在 Sprague-Dawley 大鼠血脑屏障中有机阴离子转运多肽 1a4（Oatp1a4）功能表达的性别特异性差异。
Sex-specific differences in organic anion transporting polypeptide 1a4 (Oatp1a4) functional expression at the blood-brain barrier in Sprague-Dawley rats.
机构信息
Department of Pharmacology, College of Medicine, University of Arizona, P.O. Box 245050, 1501 N. Campbell Avenue, Tucson, AZ, 85724-5050, USA.
出版信息
Fluids Barriers CNS. 2018 Sep 13;15(1):25. doi: 10.1186/s12987-018-0110-9.
BACKGROUND
Targeting endogenous blood-brain barrier (BBB) transporters such as organic anion transporting polypeptide 1a4 (Oatp1a4) can facilitate drug delivery for treatment of neurological diseases. Advancement of Oatp targeting for optimization of CNS drug delivery requires characterization of sex-specific differences in BBB expression and/or activity of this transporter.
METHODS
In this study, we investigated sex differences in Oatp1a4 functional expression at the BBB in adult and prepubertal (i.e., 6-week-old) Sprague-Dawley rats. We also performed castration or ovariectomy surgeries to assess the role of gonadal hormones on Oatp1a4 protein expression and transport activity at the BBB. Slco1a4 (i.e., the gene encoding Oatp1a4) mRNA expression and Oatp1a4 protein expression in brain microvessels was determined using quantitative real-time PCR and western blot analysis, respectively. Oatp transport function at the BBB was determined via in situ brain perfusion using [H]taurocholate and [H]atorvastatin as probe substrates. Data were expressed as mean ± SD and analyzed via one-way ANOVA followed by the post hoc Bonferroni t-test.
RESULTS
Our results showed increased brain microvascular Slco1a4 mRNA and Oatp1a4 protein expression as well as increased brain uptake of [H]taurocholate and [H]atorvastatin in female rats as compared to males. Oatp1a4 expression at the BBB was enhanced in castrated male animals but was not affected by ovariectomy in female animals. In prepubertal rats, no sex-specific differences in brain microvascular Oatp1a4 expression were observed. Brain accumulation of [H]taurocholate in male rats was increased following castration as compared to controls. In contrast, there was no difference in [H]taurocholate brain uptake between ovariectomized and control female rats.
CONCLUSIONS
These novel data confirm sex-specific differences in BBB Oatp1a4 functional expression, findings that have profound implications for treatment of CNS diseases. Studies are ongoing to fully characterize molecular pathways that regulate sex differences in Oatp1a4 expression and activity.
背景
靶向内源性血脑屏障（BBB）转运体，如有机阴离子转运多肽 1a4（Oatp1a4），可以促进治疗神经疾病的药物递送。为了优化中枢神经系统（CNS）药物递送，需要对这种转运体在 BBB 上的表达和/或活性的性别特异性差异进行特征描述。
方法
在这项研究中，我们研究了成年和青春期前（即 6 周龄）Sprague-Dawley 大鼠 BBB 上 Oatp1a4 功能表达的性别差异。我们还进行了去势或卵巢切除术手术，以评估性腺激素对 BBB 上 Oatp1a4 蛋白表达和转运活性的作用。使用定量实时 PCR 和 Western blot 分析分别确定 Slco1a4（即编码 Oatp1a4 的基因）mRNA 表达和脑微血管中的 Oatp1a4 蛋白表达。通过原位脑灌注使用[H]牛磺胆酸钠和[H]阿托伐他汀作为探针底物来确定 Oatp 在 BBB 上的转运功能。数据表示为平均值±标准差，并通过单因素方差分析（ANOVA）后进行事后 Bonferroni t 检验进行分析。
结果
我们的结果表明，与雄性大鼠相比，雌性大鼠的脑微血管 Slco1a4 mRNA 和 Oatp1a4 蛋白表达增加，[H]牛磺胆酸钠和[H]阿托伐他汀的脑摄取增加。去势雄性动物的 BBB 上 Oatp1a4 表达增强，但雌性动物的卵巢切除术对其没有影响。在青春期前的大鼠中，没有观察到脑微血管 Oatp1a4 表达的性别特异性差异。与对照组相比，去势雄性大鼠的[H]牛磺胆酸钠脑积累增加。相比之下，卵巢切除术后和对照组雌性大鼠之间[H]牛磺胆酸钠的脑摄取没有差异。
结论
这些新数据证实了 BBB Oatp1a4 功能表达的性别特异性差异，这对治疗 CNS 疾病具有深远的意义。目前正在进行研究，以充分描述调节 Oatp1a4 表达和活性的性别差异的分子途径。
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