School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Life Sci. 2022 Dec 1;310:121088. doi: 10.1016/j.lfs.2022.121088. Epub 2022 Oct 17.
Neuroinflammation is a prominent hallmark in several neurodegenerative diseases (NDs). Halting neuroinflammation can slow down the progression of NDs. Improving the efficacy of clinically available non-steroidal anti-inflammatory drugs (NSAIDs) is a promising approach that may lead to fast-track and effective disease-modifying therapies for NDs. Here, we aimed to utilize the L-type amino acid transporter 1 (LAT1) to improve the efficacy of salicylic acid as an example of an NSAID prodrug, for which brain uptake and intracellular localization have been reported earlier.
Firstly, we confirmed the improved LAT1 utilization of the salicylic acid prodrug (SA-AA) in freshly isolated primary mouse microglial cells. Secondly, we performed behavioural rotarod, open field, and four-limb hanging tests in mice, and a whole-brain proteome analysis.
The SA-AA prodrug alleviated the lipopolysaccharide (LPS)-induced inflammation in the rotarod and hanging tests. The proteome analysis indicated decreased neuroinflammation at the molecular level. We identified 399 proteins linked to neuroinflammation out of 7416 proteins detected in the mouse brain. Among them, Gps2, Vamp8, Slc6a3, Slc18a2, Slc5a7, Rgs9, Lrrc1, Ppp1r1b, Gnal, and Adcy5/6 were associated with the drug's effects. The SA-AA prodrug attenuated the LPS-induced neuroinflammation through the regulation of critical pathways of neuroinflammation such as the cellular response to stress and transmission across chemical synapses.
The efficacy of NSAIDs can be improved via the utilization of LAT1 and repurposed for the treatment of neuroinflammation. This improved brain delivery and microglia localisation can be applied to other inflammatory modulators to achieve effective and targeted CNS therapies.
神经炎症是几种神经退行性疾病（NDs）的显著标志。阻止神经炎症可以减缓 NDs 的进展。提高临床可用的非甾体抗炎药（NSAIDs）的疗效是一种很有前途的方法，可能为 NDs 带来快速有效的疾病修饰治疗方法。在这里，我们旨在利用 L 型氨基酸转运蛋白 1（LAT1）来提高水杨酸作为 NSAID 前药的疗效，之前已经报道了这种前药的脑摄取和细胞内定位。
首先，我们在新鲜分离的原代小鼠小胶质细胞中证实了水杨酸前药（SA-AA）对 LAT1 利用的改善。其次，我们在小鼠中进行了行为性旋转棒、旷场和四肢悬挂试验以及全脑蛋白质组分析。
SA-AA 前药减轻了脂多糖（LPS）诱导的旋转棒和悬挂试验中的炎症。蛋白质组分析表明分子水平上的神经炎症减轻。我们在小鼠大脑中检测到的 7416 种蛋白质中，鉴定出与神经炎症相关的 399 种蛋白质。其中，Gps2、Vamp8、Slc6a3、Slc18a2、Slc5a7、Rgs9、Lrrc1、Ppp1r1b、Gnal 和 Adcy5/6 与药物的作用有关。SA-AA 前药通过调节神经炎症的关键途径，如细胞应激反应和化学突触传递，减轻 LPS 诱导的神经炎症。
通过利用 LAT1 可以提高 NSAIDs 的疗效，并将其重新用于治疗神经炎症。这种改善的脑内传递和小胶质细胞定位可以应用于其他炎症调节剂，以实现有效的靶向中枢神经系统治疗。
