Mission Connect Mild TBI Translational Research Consortium: To Study the Role of IL-1 and TNF Receptor Activation in Neurological Deficits after TBI.

摘要

Mild traumatic brain injury (mTBI), such as mild blast injuries due to improvised exploding devices, result in long term impairment of cognition and behavior. Our hypothesis is that there are inflammatory outcomes, via the IL-1 and TNF signaling pathways, to mTBI over time that cause the neuropathogenesis responsible for the clinical outcomes. We developed and characterized an adaptation of the rat moderate brain lateral fluid percussion brain injury model (mLFP injury) and a mild blast brain injury model (mBBI) developed by us with similar resulting righting reflex response times (RRRT). Both showed increased IL-1 and TNF levels, macrophage/ microglial and astrocytic activation, blood brain barrier disruption, neuronal losses and behavioral impairment. mBBI showed increased phosphorylated Tau protein (p-Tau) levels, a neuroencephalopathy marker. For mLFP injury, we showed beneficial outcomes after IL-1 receptor blockade with FDA-approved Kineret and of TNF receptor with FDA-approved Etanercept, singly or in combination, decreased neuropathology and improved outcomes. We determined an optimal time course of treatment. For mBBI, we showed that there were increases in IL-1 and TNF levels, macrophage/ microglial and astrocytic activation, and phosphorylated Tau (p- Tau) levels, the latter indicative of neuroencephalopathy, in the injured cortex, hippocampus, thalamus and amygdala. Whereas there was an apparent correlation between the RRRT values and the p-Tau levels, general inflammatory responses were more threshold-triggered. For mBBI we showed a beneficial outcome after blockade of IL-1 receptor (IL-1R) with Kineret. These results suggest potential therapies for mild blast injuries.