Beta-amyloid (Aβ) burden and impaired neuronal autophagy contribute to secondary brain injury after traumatic brain injury (TBI). 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS) treatment has been reported to reduce Aβ aggregation and rescue behavioral deficits in Alzheimer's disease-like mice. Here, we investigated neuroprotective effects of EPPS in a mouse model of TBI. Mice subjected to controlled cortical impact (CCI) were treated with EPPS (120 mg/kg, orally) immediately after CCI and thereafter once daily for 3 or 7 days. We found that EPPS treatment profoundly reduced the accumulation of beta-amyloid precursor protein (β-APP) and Aβ over a widespread area detected in the pericontusional cortex, external capsule (EC), and hippocampal CA1 and CA3 at 3 days after TBI, accompanied by significant reduction in the TBI-induced diffuse axonal injury identified by increased immunoreactivity of SMI-32 (an indicator for axonal damage). We also found that EPPS treatment ameliorated the TBI-induced synaptic damage (as reflected by enhanced postsynaptic density 95, PSD-95), and impairment of autophagy flux in the neurons as reflected by reduced autophagy markers (LC3-II/LC3-I ratio and p62/SQSTM1) and increased lysosomal enzyme cathepsin D (CTSD) in neurons detected in the cortex and hippocampal CA1. As a result, EPPS treatment significantly reduced the TBI-induced early neuronal apoptosis (assessed by active caspase-3), and eventually prevented cortical tissue loss and hippocampal neuronal loss at 28 days after TBI. Additionally, we found that inhibition of autophagic flux with chloroquine by decreasing autophagosome-lysosome fusion significantly reversed the decreased expressions of neuronal p62/SQSTM1 and apoptosis by EPPS treatment. These data suggest that the neuroprotection by EPPS is, at least in part, related to improved autophagy flux. Finally, we found that EPPS treatment significantly improved the cortex-dependent motor and hippocampal-dependent cognitive deficits associated with TBI. Taken together, these findings support the further investigation of EPPS as a treatment for TBI.
All Science Journal Classification (ASJC) codes
- Developmental Neuroscience