A rodent model of mild traumatic brain blast injury

Abstract

One of the criteria defining mild traumatic brain injury (mTBI) in humans is a loss of consciousness lasting for less than 30 min. mTBI can result in long-term impairment of cognition and behavior. In rats, the length of time it takes a rat to right itself after injury is considered to be an analog for human return to consciousness. This study characterized a rat mild brain blast injury (mBBI) model defined by a righting response reflex time (RRRT) of more than 4 min but less than 10 min. Assessments of motor coordination relying on beam-balance and foot-fault assays and reference memory showed significant impairment in animals exposed to mBBI. This study's hypothesis is that there are inflammatory outcomes to mTBI over time that cause its deleterious effects. For example, mBBI significantly increased brain levels of interleukin (IL)-1β and tumor necrosis factor-α (TNFα) protein. There were significant inflammatory responses in the cortex, hippocampus, thalamus, and amygdala 6 hr after mBBI, as evidenced by increased levels of the inflammatory markers associated with activation of microglia and macrophages, ionized calcium binding adaptor 1 (IBA1), impairment of the blood-brain barrier, and significant neuronal losses. There were significant increases in phosphorylated Tau (p-Tau) levels, a putative precursor to the development of neuroencephalopathy, as early as 6 hr after mBBI in the cortex and the hippocampus but not in the thalamus or the amygdala. There was an apparent correlation between RRRTs and p-Tau protein levels but not IBA1. These results suggest potential therapies for mild blast injuries via blockade of the IL-1β and TNFα receptors.

Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

“…In support of this, TNFR1 is known to be expressed constitutively on neurons in the brain, 75 making it possible for constitutively or early induced mTNF to signal directly to the ischemically vulnerable neurons. Nevertheless, it is also well documented that TNF may have neurotoxic effects, not only in focal cerebral ischemia [76][77][78][79][80] but in other CNS traumatic pathologies as well, such as traumatic brain injury, [81][82][83][84][85] and strategies to inhibit or reduce TNF have proved beneficial both in animal models and humans. Since solTNF is genetically ablated in our model, it is plausible that the neuroprotective effects observed in mTNF Á/Á mice could be ascribed, at least in part, to the beneficial effects of simply removing endogenous, microglial-derived solTNF, and not necessarily to neuroprotection through mTNF signaling.…”

Tau Oligomers Derived from Traumatic Brain Injury Cause Cognitive Impairment and Accelerate Onset of Pathology in Htau Mice

“…40 Blast injury in humans and experimental animals is associated with increased levels of total and phosphorylated tau protein. 18,[40][41][42] We have previously shown that an increase in levels of tau oligomers results from fluid percussion TBI rats. 21 However, the contribution of tau oligomers to blast TBI has not yet been investigated.…”

Behavioral and inflammatory response in animals exposed to a low-pressure blast wave and supplemented with β-alanine

“…The mechanism of elevated brain carnosine and maintenance of BDNF expression in the hippocampus is not well-understood, but it may be related to carnosine’s role as a neural protectant through its action as an antioxidant (Kohen et al 1988). Oxidative stress and inflammation in the brain have been suggested to be part of the sequelae of physiological events contributing to PTSD (Wilson et al 2013), but may also contribute to the cognitive and neurodegeneration associated with mTBI (Aungst et al 2014; Perez-Polo et al 2015; Yang et al 2013). Elevation in brain carnosine may increase antioxidant capacity potentially preventing neurodegeneration associated with the inflammatory response.…”

“…Both mTBI and PTSD are disorders characterized by overlapping neural mechanisms involving alterations in dendritic remodeling, and neurogenesis within the hippocampal and prefrontal cortical regions. Although the mechanism is not completely understood, evidence does suggest that elevations in cytokine inflammatory markers may contribute to neuronal disruption in rodent models of mTBI (Perez-Polo et al 2015; Yang et al 2013). During a traumatic event, microglia are activated from a resting state and migrate to the site of injury (Jacobowitz et al 2012).…”