Proteomic analysis identifies plasma correlates of remote ischemic conditioning in the context of experimental traumatic brain injury

Abstract

Remote ischemic conditioning (RIC), transient restriction and recirculation of blood flow to a limb after traumatic brain injury (TBI), can modify levels of pathology-associated circulating protein. This study sought to identify TBI-induced molecular alterations in plasma and whether RIC would modulate protein and metabolite levels at 24 h after diffuse TBI. Adult male C57BL/6 mice received diffuse TBI by midline fluid percussion or were sham-injured. Mice were assigned to treatment groups 1 h after recovery of righting reflex: sham, TBI, sham RIC, TBI RIC. Nine plasma metabolites were significantly lower post-TBI (six amino acids, two acylcarnitines, one carnosine). RIC intervention returned metabolites to sham levels. Using proteomics analysis, twenty-four putative protein markers for TBI and RIC were identified. After application of Benjamini-Hochberg correction, actin, alpha 1, skeletal muscle (ACTA1) was found to be significantly increased in TBI compared to both sham groups and TBI RIC. Thus, identified metabolites and proteins provide potential biomarkers for TBI and therapeutic RIC in order to monitor disease progression and therapeutic efficacy. Traumatic brain injury (TBI) is a nondiscriminatory event that can affect any person at any age with any medical background. Approximately 69 million people sustain a TBI annually worldwide 1. In the United States alone, 2.87 million people suffer from TBI each year, and from those, approximately 288,000 patients are hospitalized, 56,800 people die, and over 90,000 live with permanent disabilities (CDC). Those that survive the initial insult can suffer from chronic cognitive issues and neurodegenerative diseases. A single episode of TBI can trigger progressive neurodegenerative pathologies years after the initial insult 2-7. TBI-induced neurodegenerative diseases often are diagnosed several years after the initial injury with few, if any, treatment options available to slow down or stop the progression of the disease 8. The majority of TBI incidents go unreported or are undiagnosed due to unreliable or non-existent biological indicators. Recently approved blood biomarkers for TBI indicate the need for or support the use of computed tomography (CT) imaging for diagnosis, rather than monitoring disease progression or recovery 9. Clinical care of a positive TBI diagnosis necessitates reliable monitoring of biomarkers to inform and guide treatment. Due to the absence of a monitoring biomarker, standard clinical protocols allow patients to return to action or duty based on unreliable self-reported symptom surveys 10. Premature return to normal or strenuous activities can worsen the condition and induce chronic health-related issues, further exacerbating the risk for neurodegenerative diseases 8,11. Monitoring biomarkers can track the effectiveness of interventions on TBI-related symptoms and pathologies. Currently, biomarkers for TBI include S100 calcium-binding protein B (S-100B), neuron-specific enolase (NSE), ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1) and g...

Remote ischemic conditioning-induced hyperacute and acute responses of plasma proteome in healthy young male adults: a quantitative proteomic analysis

“…In recent years, proteomic techniques have been used to better understand changes in the plasma protein expression profiles in response to RIC stimulation [Table 1]. [16][17][18][19][20][21] However, there are high levels of heterogeneity among study findings due to wide variations in study model design, selection of disease type, sampling time, and RIC frequency and effect duration [Table 1]. Long-term intervention (5 weeks, twice a week) of RIC in the experimental AIS rhesus model has shown activation of complement, endovascular homeostasis, anti-coagulation mechanism, and regulation of lipid metabolism (anti-atherogenesis).…”