Departments of Anatomy and Cell Biology.
Anesthesiology, University of Kansas Medical Center, Kansas City, KS, United States.
Pain. 2022 Dec 1;163(12):e1207-e1216. doi: 10.1097/j.pain.0000000000002667. Epub 2022 Apr 28.
Methylglyoxal (MGO) is a reactive dicarbonyl byproduct of glycolysis implicated in a growing number of neuropathic pain conditions, including chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, and radiculopathy with lumbar disk herniation. Recent studies show success in preclinical models treating these disorders with an interventional ketogenic diet. Here, we tested the hypothesis that a ketogenic diet modifies pathological MGO signaling as a mechanism underlying neuropathy improvement. We found that mice injected with MGO displayed nocifensive behaviors, whereas mice prefed a ketogenic diet were resistant to mechanical allodynia elicited by MGO. In addition, levels of circulating MGO were reduced in ketogenic diet-fed mice and negatively correlated with levels of the ketone body β-hydroxybutyrate (β-HB). Methylglyoxal is normally scavenged by the glyoxalase system, and ketogenic diet-fed mice displayed increased glyoxalase 1 activity compared with chow-fed control mice. Recent studies also suggest that ketone bodies contribute to MGO detoxification, consistent with a negative correlation between β-HB and MGO. To assess whether ketone bodies modified MGO-evoked nociception through direct MGO detoxification, we coincubated either acetoacetate or β-HB with MGO before injection. Mice receiving intraplantar MGO injection exhibit increased nociceptive behavior (lifting, licking, biting, and scratching), which was significantly reduced by coincubation with either acetoacetate or β-HB. Methylglyoxal increased phospho-extracellular signal-regulated kinase-positive cells in the spinal dorsal horn, and this evoked spinal activation was ameliorated by preincubation with acetoacetate or β-HB. These results suggest that a ketogenic diet and ketone bodies ameliorate MGO-evoked nociception, partially through detoxification of MGO, and provide rationale for therapeutic intervention with a ketogenic diet in MGO-driven pathologies.
甲基乙二醛（MGO）是糖酵解过程中的一种反应性二羰基化合物，与越来越多的神经病理性疼痛病症有关，包括化疗引起的周围神经病、糖尿病周围神经病和腰椎间盘突出症引起的神经根病。最近的研究表明，在这些疾病的临床前模型中，采用介入性生酮饮食治疗取得了成功。在这里，我们检验了这样一个假设，即生酮饮食通过改变病理性 MGO 信号作为神经病变改善的机制。我们发现，注射 MGO 的小鼠表现出伤害性行为，而预先给予生酮饮食的小鼠对 MGO 引起的机械性超敏反应具有抗性。此外，在给予生酮饮食的小鼠中，循环 MGO 的水平降低，并且与酮体β-羟丁酸（β-HB）的水平呈负相关。MGO 通常被糖氧醛酸酶系统清除，与给予标准饮食的对照小鼠相比，给予生酮饮食的小鼠显示出糖氧醛酸酶 1 活性增加。最近的研究还表明，酮体有助于 MGO 的解毒，这与β-HB 和 MGO 之间的负相关一致。为了评估酮体是否通过直接 MGO 解毒来改变 MGO 诱发的痛觉过敏，我们在注射前将乙酰乙酸盐或β-HB 与 MGO 共同孵育。接受足底内 MGO 注射的小鼠表现出增加的痛觉行为（提起、舔舐、咬和抓挠），这通过与乙酰乙酸盐或β-HB 共同孵育显著减少。MGO 增加了脊髓背角中磷酸化细胞外信号调节激酶阳性细胞的数量，并且这种诱导的脊髓激活通过与乙酰乙酸盐或β-HB 预孵育得到改善。这些结果表明，生酮饮食和酮体通过 MGO 的解毒改善 MGO 诱发的痛觉过敏，部分通过 MGO 的解毒，并为在 MGO 驱动的病理中采用生酮饮食进行治疗干预提供了依据。
