Peripheral sensory neuropathy is one of the most common complications of diabetes. Accumulating evidence suggests that chronic low-grade inflammation is involved in the pathogenesis of the disease. We hypothesize that hyperglycemia causes changes in histone acetylation and release of inflammatory mediators in the peripheral nervous system of diabetic animals with painful neuropathy; therefore blocking this increase will prevent or delay the development of neuropathy. High mobility group box 1 (HMGB1), a nuclear protein released by injured and severely stressed cells, promotes cytokine release via histone acetylation and its interaction with the Toll-like receptor (TLR). In this study we investigated the changes in inflammatory mediators and histone modifications in the dorsal root ganglia (DRG) and spinal cord dorsal horn neurons as well as compared the changes in behavior with treatment. Type 2 diabetic (T2D) animals with pain were treated with HMGB1 inhibitor Glycyrrhizin (GLC) for 2 days a week for 3 weeks at 50 mg/kg I.P. injection 6 weeks after diabetes. T2D animals demonstrated significant changes in thermal hyperalgesia manifested by a decrease in withdrawal latency to heat, mechanical hyperalgesia as measured by the Randall Sellito method of paw pressure at 6 weeks after diabetes and also exhibited marked increases in HMGB1, IL1β, TLR4 and H3K9 acetylation as determined by the Western blot analysis and immunohistochemistry. We analyzed the T2D animals with treatment or without treatment at 3 weeks after treatment. Our results show that animals treated with GLC had significant decrease in thermal hyperalgesia along with changes in histone acetylation and expression of inflammatory mediators. This preliminary study suggests that HMGB1 and histone acetylation play an important role in the inflammatory aspect of the painful neuropathy in T1D animals and may provide a novel treatment approach for this difficult-to-treat complication of diabetes.
M. Chattopadhyay: None. V. Thakur: None.