Long-lasting and fast methylglyoxal-scavenging peptide CycK(Myr)R4E alleviates chronic pain in type 2 diabetic mice.

INTRODUCTION

Pathological levels of methylglyoxal (MG), a reactive dicarbonyl product of glucose, contribute to major neurological complications associated with type II diabetes, including chronic neuropathic pain. Strategies to target elevated MG have included small molecule MG scavengers, but scavenger deficiencies in proteolytic stability and onset of scavenging activity have precluded clinical translation. To address this gap, we developed a long-lasting and highly reactive cyclic peptide CycK(Myr)R4E, and here evaluated its antihyperalgesic efficacy in the db/db mouse model of type II diabetes painful diabetic neuropathy.

OBJECTIVES

To test the hypothesis that CycK(Myr)R4E can reduce behavioral and molecular signs of painful diabetic neuropathy.

METHODS

We assessed heat hypersensitivity as an index of hyperalgesia, and touch-evoked expression of phosphorylated extracellular signal-regulated kinase as a measure of neuronal activity in spinal cord dorsal horn.

RESULTS

We report that a single systemic injection of CycK(Myr)R4E (3 mg/kg) reversed heat hypersensitivity. Repeated systemic injection of CycK(Myr)R4E (0.125 mg/kg, 3 times per week, 6-12 weeks of age) prevented heat hypersensitivity and reduced stimulus-evoked phosphorylated extracellular signal-regulated kinase.

CONCLUSION

These studies promote CycK(Myr)R4E as the most promising MG scavenger for the prevention and treatment of hyperalgesia in type 2 diabetic neuropathic pain.