The Major Cholesterol Metabolite Cholestane-3β,5α,6β-Triol Functions as an Endogenous Neuroprotectant
The Major Cholesterol Metabolite Cholestane-3β,5α,6β-Triol Functions as an Endogenous Neuroprotectant
复制标题
DOI：
10.1523/jneurosci.0344-14.2014
复制
发表时间：
2014-08-20
影响因子：
5.3
通讯作者：
Yan, Guangmei
中科院分区：
文献类型：
--
作者：
Hu, Haiyan;Zhou, Yuehan;Yan, Guangmei
NMDA型谷氨酸受体的过度刺激被认为是导致包括脑和脊髓缺血在内的各种疾病中CNS神经元死亡的原因。然而，这些受体调节的内在和生理机制基本上是未知的。在这里，我们报告，胆固醇的主要代谢产物胆甾烷-3 β，5 α，6 β-三醇（三醇），是一种内源性神经保护剂，并通过负调节NMDA受体在体外和体内保护神经元损伤。用三醇处理培养的神经元可防止谷氨酸诱导的神经毒性，并且三醇的给药显著降低兔脊髓缺血和大鼠短暂局灶性脑缺血后的神经元损伤。诱导性三醇升高与兔脊髓缺血预处理及随后的神经保护作用有关。这种神经保护作用可通过预先给予三醇合成的特异性抑制剂而有效地消除。生理浓度的三醇减弱谷氨酸诱导的[Ca 2 +]（i），并降低培养的皮层神经元和瞬时转染NR 1/NR 2B NMDA受体的HEK-293细胞中NMDA介导的内向电流。[H-3]三醇与小脑颗粒神经元的饱和结合和[H-3] MK-801与NMDA受体的结合被三醇取代，表明NMDA受体的直接阻断可能是神经保护特性的基础。我们的研究结果表明，天然存在的氧化固醇，主要的胆固醇代谢物三醇，功能作为内源性神经保护剂在体内，这可能会提供新的见解，了解和开发潜在的治疗疾病的中枢神经系统。
Overstimulation of NMDA-type glutamate receptors is believed to be responsible for neuronal death of the CNS in various disorders, including cerebral and spinal cord ischemia. However, the intrinsic and physiological mechanisms of modulation of these receptors are essentially unknown. Here we report that cholestane-3 beta,5 alpha,6 beta-triol (triol), a major metabolite of cholesterol, is an endogenous neuro-protectant and protects against neuronal injury both in vitro and in vivo via negative modulation of NMDA receptors. Treatment of cultured neurons with triol protects against glutamate-induced neurotoxicity, and administration of triol significantly decreases neuronal injury after spinal cord ischemia in rabbits and transient focal cerebral ischemia in rats. An inducible elevation of triol is associated with ischemic preconditioning and subsequent neuroprotection in the spinal cord of rabbits. This neuroprotection is effectively abolished by preadministration of a specific inhibitor of triol synthesis. Physiological concentrations of triol attenuate [Ca2+](i) induced by glutamate and decrease inward NMDA-mediated currents in cultured cortical neurons and HEK-293 cells transiently transfected with NR1/NR2B NMDA receptors. Saturable binding of [H-3] triol to cerebellar granule neurons and displacement of [H-3] MK-801 binding to NMDA receptors by triol suggest that direct blockade of NMDA receptors may underlie the neuroprotective properties. Our findings suggest that the naturally occurring oxysterol, the major cholesterol metabolite triol, functions as an endogenous neuroprotectant in vivo, which may provide novel insights into understanding and developing potential therapeutics for disorders in the CNS.