Reduction of Astrocyte and Microglial Activation in Insulin/Saline‐treated Diabetic Ketoacidosis by the KCa3.1 Blocker TRAM‐34

Abstract

Previous studies have provided evidence that diabetic ketoacidosis (DKA) and/or its treatment with insulin and saline (I/S) causes brain injury in children. However, mechanisms underlying DKA‐related brain injury have been poorly understood. In recent studies using immunohistochemistry (IHC) in a streptozotocin (STZ)‐induced DKA juvenile rat model, we examined expression of glial fibrillary acidic protein (GFAP) and CD‐11b protein (OX42) in hippocampus, cortex and striatum at 4, 24 and 72 hr after I/S treatment. We found increased GFAP in hippocampus as well as increased OX42 in both hippocampus and cortex, suggesting that reactive gliosis and microglial activation occur during DKA‐related brain injury. Other studies have shown that TRAM‐34, a KCa3.1 channel blocker, reduces microglial activation in the rat middle cerebral artery occlusion model of cerebral ischemia. The present study was conducted to determine whether TRAM‐34 could also reduce DKA‐related inflammatory changes in the brain. We used IHC to investigate the effects of TRAM‐34 on GFAP and OX‐42 expression in brain sections from juvenile rats with STZ‐induced DKA before, during and after treatment with insulin and saline. As in previous studies, OX42 staining intensity was increased in the hippocampus and cortex during DKA and increased further 4 hours after I/S treatment in a manner sustained through 24 and 72 hours after recovery from DKA. GFAP staining intensity was also increased over the same time course in hippocampus but not cortex. However, in rats administered TRAM‐34 (IP, 40 mg/kg) at the start of I/S treatment, staining intensities of both OX42 and GFAP were significantly reduced at all time points after DKA. OX42 staining intensity was also decreased during DKA prior to I/S treatment in TRAM‐34 treated rats. We conclude that DKA causes inflammatory changes in the brain including reactive gliosis and activation of microglia. Treatment with TRAM‐34 not only decreases microglial activation but also reduces reactive gliosis, suggesting an overall decrease in the brain's inflammatory response to DKA.Support or Funding InformationSupported by ADA