Blast-induced neurotrauma (BINT) is a prevalent brain injury within both military and civilian populations due to current engagement in overseas conflict and ongoing terrorist events worldwide. In the early 2000s, 78% of injuries were attributable to an explosive mechanism during overseas conflicts which has led to increased incidences of BINT [1a]. Clinical manifestations of BINT include long-term psychological impairments which are driven by the underlying cellular and molecular sequelae of the injury. Development of effective treatment strategies is limited by the lack of understanding on the cellular and molecular level [2a]. The overall hypothesis of this work is that epigenetic regulatory mechanisms contribute to the progression of the BINT pathology and neurological impairments. Epigenetic mechanisms, including DNA methylation and histone acetylation, are important processes by which cells coordinate specific response to environmental stimuli. To date, the role of epigenetics in BINT remains largely unknown.
To test this hypothesis, an established rodent model of BINT was employed [3a]. Analysis of DNA methylation, which is involved in memory processes, showed decreased levels one week following injury which was accompanied by decreased expression of DNA methyltransferase-1, which is responsible for facilitating the addition of methyl groups to DNA. The one week time point also showed dramatic decreases in histone acetylation which correlated to a decline in memory. This change was observed in astrocytes and may provide a mechanistic understanding of blast-induced reactive astrocytosis.
Diagnosis of BINT has proved clinically difficult, but recent studies have begun developing biomarkers as diagnostic tools. An accumulation of cell-free nucleic acids were measured within the cerebrospinal fluid one month after injury. Concentrations of these molecules shows promise in discriminating between injured and non-injured animals. Importantly, these moleculare are also susceptible to methylation processes and provide an epigenetic biomarker. Such a biomarker may provide improved specificity and clinical relevance upon proper characterization.
To date, the diagnostic and therapeutic efforts of BINT have been limited by the lack of a mechanistic understanding of the injury. This work provides novel diagnostic and therapeutic targets and the clinical potential has been demonstrated.
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