Hepatocyte Growth Factor/MET Activator Rescues Working Memory Deficits After Repeated Mild Traumatic Brain Injury

Abstract

Mild traumatic brain injury (mTBI) can produce persistent cognitive and behavioral deficits. These impairments result in a reduced quality of life and difficulty returning to work, school, or other activities. Individuals with repeated injuries show increased risk for greater cognitive impairment and persistence of symptoms. A variety of pharmacological approaches have been tried to limit cognitive symptoms and other aspects of secondary injury following mTBI. However, their efficacy and ability to treat the sequela of mTBI remains disputed and no FDA-approved drug exists for mTBI. However, neurotrophins have considerable promise as regenerative therapies for mTBI by exhibiting procognitive, neuroprotective, and anti-inflammatory actions. One neurotrophin, hepatocyte growth factor and its receptor MET (HGF/MET) are upregulated in response to CNS injury within the prefrontal cortex and other regions supporting memory and higher cognitive function impaired by TBI. HGF/MET activation can be anti-inflammatory and neuroprotective, yet an understanding of its actions on cognitive function after mTBI is limited. Using a closed-head midline impact model of mild TBI, we characterized the actions of the HGF/MET system on working memory performance after repeated injury. Following repeated mild TBI, the HGF/MET positive modulator dose-dependently rescued the working memory deficits following injury. These actions indicate that peptidergic transmitter systems including HGF/MET may hold critical pharmacological targets for treating the neurosequela of TBI.