Ketogenic diet prevents methylglyoxal-evoked nociception by scavenging methylglyoxal

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 ...
Source: Pain - Category: Anesthesiology Tags: Research Paper Source Type: research