Garcia-Segura L M, Azcoitia I, DonCarlos L L
Instituto Cajal, CSIC, Madrid, Spain.
Prog Neurobiol. 2001 Jan;63(1):29-60. doi: 10.1016/s0301-0082(00)00025-3.
This review highlights recent evidence from clinical and basic science studies supporting a role for estrogen in neuroprotection. Accumulated clinical evidence suggests that estrogen exposure decreases the risk and delays the onset and progression of Alzheimer's disease and schizophrenia, and may also enhance recovery from traumatic neurological injury such as stroke. Recent basic science studies show that not only does exogenous estradiol decrease the response to various forms of insult, but the brain itself upregulates both estrogen synthesis and estrogen receptor expression at sites of injury. Thus, our view of the role of estrogen in neural function must be broadened to include not only its function in neuroendocrine regulation and reproductive behaviors, but also to include a direct protective role in response to degenerative disease or injury. Estrogen may play this protective role through several routes. Key among these are estrogen dependent alterations in cell survival, axonal sprouting, regenerative responses, enhanced synaptic transmission and enhanced neurogenesis. Some of the mechanisms underlying these effects are independent of the classically defined nuclear estrogen receptors and involve unidentified membrane receptors, direct modulation of neurotransmitter receptor function, or the known anti-oxidant activities of estrogen. Other neuroprotective effects of estrogen do depend on the classical nuclear estrogen receptor, through which estrogen alters expression of estrogen responsive genes that play a role in apoptosis, axonal regeneration, or general trophic support. Yet another possibility is that estrogen receptors in the membrane or cytoplasm alter phosphorylation cascades through direct interactions with protein kinases or that estrogen receptor signaling may converge with signaling by other trophic molecules to confer resistance to injury. Although there is clear evidence that estradiol exposure can be deleterious to some neuronal populations, the potential clinical benefits of estrogen treatment for enhancing cognitive function may outweigh the associated central and peripheral risks. Exciting and important avenues for future investigation into the protective effects of estrogen include the optimal ligand and doses that can be used clinically to confer benefit without undue risk, modulation of neurotrophin and neurotrophin receptor expression, interaction of estrogen with regulated cofactors and coactivators that couple estrogen receptors to basal transcriptional machinery, interactions of estrogen with other survival and regeneration promoting factors, potential estrogenic effects on neuronal replenishment, and modulation of phenotypic choices by neural stem cells.
本综述强调了临床和基础科学研究的最新证据，这些证据支持雌激素在神经保护中的作用。累积的临床证据表明，雌激素暴露可降低阿尔茨海默病和精神分裂症的风险，延缓其发病和进展，还可能促进创伤性神经损伤（如中风）后的恢复。最近的基础科学研究表明，外源性雌二醇不仅能降低对各种形式损伤的反应，而且大脑自身会在损伤部位上调雌激素合成和雌激素受体表达。因此，我们对雌激素在神经功能中作用的认识必须拓宽，不仅要包括其在神经内分泌调节和生殖行为中的功能，还应包括对退行性疾病或损伤的直接保护作用。雌激素可能通过多种途径发挥这种保护作用。其中关键的途径包括雌激素依赖性的细胞存活、轴突发芽、再生反应、增强的突触传递和增强的神经发生改变。这些效应的一些潜在机制独立于经典定义的核雌激素受体，涉及未明确的膜受体、神经递质受体功能的直接调节或雌激素已知的抗氧化活性。雌激素的其他神经保护作用确实依赖于经典的核雌激素受体，通过该受体，雌激素改变雌激素反应基因的表达，这些基因在细胞凋亡、轴突再生或一般营养支持中发挥作用。另一种可能性是，膜或细胞质中的雌激素受体通过与蛋白激酶的直接相互作用改变磷酸化级联反应，或者雌激素受体信号传导可能与其他营养分子的信号传导汇聚，从而赋予对损伤的抗性。尽管有明确证据表明雌二醇暴露可能对某些神经元群体有害，但雌激素治疗增强认知功能的潜在临床益处可能超过相关的中枢和外周风险。未来对雌激素保护作用进行研究的令人兴奋且重要的途径包括可在临床上使用以带来益处而无不当风险的最佳配体和剂量、神经营养因子和神经营养因子受体表达的调节、雌激素与将雌激素受体与基础转录机制偶联的调节辅因子和共激活因子的相互作用、雌激素与其他存活和再生促进因子的相互作用、雌激素对神经元补充的潜在影响以及神经干细胞对表型选择的调节。
