Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Street Coronel Francisco H dos Santos S/N, P.O. Box 19031, Curitiba, PR 81540-990, Brazil.
Department of Pathological Sciences, State University of Londrina, Londrina, PR, Brazil.
Prog Neuropsychopharmacol Biol Psychiatry. 2024 Jul 13;133:111028. doi: 10.1016/j.pnpbp.2024.111028. Epub 2024 May 15.
Protectin DX (PDX), a specialized pro-resolving lipid mediator, presents potential therapeutic applications across various medical conditions due to its anti-inflammatory and antioxidant properties. Since type-1 diabetes mellitus (T1DM) is a disease with an inflammatory and oxidative profile, exploring the use of PDX in addressing T1DM and its associated comorbidities, including diabetic neuropathic pain, depression, and anxiety becomes urgent. Thus, in the current study, after 2 weeks of T1DM induction with streptozotocin (60 mg/kg) in Wistar rats, PDX (1, 3, and 10 ng/animal; i.p. injection of 200 μl/animal) was administered specifically on days 14, 15, 18, 21, 24, and 27 after T1DM induction. We investigated the PDX's effectiveness in alleviating neuropathic pain (mechanical allodynia; experiment 1), anxiety-like and depressive-like behaviors (experiment 2). Also, we studied whether the PDX treatment would induce antioxidant effects in the blood plasma, hippocampus, and prefrontal cortex (experiment 3), brain areas involved in the modulation of emotions. For evaluating mechanical allodynia, animals were repeatedly submitted to the Von Frey test; while for studying anxiety-like responses, animals were submitted to the elevated plus maze (day 26) and open field (day 28) tests. To analyze depressive-like behaviors, the animals were tested in the modified forced swimming test (day 28) immediately after the open field test. Our data demonstrated that PDX consistently increased the mechanical threshold throughout the study at the two highest doses, indicative of antinociceptive effect. Concerning depressive-like and anxiety-like behavior, all PDX doses effectively prevented these behaviors when compared to vehicle-treated T1DM rats. The PDX treatment significantly protected against the increased oxidative stress parameters in blood plasma and in hippocampus and prefrontal cortex. Interestingly, treated animals presented improvement on diabetes-related parameters by promoting weight gain and reducing hyperglycemia in T1DM rats. These findings suggest that PDX improved diabetic neuropathic pain, and induced antidepressant-like and anxiolytic-like effects, in addition to improving parameters related to the diabetic condition. It is worth noting that PDX also presented a protective action demonstrated by its antioxidant effects. To conclude, our findings suggest PDX treatment may be a promising candidate for improving the diabetic condition per se along with highly disabling comorbidities such as diabetic neuropathic pain and emotional disturbances associated with T1DM.
保护素 DX（PDX）是一种专门的促解决脂质介质，由于其具有抗炎和抗氧化特性，因此在各种医学病症中具有潜在的治疗应用。由于 1 型糖尿病（T1DM）是一种具有炎症和氧化特征的疾病，因此探索 PDX 在解决 T1DM 及其相关合并症（包括糖尿病性神经痛、抑郁和焦虑）中的作用变得紧迫。因此，在本研究中，在 Wistar 大鼠中用链脲佐菌素（60mg/kg）诱导 T1DM 2 周后，在 T1DM 诱导后第 14、15、18、21、24 和 27 天，分别用 PDX（1、3 和 10ng/动物；腹腔内注射 200μl/动物）进行治疗。我们研究了 PDX 在缓解神经痛（机械性痛觉过敏；实验 1）、焦虑样和抑郁样行为（实验 2）方面的有效性。此外，我们还研究了 PDX 治疗是否会在血浆、海马体和前额叶皮层（实验 3）中诱导抗氧化作用，这些脑区参与情绪的调节。为了评估机械性痛觉过敏，动物反复接受 Von Frey 测试；而在研究焦虑样反应时，动物接受高架十字迷宫（第 26 天）和旷场（第 28 天）测试。为了分析抑郁样行为，动物在旷场测试后立即在改良强迫游泳测试（第 28 天）中进行测试。我们的数据表明，在研究过程中，PDX 始终以两种最高剂量持续增加机械阈值，表明具有镇痛作用。关于抑郁样和焦虑样行为，与接受 vehicle 治疗的 T1DM 大鼠相比，所有 PDX 剂量均能有效预防这些行为。PDX 治疗显著防止了血浆和海马体及前额叶皮层中氧化应激参数的增加。有趣的是，治疗动物通过促进体重增加和降低 T1DM 大鼠的高血糖，改善了与糖尿病相关的参数。这些发现表明，PDX 改善了糖尿病性神经痛，并诱导了抗抑郁样和抗焦虑样作用，同时改善了与糖尿病相关的参数。值得注意的是，PDX 还表现出抗氧化作用的保护作用。总之，我们的研究结果表明，PDX 治疗可能是一种有前途的候选药物，可改善糖尿病本身以及与 1 型糖尿病相关的高度致残合并症，如糖尿病性神经痛和情绪障碍。
