Abstract
Blast-induced traumatic brain injury (bTBI) is one of the major causes of persistent disabilities in Service Members, and a history of bTBI has been identified as a primary risk factor for developing age-associated neurodegenerative diseases. Clinical observations of several military blast casualties have revealed a rapid age-related loss of white matter integrity in the brain. In the present study, we have tested the effect of single and tightly coupled repeated blasts on cellular senescence in the rat brain. Isoflurane-anesthetized rats were exposed to either a single or 2 closely coupled blasts in an advanced blast simulator. Rats were euthanized and brains were collected at 24 h, 1 month and 1 year post-blast to determine senescence-associated-β-galactosidase (SA-β-gal) activity in the cells using senescence marker stain. Single and repeated blast exposures resulted in significantly increased senescence marker staining in several neuroanatomical structures, including cortex, auditory cortex, dorsal lateral thalamic nucleus, geniculate nucleus, superior colliculus, ventral thalamic nucleus and hippocampus. In general, the increases in SA-β-gal activity were more pronounced at 1 month than at 24 h or 1 year post-blast and were also greater after repeated than single blast exposures. Real-time quantitative RT-PCR analysis revealed decreased levels of mRNA for senescence marker protein-30 (SMP-30) and increased mRNA levels for p21 (cyclin dependent kinase inhibitor 1A, CDKN1A), two other related protein markers of cellular senescence. The increased senescence observed in some of these affected brain structures may be implicated in several long-term sequelae after exposure to blast, including memory disruptions and impairments in movement, auditory and ocular functions.
Highlights
The incidence of blast-induced traumatic brain injury in the military increased significantly after the introduction of improvised explosive devices, with recent reports that 80% of mild TBI cases are related to blast exposure [1]
Using diffusion tensor imaging (DTI), a large number of military service members were evaluated to determine whether blast exposure affected the integrity of brain white matter [19]
The diffusion contrast measures, fractional anisotropy and radial diffusivity, showed that white matter integrity in blast-exposed veterans and pre-deployed service members was significantly lower than was recorded in military personnel without a history of blast exposure, and further suggested that the degree of the loss of white matter integrity was directly proportional to the severity and number of blast exposures [19]
Summary
The incidence of blast-induced traumatic brain injury (bTBI) in the military increased significantly after the introduction of improvised explosive devices, with recent reports that 80% of mild TBI cases are related to blast exposure [1]. Both clinical and pre-clinical observations have prompted suggestions that bTBI yields a predisposition to age-related neurodegenerative disorders [7,8,9,10,11,12]. Acute and chronic development of tauopathy has been reported after blast exposure [8, 13], in which the phosphorylation of Tau protein disrupts microtubule assembly in neurons yielding tauopathy characterized by the formation of neurofibrillary tangles seen in neurodegenerative disorders such as Alzheimer’s disease (AD) [14,15,16]. The neuropathology of AD is associated with aging, no studies have yet definitively illustrated whether brain injury after blast exposure accelerate the aging process
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