Novel EPO peptide therapy for chronic rmTBI dependent neurodegeneration and neuroinflammation

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This project examines a treatment for chronic repeated mild traumatic brain injury (rmTBI). rmTBI is a chronic neurodegenerative disease afflicting individuals who have received multiple concussive head injuries such as soldiers and contact sport players. There is no known cure for this disease that is often marked by progressive neurological deterioration. rmTBI can lead to memory loss, mood problems, suicidality, and dementia. The disease is associated with chronic neuroinflammation, axonal injury and brain atrophy. There is extensive evidence that long-term inflammation worsens neurodegenerative disease. Our laboratory has developed JM4, a novel immune/inflammatory regulatory agent. JM4 is a short peptide derived from the cytokine erythropoietin. Whole molecule erythropoietin has well established neuroprotective and immune/inflammatory modulating effects, however, its use in clinical settings is limited since it can lead to dangerous polycythemic levels of red blood cells. JM4 crosses the blood-brain barrier and retains erythropoietin's beneficial effects without the side effect of hematopoiesis. Preliminary studies showed that it was highly effective in reducing the immune/inflammatory responses in models of experimental autoimmune encephalomyelitis and that even a brief course of JM4 induced long term improvement. It also decreased neuropathology and clinical deficit in acute traumatic brain injury. Furthermore, in a mouse model of frontotemporal dementia, it reduced clinical signs, microglial and astrocytic activation and tauopathy. JM4 has completed preclinical development and was recently approved by the FDA as an Investigational New Drug (IND) for the treatment of acute multiple sclerosis flare-ups. This current study examines the hypothesis that JM4 will have beneficial effects in slowing or reversing deficits in chronic rmTBI by profoundly reducing the inflammatory response. Our preliminary data showed that JM4 can reduce chronic rmTBI even when administered a year after the initial injuries. We will use a validated repeat weight drop mouse model of chronic rmTBI to evaluate the therapeutic potential of JM4 in the following experiments: SA1. We found that a JM4 dose of 10ug/day was effective therapy in animal models of tauopathy, MS, and acute TBI; however, the optimal dose of JM4 in chronic rmTBI may not be the same. Accordingly, we will establish a long duration JM4 dose response curve initiated at 12 months after injury. Animals will be tested for behavioral deficit at 1, 6, 12, and 18 months after impact and sacrificed at 18 months. SA2. We will examine whether short-term pulse JM4 therapy may also be effective in chronic rmTBI. The experimental design will be identical to SA1, but JM4 therapy will be restricted to 30 days. SA3. We believe that synaptic dysfunction is a major contributor to chronic cognitive deficit in TBI patients. To correlate cognitive performance with electrophysiological measures within subjects, synaptic transmission and long-term potentiation (LTP) will be measured in chronic injured and control mice by electrophysiology. Brain slices will be used to assess basal synaptic transmission and LTP at the CA3-CA1 synapses in untreated and treated chronic rmTBI mice. SA4. We will examine JM4 effects on blood biomarkers, immuno/inflammatory activation and neuropathology at 18 months (terminal endpoint) within animals who received either brief JM4 pulse therapy for 1 month or after receiving sustained JM4 treatment for a full 6 months prior to sacrifice. We anticipate that JM4 treatment in advanced chronic rmTBI mice will reduce inflammation and decrease or eliminate both behavioral and neuropathological signs of rmTBI. If successful this will be the first potential treatment developed for this disease.