Therapeutic potential of orally applied KB-R7943 in streptozotocin-induced neuropathy in rats

Abstract

Both peripheral neuropathy and depression can be viewed as neurodegeneration's consequences of diabetes, at least in part coexisting with or resulting from sodium-calcium dysbalance. This study aims to assess the therapeutic potential of the orally applied reverse-mode inhibitor of the sodium-calcium exchanger (NCX) KB-R7943 in the streptozotocin (STZ) diabetes model in rats. A pilot pharmacokinetic (PK) study with high-performance liquid chromatography with high-resolution tandem mass spectrometric detection revealed higher drug exposure (AUC), lower volume of distribution (Vd) and clearance (Cl), and faster decline of the plasma concentration (ƛ) in rats with diabetes vs. controls. Brain and heart accumulation and urinary excretion of the unmetabolized KB-R7943 at least 24 h were also demonstrated in all rats. However, heart and hippocampus KB-R7943 penetration (AUCtissue/AUCplasma) was higher in controls vs. diabetic rats. The development of thermal, mechanical, and chemical-induced allodynia was assessed with the Cold plate test (CPT), Randall-Stiletto (R–S) test, and 0.5% formalin test (FT). Amitriptyline 10 mg/kg, KB-R7943 5 mg/kg, or 10 mg/kg p.o once daily was applied from the 28th to the 49th day. The body weight, coat status, CPT, R–S, and FT were evaluated on days (−5), 0, and 42. On day 41, a forced swim test and 24-h spontaneous physical activities were assessed. The chronic treatment effects were calculated as % of the maximum. A dose-depended amelioration of neuropathic and depression-like effects was demonstrated. The oral application of KB-R7943 for potentially treating neurodegenerative consequences of diabetes merits further studies. The brain, heart, and kidneys are essential contributors to the PKs of this drug, and their safety involvement needs to be further characterized.

Keywords

• Diabetic neuropathy
• KB-R7943
• Amitriptyline
• Behavior tests
• Pharmacokinetics