The glutathione-dependent neuroprotective activity of the blood-CSF barrier is inducible through the Nrf2 signaling pathway during postnatal development.
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引用次数: 0
Abstract
Background: Choroid plexuses regulate the exchanges between the blood and the CSF, and provide trophic factors necessary to brain development. They also express detoxifying enzymes that protect the developing brain from harmful substances. Targeting the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway may enhance the detoxification capabilities of choroid plexuses that are linked to glutathione conjugation, but little is known about mechanisms of enzyme induction in this tissue.
Methods: Rat pups were treated with dimethylfumarate and the subcellular localization of Nrf2 was analyzed in the choroidal tissue by confocal imaging. Glutathione-S-transferase (GST) activity was assessed ex vivo in the choroidal tissue, and 1-chloro-2,4-dinitrobenzene, a toxicant and prototypic GST substrate, was used to evaluate in vivo the efficiency of the glutathione-dependent enzymatic barrier function of choroid plexuses. Nrf2 knockout rat pups were used to establish the Nrf2 dependency of GST induction in this tissue.
Results: We show an early postnatal expression of Nrf2 in the rat choroidal tissue. Treatment of rat pups with dimethylfumarate triggers Nrf2 nuclear translocation in choroidal epithelial cells. This treatment increases GST activity in choroid plexus, and reduces the blood-to-CSF permeation of 1-chloro-2,4-dinitrobenzene. In Nrf2 knockout rats, the constitutive activity of the choroidal glutathione-dependent detoxifying machinery is maintained, but the efficacy of dimethylfumarate to induce glutathione conjugation in the choroid plexuses is strongly reduced, indicating that dimethylfumarate acts mainly through the Nrf2 signaling pathway.
Conclusions: This work shows that the glutathione-dependent detoxifying function of the blood-CSF barrier can be pharmacologically enhanced through the Nrf2 signaling pathway to better protect the neural fluid environment from drug and toxic accumulation during the neonatal period.
背景：脉络膜丛调节血液和脑脊液之间的交换，并提供脑发育所必需的营养因子。它们还表达解毒酶，保护发育中的大脑免受有害物质的侵害。靶向核因子（红细胞衍生2）样2 （Nrf2）信号通路可能增强与谷胱甘肽结合相关的脉络膜丛的解毒能力，但对该组织中酶诱导的机制知之甚少。方法：用富马酸二甲酯处理大鼠幼崽，用共聚焦成像方法分析Nrf2在脉络膜组织中的亚细胞定位。在离体脉络膜组织中评估谷胱甘肽- s -转移酶（GST）的活性，并使用1-氯-2,4-二硝基苯（一种有毒的原型GST底物）来评估体内脉络膜丛谷胱甘肽依赖的酶屏障功能的效率。利用Nrf2敲除大鼠幼仔建立GST诱导Nrf2依赖性。结果：我们发现Nrf2在出生后早期在大鼠脉络膜组织中表达。用富马酸二甲基处理大鼠幼崽可触发脉络膜上皮细胞Nrf2核易位。这种处理增加了脉络膜丛GST的活性，减少了1-氯-2,4-二硝基苯的血液到脑脊液的渗透。在Nrf2基因敲除大鼠中，脉络膜谷胱甘肽依赖性解毒机制的组成活性得以维持，但富马酸二甲基诱导脉络膜丛谷胱甘肽偶联的功效明显降低，表明富马酸二甲基主要通过Nrf2信号通路起作用。结论：本研究提示新生儿期血csf屏障的谷胱甘肽依赖性解毒功能可通过Nrf2信号通路在药理学上得到增强，从而更好地保护神经液环境免受药物和毒性积累的影响。
期刊介绍：
"Fluids and Barriers of the CNS" is a scholarly open access journal that specializes in the intricate world of the central nervous system's fluids and barriers, which are pivotal for the health and well-being of the human body. This journal is a peer-reviewed platform that welcomes research manuscripts exploring the full spectrum of CNS fluids and barriers, with a particular focus on their roles in both health and disease.
At the heart of this journal's interest is the cerebrospinal fluid (CSF), a vital fluid that circulates within the brain and spinal cord, playing a multifaceted role in the normal functioning of the brain and in various neurological conditions. The journal delves into the composition, circulation, and absorption of CSF, as well as its relationship with the parenchymal interstitial fluid and the neurovascular unit at the blood-brain barrier (BBB).
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