Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Solna, Sweden.
Discovery and Research, AlzeCure Pharma AB, Huddinge, Sweden.
Br J Pharmacol. 2021 Aug;178(16):3194-3204. doi: 10.1111/bph.15353. Epub 2021 Feb 4.
The cerebrospinal fluid (CSF)/plasma albumin ratio (QAlb) is believed to reflect the integrity of the blood-brain barrier (BBB). Recently, we reported that QAlb is lower in females. This may be important for uptake of neurotoxic 27-hydroxycholesterol (27OH) by the brain in particular because plasma levels of 27OH are higher in males. We studied sex differences in the relation between CSF and plasma levels of 27OH and its major metabolite 7α-hydroxy-3-oxo-4-cholestenoic acid (7HOCA) with QAlb. We tested the possibility of sex differences in the brain metabolism of 27OH and if its flux into the brain disrupted integrity of the BBB.
We have examined our earlier studies looking for sex differences in CSF levels of oxysterols and their relation to QAlb. We utilized an in vitro model for the BBB with primary cultured brain endothelial cells to test if 27OH has a disruptive effect on this barrier. We measured mRNA and protein levels of CYP7B1 in autopsy brain samples.
The correlation between CSF levels of 27OH and QAlb was higher in males whereas, with 7HOCA, the correlation was higher in females. No significant sex difference in the expression of CYP7B1 mRNA in brain autopsy samples. A correlation was found between plasma levels of 27OH and QAlb. No support was obtained for the hypothesis that plasma levels of 27OH have a disruptive effect on the BBB.
The sex differences are discussed in relation to negative effects of 27OH on different brain functions.
This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
脑脊液（CSF）/血浆白蛋白比值（QAlb）被认为反映了血脑屏障（BBB）的完整性。最近，我们报道称女性的 QAlb 较低。这对于神经毒性 27-羟胆固醇（27OH）被大脑摄取可能很重要，因为男性的血浆 27OH 水平较高。我们研究了 CSF 和血浆 27OH 及其主要代谢物 7α-羟基-3-氧代-4-胆甾烯酸（7HOCA）与 QAlb 之间的关系中存在的性别差异。我们测试了 27OH 脑内代谢是否存在性别差异，以及其流入大脑是否破坏了 BBB 的完整性。
我们检查了我们之前的研究，寻找 CSF 中氧化固醇水平的性别差异及其与 QAlb 的关系。我们利用原代培养的脑内皮细胞的 BBB 体外模型来测试 27OH 是否对这种屏障具有破坏性影响。我们测量了尸检脑组织样本中 CYP7B1 的 mRNA 和蛋白水平。
27OH 与 QAlb 之间的相关性在男性中更高，而在女性中与 7HOCA 的相关性更高。尸检脑组织样本中 CYP7B1 mRNA 的表达没有显著的性别差异。发现了血浆 27OH 水平与 QAlb 之间的相关性。没有证据支持血浆 27OH 水平对 BBB 具有破坏性影响的假设。
这些性别差异与 27OH 对不同脑功能的负面影响有关。
本文是关于氧化固醇、终身健康和治疗学的专题的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
