Inhibition of the Cysteine Protease Cathepsin K Attenuates Diabetic Neuropathic Pain

Abstract ID 102312 Poster Board 091 Background and Aim: Diabetes mellitus is escalating at epidemic proportions worldwide, posing a huge clinical and economic burden on society. Diabetic peripheral neuropathy (DPN) is a painful and debilitating complication of diabetes that develops in 30-50% of diabetic patients. The drugs currently available to treat DNP lack specificity and only transiently relieve neuropathic pain. Recent studies demonstrated that the cysteine protease cathepsin K plays a critical role in the development of nociceptive pain, and genetic knockout of cathepsin K protects against chemical hypersensitivity in mice. The present study was undertaken to assess the efficacy of cathepsin K inhibition in alleviating DNP. Methods: Five-week-old C57BL/6J mice were rendered diabetic through a single intraperitoneal injection of streptozotocin (STZ, 150 mg/kg, dissolved in 50 mM citrate buffer), while the control animals received the buffer (n=10 per group). DNP was confirmed in diabetic mice using baseline measurements of peripheral nerve functions by determining mechanical response latency. Diabetic animals were challenged with a single intraperitoneal injection of Cathepsin K inhibitor II (0.01 mg/kg, EMD Millipore # 21937), and the measurements were repeated. Data were expressed as mean ± S.E.M and statistically evaluated using the paired Student t-test. Results: STZ injections induced diabetes in the mice as evidenced by elevated blood glucose levels (459.22 ± 35.8 mg/dL). Diabetic mice exhibited mechanical hyposensitivity as indicated by a twofold increase in the von Frey filament threshold (4.75 ± 0.54 g) relative to controls (2.76 ± 0.55 g, p ≥ 0.05, n=10). Treatment with cathepsin inhibitor II resulted in a complete reversal of the diabetes-induced mechanical hyposensitivity (2.42 ± 0.60 g, p ≥ 0.05) (Fig. 1). Cathepsin K inhibitor did not alter the blood glucose levels in these animals. Conclusion: Inhibition of cathepsin K may represent a viable strategy to treat DNP. Research reported in this publication was supported in part by the Institutional Development Awards (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM121310.