Role of HGF/cMet Signaling Pathways in Neuroprotection, Neuroinflammation, and Cognitive Function after Mild Traumatic Brain Injury

This project investigates the role of the hepatocyte growth factor (HGF)/cMet signaling pathway in neuroprotection, neuroinflammation and cognitive function following repeated mild traumatic brain injury (TBI). The team frames the study within a significant public health context: TBI lacks FDA-approved treatments and mild TBI constitutes over 75% of cases, frequently producing lasting deficits in attention, memory, and motor function. Young adults are particularly vulnerable to repeated mild TBI, and repeat injuries amplify the brain's susceptibility to subsequent insults and produce more severe cognitive and behavioral dysfunction. These impairments reduce quality of life and prolong return to work, school, or sport for an estimated 1.6 to 3.8 million individuals annually in the United States. 

Collaborators focus on the brain HGF system, emphasizing that HGF and its receptor, cMET, are expressed in cortical and hippocampal regions critical for attention, memory, and sensorimotor processes. Prior work in ischemic injury and neurodegeneration models indicates that activating HGF/cMet in the central nervous system can be both neuroprotective and procognitive. Building on this background, the research tests the hypothesis that activation of HGF/cMet after repetitive mild TBI can reverse or ameliorate cognitive impairments, with a particular emphasis on spatial working memory and sensorimotor function. The study examines whether pharmacologic potentiation of HGF/cMet signaling can rescue deficits produced by repeated mild injury.

The team evaluates dihexa, a known potentiator of HGF/cMet signaling, in behavioral paradigms sensitive to working memory and sensorimotor performance. Results reported by the group indicate that dihexa produced dose-dependent rescue of TBI-induced impairments in a delayed alternation task, a measure of spatial working memory. Mechanistic interpretation provided in the abstract states that cMET activation is both sufficient and necessary for dihexa's beneficial effects on working memory after repeated mild TBI. These findings suggest a potential therapeutic role for HGF/cMet pathway activation in addressing the behavioral and cognitive consequences of repeated mild TBI. 

The project underscores translational potential by linking molecular targets HGF and cMet with measurable cognitive outcomes in an injury model relevant to a large affected population. By demonstrating dose-dependent behavioral rescue, the work supports further exploration of HGF/cMet modulation as a strategy for mitigating the long-term cognitive and motor sequelae of repeated mild brain injuries. It also situates the research within an urgent clinical need given the absence of approved treatments and the high incidence of mild and repeated TBI.

It is important to note that the abstract available in the Rowan Digital Works repository indicates that the paper has been withdrawn. The withdrawal is recorded at the end of the posted abstract and should be considered when interpreting the presented findings. Nonetheless, the study as described frames a coherent experimental approach linking HGF/cMet signaling to cognitive recovery after repeated mild TBI and highlights dihexa as a pharmacologic tool used to probe this pathway's therapeutic potential.