Fernández-Martínez Eduardo, Morales-Ríos Martha S, Pérez-Alvarez Víctor, Muriel Pablo
Section of Pharmacology, CINVESTAV-I.P.N., Apdo. Postal 14-740, México 07000, DF.
Biochem Pharmacol. 2004 Oct 1;68(7):1321-9. doi: 10.1016/j.bcp.2004.06.018.
Thalidomide has shown to inhibit, selectively and mainly the cytokine tumor necrosis factor-alpha (TNF-alpha), thus, thalidomide has inhibitory consequences on other cytokines; this is ascribed as an immunomodulatory effect. Novel thalidomide analogs are reported with immunomodulatory activity. The aim of this work was to synthesize some of these analogs and to assess them as immunomodulatory agents in an acute model of LPS-induced septic challenge in rat. Animal groups received orally twice a day vehicle carboxymethylcellulose (0.9%), or thalidomide in suspension (100mg/kg), or analogs in an equimolar dose. Two hours after last dose, rats were injected with saline (NaCl, 0.9%, i.p.) or LPS (5mg/kg, i.p.). Groups were sacrificed 2h after injection and samples of blood and liver were obtained. TNF-alpha, interleukin-6, -1beta, and -10 (IL-6, IL-1beta, IL-10) were quantified by enzyme linked immunosorbent assay (ELISA) and studied in plasma and liver. After 2h of LPS-induction, different patterns of measured cytokines were observed with thalidomide analogs administration evidencing their immunomodulatory effects. Interestingly, some analogs decreased significantly plasma and hepatic levels of LPS-induced proinflammatory TNF-alpha and others increased plasma concentration of anti-inflammatory IL-10. Thalidomide analogs also showed slight effects on the remaining proinflammatory cytokines. Differences among immunomodulatory effects of analogs can be related to potency, mechanism of action, and half lives. Thalidomide analogs could be used as a pharmacological tool and in therapeutics in the future.
沙利度胺已显示出能选择性地且主要抑制细胞因子肿瘤坏死因子-α（TNF-α），因此，沙利度胺对其他细胞因子也有抑制作用；这被归因于一种免疫调节作用。据报道，新型沙利度胺类似物具有免疫调节活性。这项工作的目的是合成其中一些类似物，并在大鼠脂多糖诱导的败血症急性模型中评估它们作为免疫调节药物的效果。动物分组每天口服两次赋形剂羧甲基纤维素（0.9%），或沙利度胺悬浮液（100mg/kg），或等摩尔剂量的类似物。最后一次给药两小时后，给大鼠注射生理盐水（0.9%的NaCl，腹腔注射）或脂多糖（5mg/kg，腹腔注射）。注射后2小时处死各组动物，获取血液和肝脏样本。通过酶联免疫吸附测定（ELISA）对TNF-α、白细胞介素-6、-1β和-10（IL-6、IL-1β、IL-10）进行定量，并在血浆和肝脏中进行研究。脂多糖诱导2小时后，观察到给予沙利度胺类似物后所测细胞因子的不同模式，证明了它们的免疫调节作用。有趣的是，一些类似物显著降低了脂多糖诱导的促炎TNF-α的血浆和肝脏水平，而其他类似物则提高了抗炎IL-10的血浆浓度。沙利度胺类似物对其余促炎细胞因子也有轻微影响。类似物免疫调节作用的差异可能与效力、作用机制和半衰期有关。沙利度胺类似物未来可作为一种药理学工具并用于治疗。
