Researchers argue that metabolic dysfunction, including reduced mitochondrial energy status in

the brain with increased metabolic demands but decreased energy stores with a low ATP/DTP ratio and increased lactate/pyruvate ratio, may play a role (Jenkins et al., 1989; Vespa et al., 2005; Vagnozzi et al., 2008). Yuen et al. (2009) suggested that mild trauma AZD6738 clinical trial stimulates a type of sodium channelopathy on axons, which, in turn, intensifies pathophysiological responses to succeeding minor injuries. Longhi et al. (2005) reported that increased brain vulnerability after repeated concussions occurs via axonal damage, which is significantly amplified. In the next section, we more closely consider some of the molecular mechanisms underlying traumatic brain injury. There are two main categories of brain damage due to trauma: focal damage and diffuse injury. Focal injury includes cortical or subcortical contusions and lacerations, as well as intracranial bleedings (subarachnoid hemorrhage and subdural hematoma). Focal injury is due to severe direct impact on the brain and is thus mainly seen in severe cases of TBI. Diffuse injury is caused by stretching and tearing of the brain tissue and does not need any skull fracture or direct impact or crush injury to the brain

surface and is therefore also Metformin mouse seen in cases with mild TBI. The main form of diffuse injury is called diffuse axonal injury (DAI), which is due to acceleration/deceleration forces that lead to shearing of axons. In the following subsections, we discuss the neurobiology of acute mild TBI or concussion, considering how accurate this may be examined in different forms of animal models. We also review the chronic degenerative brain disorder CTE, which is found in contact sports athletes, and its similarity to other neurodegenerative disorders, especially Alzheimer’s disease and Parkinson’s disease (PD). Animal models have been used in numerous studies to examine the neurobiology and mechanisms of TBI. Many studies exploring the neurobiology and neurochemistry

of acute TBI are based on invasive animal TBI models in which the brain is exposed by craniotomy, and the cortex is subjected first to injury by crush or compression, for example, by a rigid impactor (controlled cortical impact), weight drop, vacuum deformation, or by fluid percussion (for review, see O’Connor et al., 2011). These direct crush animal TBI models have been found to have a high variability in outcome, ranging from minor symptoms to fatal outcome, from a minor change in impact (Nilsson et al., 1990), which might limit their utility as models of human mild TBI. Animal TBI models based on acceleration/deceleration of the skull and brain that replicate the dynamics of damage due to rotational forces leading to diffuse brain injury have been difficult to develop, due to the lower mass of the animal brain (O’Connor et al., 2011; Johnson et al., 2012).