusion following ischemia initiates a secondary phase of damage via inflammation.An extensive array of biological (4) and pharmacological (5) neuroprotective agents has been investigated for treatment of SCI. Such agents include nonsteroidal anti-inflammatory drug, erythropoietin, anti-CD11d antibodies, minocycline, estrogen, progesterone, riluzole, polyethylene glycol, atorvastatin, and pioglitazone (5). The corticosteroid methylprednisolone has been extensively used to treat patients with SCI but failed to gain Food and Drug Administration approval due to limited neuroprotection and controversial results (6). Of the above agents, one of the most intriguing is the female sex hormone estrogen, which has been shown to exhibit broad neuroprotective effects in both acute injury (7) and chronic neurodegenerative diseases (8). Epidemiological data reveal that postmenopausal women are at higher risk for stroke, cognitive impairment, and neurodegenerative disease, suggesting a beneficial effect of estrogen (9). Although initial reports from the Women’s Health Initiative suggested that hormone replacement with high doses of conjugated equine estrogens (ie, not 17β-estradiol) with or without medroxyprogesterone acetate appeared to increase stroke and worsen cognition, subsequent reanalysis suggests that early postmenopausal treatment is in fact beneficial, results that have led to the “timing hypothesis” of estrogen replacement therapy and the use of lower doses of physiological/endogenous estrogens (ie, 17β-estradiol). The neuroprotective role of endogenous estrogens was first suggested by studies of global cerebral ischemia–reperfusion injury in which ovariectomized female rats supplemented with 17β-estradiol sustained less neuronal damage than control animals (10). Since then, the neuroprotective effects of estrogens have been widely documented using multiple models in both female and male rodents, suggesting therapeutic potential in both women and men (9).
