COX-2 inhibition by diclofenac is associated with decreased apoptosis and lesion area after experimental focal penetrating traumatic brain injury in rats

Traumatic brain injury (TBI) is followed by a secondary inflammation in the brain. The inflammatory response includes prostanoid synthesis by the inducible enzyme cyclooxygenase-2 (COX-2). Inhibition of COX-2 is associated with improved functional outcome in experimental TBI models, although central nervous system-specific effects are not fully understood. Animal studies report better outcomes in females than males. The exact mechanisms for this gender dichotomy remain unknown. In an initial study we reported increased COX-2 expression in male rats, compared to female, following experimental TBI. It is possible that COX-2 induction is directly associated with increased cell death after TBI. Therefore, we designed a sequential study to investigate the blocking of COX-2 specifically, using the established COX-2 inhibitor diclofenac. Male Sprague-Dawley rats weighing between 250 and 350 g were exposed to focal penetrating TBI and randomly selected for diclofenac treatment (5 ?g intralesionally, immediately following TBI) (n = 8), controls (n = 8), sham operation (n = 8), and normal (no manipulation) (n = 4). After 24 h, brains were removed, fresh frozen, cut into 14?m coronal sections and subjected to COX-2 immunofluorescence, Fluoro Jade, TUNEL, and lesion area analyses. Diclofenac treatment decreased TUNEL staining indicative of apoptosis with a mean change of 54% (p 0.05) and lesion area with a mean change of 55% (p 0.005). Neuronal degeneration measured by Fluoro Jade and COX-2 protein expression levels were not affected. In conclusion, COX-2 inhibition by diclofenac was associated with decreased apoptosis and lesion area after focal penetrating TBI and may be of interest for further studies of clinical applications

Effect of age on amount and distribution of diffuse axonal injury after rotational trauma

Injury thresholds for diffuse axonal injuries (DAI) due to rotational head trauma are being developed. However, age may influence injury risk. Understanding this relationship is necessary for the development of injury criteria for children and elderly. Here rats were exposed to sagittal plane rotational acceleration head trauma and the outcome studied using Amyloid Precursor Protein to detect axonal injuries. For relatively young animals, DAI were found in and along the border of the corpus callosum and in the brainstem when rotational acceleration exceeded 1.1 Mrad/s2. Slightly older animals required higher accelerations to exhibit similar injury levels and the injury patterns were different. In conclusion, a previous study showed that the onset of diffuse axonal injuries started to appear at 10 krad/s2 with a duration of 4 ms, when scaled for humans, whereas new data indicate that this onset is slightly higher for occupants thata atre approximately 15 years older

Injury threshold for sagittal plane rotational induced diffuse axonal injuries

Sagittal plane rotational acceleration induced diffuse axonal injury threshold was investigated using an animal model in which the heads of the rats were exposed to selected rotation accelerations. Post-trauma survival times ranged from 3 to 120 h. Numerous S100 serum concentrations, brain tissue stained for β-Amyloid Precursor Protein (β-APP), and probes for Cyclooxygenase 2 (COX2) mRNA were used to detect affected nerve cells, decaying axons, and cytoskeletal changes, respectively. Scaling laws were applied to estimate injury thresholds for the human brain. Confocal imaging revealed bands of β-APP-positive axons in the corpus callosum and its edges in animals exposed to rotational accelerations >1.1 Mrad/s2. Similarly, for COX2 presence and S100 concentrations at >0.9 Mrad/s2, the numbers of stained cells in the cortex and hippocampus and the concentrations increased. The data clearly indicate that the rat brain is injured at a specific rotational acceleration. Scaled to that of humans this would be 10 krad/s2 with a duration of 4 ms

Effect of age on amount and distribution of diffuse axonal injury after rotational trauma

Traumatic brain injuries (TBI) are a major public health problem in term of suffering and cost for society. About 40% of the TBI patients admitted to hospitals are non-focal injuries, usually referred to as distributed brain injuries (DBI). Studies have hypothesized that the resulting strains in the brain tissue are the primary cause of neurological deficiencies following DBI. These strains commonly appear when the skull is accelerated and the brain mass, due to its inertia, lags behind or continues its motion relative the skull. It has been suggested that the severity of the injury correlates with the amplitude of the angular acceleration, or with the resulting angular velocity. Among DBI, diffuse axonal injury (DAI) is common and regularly results in unconsciousness or death. Past studies have suggested DAI injury criteria and thresholds that can be used with crash test dummies and mathematical models of the human. However, these past studies have been performed with rather young animals. In addition, some studies have shown that brain properties change as we grow older; it is likely that this have an effect on the risk of DAI following a rotational head injury. Therefore, the aim of this study is to investigate the distribution of axonal injuries in the brain following sagittal plane rotation trauma and to determine if the injury threshold changes when the subjects grow older. In this study rats were exposed to sagittal plane rotational acceleration head trauma and the outcome studied using Amyloid Precursor Protein to detect axonal injuries. For relatively young animals, DAI were found in and along the border of the corpus callosum and in the brainstem when rotational acceleration exceeded 1.1 Mrad/s2. Slightly older animals required higher accelerations to exhibit similar injury levels and the injury patterns were different. We hypothesise that the lower injury scores for the older subjects could be due to differences in tolerance to tissue strains or, as indicated in the literature, that the differences were due to changes in the constitutive properties of the brain tissue. The latter suggests, in combination with the observed differences between older and younger individuals, that additional studies on brain tissue properties, and studies on rotational acceleration induced DAI, should be carried out using even younger and older animals than used in this study. In conclusion, a previous study showed that the onset of diffuse axonal injuries started to appear at 10 krad/s2 with a duration of 4 ms, when data were scaled for humans, whereas new data indicate that this onset is slightly higher for occupants that are approximately 15 years older