Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
Medicina (Kaunas). 2020 Oct 29;56(11):573. doi: 10.3390/medicina56110573.
Insulin resistance (IR) is a serious condition leading to development of diabetes and cardiovascular complications. Hyper-activation of cannabinoid receptors-1 (CB1) has been linked to the development of metabolic disorders such as IR. Therefore, the effect of blocking CB1 on the development of IR was investigated in the present study. A 12-week high-fructose/high-salt feeding model of metabolic syndrome was used to induce IR in male Wistar rats. For this purpose, two different CB1-antagonists were synthesized and administered to the rats during the final four weeks of the study, AM6545, the peripheral neutral antagonist and AM4113, the central neutral antagonist. High-fructose/salt feeding for 12 weeks led to development of IR while both AM6545 and AM4113, administered in the last 4 weeks, significantly inhibited IR. This was correlated with increased animal body weight wherein both AM6545 and AM4113 decreased body weight in IR animals but with loss of IR/body weight correlation. While IR animals showed significant elevations in serum cholesterol and triglycerides with no direct correlation with IR, both AM6545 and AM4113 inhibited these elevations, with direct IR/cholesterol correlation in case of AM6545. IR animals had elevated serum uric acid, which was reduced by both AM6545 and AM4113. In addition, IR animals had decreased adiponectin levels and elevated liver TNFα content with strong IR/adiponectin and IR/TNFα correlations. AM6545 inhibited the decreased adiponectin and the increased TNFα levels and retained the strong IR/adiponectin correlation. However, AM4113 inhibited the decreased adiponectin and the increased TNFα levels, but with loss of IR/adiponectin and IR/TNFα correlations. Both CB1 neutral antagonists alleviated IR peripherally, and exerted similar effects on rats with metabolic syndrome. They also displayed anti-dyslipidemic, anti-hyperurecemic and anti-inflammatory effects. Overall, these results should assist in the development of CB1 neutral antagonists with improved safety profiles for managing metabolic disorders.
胰岛素抵抗（IR）是导致糖尿病和心血管并发症发展的严重疾病。大麻素受体 1（CB1）的过度激活与代谢紊乱的发展有关，如 IR。因此，本研究旨在研究阻断 CB1 对 IR 发展的影响。
本研究采用 12 周高果糖/高盐喂养代谢综合征模型诱导雄性 Wistar 大鼠产生 IR。为此，合成了两种不同的 CB1 拮抗剂，并在研究的最后四周给予大鼠，分别是外周中性拮抗剂 AM6545 和中枢中性拮抗剂 AM4113。
12 周高果糖/盐喂养导致 IR 的发生，而在最后 4 周给予 AM6545 和 AM4113 均能显著抑制 IR。这与动物体重增加有关，其中 AM6545 和 AM4113 降低了 IR 动物的体重，但失去了 IR/体重的相关性。虽然 IR 动物的血清胆固醇和甘油三酯显著升高，但与 IR 无直接相关性，而 AM6545 和 AM4113 抑制了这些升高，而 AM6545 则与胆固醇有直接的 IR 相关性。IR 动物的血清尿酸升高，而 AM6545 和 AM4113 均可降低其水平。此外，IR 动物的脂联素水平降低，肝脏 TNFα 含量升高，且脂联素和 TNFα 与 IR 之间具有很强的相关性。AM6545 抑制了脂联素的降低和 TNFα 水平的升高，同时保留了脂联素与 IR 之间的强相关性。然而，AM4113 抑制了脂联素的降低和 TNFα 水平的升高，但失去了脂联素与 IR 之间以及 TNFα 与 IR 之间的相关性。
两种 CB1 中性拮抗剂均能减轻外周组织的 IR，并对代谢综合征大鼠产生类似的作用。它们还具有抗血脂异常、抗高尿酸血症和抗炎作用。总之，这些结果将有助于开发具有更好安全性的 CB1 中性拮抗剂，以用于治疗代谢紊乱。
