Repeated Blast Exposures Cause Brain DNA Fragmentation in Mice

Abstract

The pathophysiology of blast-induced traumatic brain injury (TBI) and subsequent behavioral deficits are not well understood. Unraveling the mechanisms of injury is critical to derive effective countermeasures against this form of neurotrauma. Preservation of the integrity of cellular DNA is crucial for the function and survival of cells. We evaluated the effect of repeated blast exposures on the integrity of brain DNA and tested the utility of cell-free DNA (CFD) in plasma as a biomarker for the diagnosis and prognosis of blast-induced polytrauma. The results revealed time-dependent breakdown in cellular DNA in different brain regions, with the maximum damage at 24 h post-blast exposures. CFD levels in plasma showed a significant transient increase, which was largely independent of the timing and severity of brain DNA damage; maximum levels were recorded at 2 h after repeated blast exposure and returned to baseline at 24 h. A positive correlation was observed between the righting reflex time and CFD level in plasma at 2 h after blast exposure. Brain DNA damage subsequent to repeated blast was associated with decreased mitochondrial membrane potential, increased release of cytochrome C, and up-regulation of caspase-3, all of which are indicative of cellular apoptosis. Shock-wave-induced DNA damage and initiation of mitochondrial-driven cellular apoptosis in the brain after repeated blast exposures indicate that therapeutic strategies directed toward inhibition of DNA damage or instigation of DNA repair may be effective countermeasures.

Role of Microvascular Disruption in Brain Damage from Traumatic Brain Injury

“…Brain damage from TBI was reported to be associated with decreased mitochondrial membrane potential and increased release of cytochrome C in rodents—both indicative of cellular apoptosis (179). Cleaved-caspase-3 and caspase-3 enzyme activity was reportedly increased in TBI animals versus control (32).…”

Acute decrease in alkaline phosphatase after brain injury: A potential mechanism for tauopathy

“…Unlike weight drop, where injury is localized to the brain, blast is a whole body insult affecting multiple organ systems; consequently, changes in total alkaline phosphatase activity in the circulation after blast may more generally reflect the net outcome of its composite effects on multiple organ systems and not just brain. In particular, since blast exposure disrupts cell membranes in various organs resulting in the release of enzymes and other intracellular components [0,1,31], it is possible that unlike weight drop injury, blast exposure causes the release/leakage of different alkaline phosphatase isozymes into the plasma from peripheral organs such as liver, kidney, intestine, placenta, bone etc., all of which contribute to the alkaline phosphatase activity measured in plasma after blast exposure.…”

Blast-induced traumatic brain injury: a new trend of blast injury research

“…Researchers in the Walter Reed Army Institute of Research have done a lot of work in recent years, including the molecular changes of neurons, 17 energy metabolism, hormones level, 18 changes in the neurotransmitter, 19 dysfunctions of the organelles 20 and the DNA mutation. 21 It is notable that the research interests have shifted from the truncal and extremity injuries to the bTBI.…”