R-phenylpiracetam (R-PhP, (4R)-2-(4-phenyl-2-oxopyrrolidin-1-yl)acetamide) is an optical isomer of phenotropil, a clinically-used nootropic drug that improves physical condition and cognition. Recently, R-PhP was shown to bind to the dopamine transporter (DAT). Since growing evidence suggests that dysfunction of the dopaminergic system is associated with persistent neuroinflammation, the aim of this study was to determine whether R-PhP, an inhibitor of DAT, has neuroprotective and anti-inflammatory effects in male mice. The pharmacokinetic profiles of R-PhP in mouse plasma and its bioavailability in brain tissue were assessed. To study possible molecular mechanisms involved in the anti-inflammatory activity of R-PhP, target profiling was performed using radioligand binding and enzymatic activity assays. To clarify the neuroprotective and anti-inflammatory effects of R-PhP, we used a lipopolysaccharide (LPS)-induced endotoxaemia model characterized by reduced body temperature and overexpression of inflammatory genes in the brain. In addition, the antinociceptive and anti-inflammatory effects of R-PhP were tested using carrageenan-induced paw oedema and formalin-induced paw-licking tests. R-PhP (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (ip) and peroral (po) injections. The maximal concentration of R-PhP in the brain tissues was 28 µg/g and 18 µg/g tissue after ip and po administration, respectively. In radioligand binding assays, DAT was the only significant molecular target found for R-PhP. A single ip injection of R-PhP significantly attenuated the LPS-induced body temperature reduction and the overexpression of inflammatory genes, such as tumour necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β) and inducible nitric oxide synthase (iNOS). Seven-day po pretreatment with R-PhP dose-dependently reduced paw oedema and the antinociceptive response, as shown by the carrageenan-induced paw oedema test. In addition, R-PhP decreased the nociceptive response during the inflammatory phase in the formalin-induced paw-licking test. Our study showed that R-PhP possesses neuroprotective and anti-inflammatory effects, demonstrating the potential of DAT inhibitors as effective therapeutics.

R-苯基吡乙酰胺（R -PhP，（4 R）-2-（4-苯基-2-氧吡咯烷-1-基）乙酰胺）是phenotropil的旋光异构体，phenotropil是一种临床使用的促智药物，可改善身体状况和认知能力。最近，显示R -PhP结合多巴胺转运蛋白（DAT）。由于越来越多的证据表明多巴胺能系统功能障碍与持续性神经发炎有关，因此本研究的目的是确定DAT抑制剂R -PhP在雄性小鼠中是否具有神经保护和抗炎作用。R的药代动力学特征 评估了小鼠血浆中的PhP及其在脑组织中的生物利用度。为了研究与R - PhP的抗炎活性有关的可能分子机制，使用放射性配体结合和酶活性测定法进行了靶标分析。为了阐明R - PhP的神经保护和抗炎作用，我们使用了脂多糖（LPS）诱导的内毒素血症模型，其特征在于体温降低和脑内炎性基因的过度表达。另外，使用角叉菜胶诱导的爪水肿和福尔马林诱导的舔爪试验测试了R -PhP的抗伤害感受和抗炎作用。[R-腹膜内（ip）和经口（po）注射后15分钟，PhP（50 mg / kg）到达脑组织。腹膜内和口服给药后，脑组织中R -PhP的最大浓度分别为28 µg / g和18 µg / g。在放射性配体结合测定中，DAT是R -PhP的唯一重要分子靶标。腹膜内注射R -PhP可显着减弱LPS诱导的体温降低和炎症基因的过度表达，例如肿瘤坏死因子-α（TNF-α），白介素1β（IL-1β）和诱导型一氧化氮合酶。 （iNOS）。用R进行7天po预处理-角叉菜胶诱导的爪水肿试验显示-PhP剂量依赖性地减少了爪水肿和抗伤害感受性反应。另外，在福尔马林诱导的舔爪试验中，R -PhP在炎症阶段降低了伤害感受性反应。我们的研究表明，R -PhP具有神经保护和抗炎作用，证明了DAT抑制剂作为有效疗法的潜力。