Blast Exposure Leads to Accelerated Cellular Senescence in the Rat Brain

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.

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

“…The results of this study are consistent with recently published mouse models of mTBI in which DNA damage has been reported in the early (24 h) period [ 3 , 123 , 151 ]. Our own studies on human autopsy cases showed strong evidence of DSBs in brains of athletes with a history of rmTBI [ 131 , 132 ].…”

“…This can lead to widespread DNA damage [ 28 ]. Indeed, accumulation of DNA damage has been reported in various models of mTBI [ 3 , 123 , 151 ] and our lab has previously shown evidence of double-strand breaks (DSBs) in human brains with mTBI history [ 131 , 132 ]. Although cells throughout the body regularly encounter DNA damage from endogenous sources, such as metabolic reactive oxygen species (ROS), the cell’s DNA damage response (DDR) can become overwhelmed when facing pathological levels of damage.…”

“…Cellular senescence is characterized by cell-cycle arrest, chronic inflammation via the production of senescence-associated secretory phenotype (SASP) factors, morphological abnormalities, and anti-apoptotic gene expression signatures. Senescent cells accumulate with age [ 23 , 157 , 175 ], neurodegenerative disease and cognitive decline [ 15 ], neuropsychiatric disorders [ 33 ], and have recently been discovered to accumulate after TBI [ 3 , 123 , 131 , 132 , 151 ].…”

Blast Exposure Causes Long-Term Degeneration of Neuronal Cytoskeletal Elements in the Cochlear Nucleus: A Potential Mechanism for Chronic Auditory Dysfunctions

“…The advanced blast simulator (ABS) described previously was used for the blast exposure ( 18 , 19 ). For blast exposure, the rats were anesthetized with 4% isoflurane for 8 min and secured in a longitudinal (i.e., rat facing the oncoming shockwave) prone orientation in the test section of the ABS.…”

“…To produce moderate injury to the auditory system, we used Valmax membranes yielding peak positive static pressures of ~19 psi with a positive phase duration of 4–5 msec. For tightly coupled repeated blast exposures, the rats were exposed to two 19-psi blast overpressure waves separated by 2 min as described earlier ( 18 , 19 ). Sham control rats received only the anesthesia and handling and were not exposed to blast.…”