Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61 Cheomdan-ro, Dong-gu, Daegu, 41068, South Korea.
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, 80 Cheombok-ro, Dong-gu, Daegu, 41061, South Korea.
J Neuroinflammation. 2018 Oct 11;15(1):286. doi: 10.1186/s12974-018-1321-3.
Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer's disease (AD). Thus, modulating the neuroinflammatory response represents a potential therapeutic strategy for treating neurodegenerative diseases. Several recent studies have shown that dopamine (DA) and its receptors are expressed in immune cells and are involved in the neuroinflammatory response. Thus, we recently developed and synthesized a non-self-polymerizing analog of DA (CA140) and examined the effect of CA140 on neuroinflammation.
To determine the effects of CA140 on the neuroinflammatory response, BV2 microglial cells were pretreated with lipopolysaccharide (LPS, 1 μg/mL), followed by treatment with CA140 (10 μM) and analysis by reverse transcription-polymerase chain reaction (RT-PCR). To examine whether CA140 alters the neuroinflammatory response in vivo, wild-type mice were injected with both LPS (10 mg/kg, intraperitoneally (i.p.)) and CA140 (30 mg/kg, i.p.), and immunohistochemistry was performed. In addition, familial AD (5xFAD) mice were injected with CA140 or vehicle daily for 2 weeks and examined for microglial and astrocyte activation.
Pre- or post-treatment with CA140 differentially regulated proinflammatory responses in LPS-stimulated microglia and astrocytes. Interestingly, CA140 regulated D1R levels to alter LPS-induced proinflammatory responses. CA140 significantly downregulated LPS-induced phosphorylation of ERK and STAT3 in BV2 microglia cells. In addition, CA140-injected wild-type mice exhibited significantly decreased LPS-induced microglial and astrocyte activation. Moreover, CA140-injected 5xFAD mice exhibited significantly reduced microglial and astrocyte activation.
CA140 may be beneficial for preventing and treating neuroinflammatory-related diseases, including AD.
神经炎症与包括阿尔茨海默病（AD）在内的神经退行性疾病有关。因此，调节神经炎症反应代表了治疗神经退行性疾病的一种潜在治疗策略。最近的几项研究表明，多巴胺（DA）及其受体存在于免疫细胞中，并参与神经炎症反应。因此，我们最近开发并合成了一种非自聚合的 DA 类似物（CA140），并研究了 CA140 对神经炎症的影响。
为了确定 CA140 对神经炎症反应的影响，用脂多糖（LPS，1μg/mL）预处理 BV2 小胶质细胞，然后用 CA140（10μM）处理，并通过逆转录-聚合酶链反应（RT-PCR）进行分析。为了研究 CA140 是否改变体内的神经炎症反应，用 LPS（10mg/kg，腹腔内（i.p.））和 CA140（30mg/kg，i.p.）注射野生型小鼠，并进行免疫组织化学分析。此外，用 CA140 或载体每日注射家族性 AD（5xFAD）小鼠 2 周，并检查小胶质细胞和星形胶质细胞的激活情况。
CA140 的预或后处理以不同的方式调节 LPS 刺激的小胶质细胞和星形胶质细胞中的促炎反应。有趣的是，CA140 通过调节 D1R 水平来调节 LPS 诱导的促炎反应。CA140 显著下调 LPS 诱导的 BV2 小胶质细胞中 ERK 和 STAT3 的磷酸化。此外，CA140 注射的野生型小鼠表现出 LPS 诱导的小胶质细胞和星形胶质细胞激活明显减少。此外，CA140 注射的 5xFAD 小鼠表现出小胶质细胞和星形胶质细胞激活明显减少。
CA140 可能有益于预防和治疗包括 AD 在内的神经炎症相关疾病。
