LAUSR

ABSTRACT Methylglyoxal 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 disc 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 methylglyoxal signaling as a mechanism underlying neuropathy improvement. We found that mice injected with methylglyoxal displayed nociceptive behaviors, whereas mice pre-fed a ketogenic diet were resistant to mechanical allodynia elicited by methylglyoxal. In addition, levels of circulating methylglyoxal were reduced in ketogenic diet-fed mice and negatively correlated with levels of the ketone body β-hydroxybutyrate. Methylglyoxal is normally scavenged by the glyoxalase system, and ketogenic diet-fed mice displayed increased glyoxalase 1 activity compared to chow-fed control mice. Recent studies also suggest ketone bodies contribute to methylglyoxal detoxification, consistent with negative correlation between β-hydroxybutyrate and methylglyoxal. To assess whether ketone bodies modified methylglyoxal-evoked nociception via direct methylglyoxal detoxification, we coincubated either acetoacetate or β-hydroxybutyrate with methylglyoxal prior to injection. Mice receiving intraplantar methylglyoxal injection exhibit increased nociceptive behavior (lifting, licking, biting, scratching), which was significantly reduced by coincubation with either acetoacetate or β-hydroxybutyrate. Methylglyoxal increased phospho-ERK-positive cells in the spinal dorsal horn, and this evoked spinal activation was ameliorated by preincubation with acetoacetate or β-hydroxybutyrate. These results suggest that a ketogenic diet and ketone bodies ameliorate methylglyoxal-evoked nociception, partially through detoxification of methylglyoxal, and provide rationale for therapeutic intervention with a ketogenic diet in methylglyoxal-driven pathologies.