Abstract
BackgroundIdentification of molecular alterations of damaged tissue in patients with neurological disorders can provide novel insight and potential therapeutic target for treatment of the diseases. It has been suggested by animal studies that connexins (CXs), a family of gap junction proteins, could contribute to neuronal cell death and associate with neurological deficits during trauma‐induced damage. Nevertheless, whether specific CXs are involved in traumatic brain injury (TBI) has remained unexplored in human patients.MethodsIn a clinical setting, we performed a correlation study of 131 TBI patients who received brain surgery. CXs (including CX40, CX43, and CX45) were examined in the harvested brain tissues for studying the relationships with the Glasgow Coma Scale scores of the patients.ResultsSpecifically, the protein levels of CX43 (negatively) and CX40 (positively) are associated with the extent of disease severity. Meanwhile, the phosphorylation status of CX43 was strongly associated with the severe TBI patients who contain relatively high kinase activities of PKC (protein kinase C) and MAPK (mitogen‐activated protein kinase), two possible activators for CX43 phosphorylation.ConclusionThese data highlight that a cluster of connexin family gap junction proteins not previously studied in humans is significantly correlated with the disease progression of TBI.
Highlights
Traumatic brain injury (TBI) is a global health problem, with an estimated 10 million patients affected annually around the world (Hyder, Wunderlich, Puvanachandra, Gururaj, & Kobusingye, 2007)
CX43 phosphorylation is known to be activated by protein kinases such as PKA, PKC, and MAPK (Schulz et al, 2015)
The individuals with the lowest Glasgow Coma Scale (GCS) score reflecting the most severe defects contained the lowest levels of CX43 protein (p = .003, r = .8642), the highest levels of CX40 protein (p = .002, r = −.8933) and CX43 phosphorylation (p = .007, r = −.8714), and accompanied by the enhanced activities of PKC (p = .009, r = −.8597) and MAPK (p = .007, r = −.8459)
Summary
Traumatic brain injury (TBI) is a global health problem, with an estimated 10 million patients affected annually around the world (Hyder, Wunderlich, Puvanachandra, Gururaj, & Kobusingye, 2007). Dissecting the molecular alterations of brain tissues following TBI could potentially identify therapeutic targets It may facilitate the delineation of the neuron cell damage that helps brain injury diagnosis, improving the care management of TBI patients at high risk of severely adverse symptoms in clinic. Other CXs were found to be expressed in the astrocytes or microglia localized in the injury sites of the brain, and their levels are altered as well during the development of brain injury in animals (Lin et al, 2002; Moon, Choi, Kim, Kim, & Sun, 2010; Ohsumi et al, 2006; Xie, Cui, Deng, & Feng, 2015) Together, these preclinical studies have suggested that the CXs could contribute to the propagations of injury-related signals and potentially correlate with the pathological status of the CNS injury in TBI. The results may provide further human evidence to suggest connexin proteins as essential players involved in TBI-related neuronal deficits
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