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Purpose Repetitive mild traumatic brain injury (TBI) is a major military and sports health concern. The purpose of this study was to determine if a diet rich in omega-3 fatty acids would reduce cognitive deficits and neuronal cell death in a novel fluid percussion rat model of repetitive mild TBIs. Methods Thirty-two Sprague-Dawley rats were assigned to either an experimental rat chow enhanced with 6% fish oil (source of omega-3 fatty acids) or a control rat chow. Both rat chows contained equivalent quantities of calories, oil, and nutrients. After four weeks, both groups received mild repetitive bilateral fluid percussion TBIs on two sequential days. Pre-injury diets were resumed, and the animals were monitored for two weeks. On post-injury days 10-14, Morris Water Maze testing was performed to assess spatial learning and cognitive function. Animals were euthanized at 14 days post-injury to obtain specimens for neurohistopathology. Results There was no difference in pre-injury weight gain between groups. Post-injury, animals on the fish oil diet lost less weight and recovered their weight significantly faster. By 14 days, the fish oil diet group performed significantly better in the Morris Water Maze. Neurohistopathology identified a non-significant trend toward a higher density of hippocampal neurons in the fish oil diet group. Conclusions Pre-injury dietary supplementation with fish oil improves recovery of body weight and provides a small improvement in cognitive performance in a rat model of multiple mild TBIs.

Fluid percussion was first conceptualized in the 1940s and has evolved into one of the leading laboratory methods for studying experimental traumatic brain injury (TBI). Over the decades, fluid percussion has been used in numerous species and today is predominantly applied to the rat. The fluid percussion technique rapidly injects a small volume of fluid, such as isotonic saline, through a circular craniotomy onto the intact dura overlying the brain cortex. In brief, the methods involve surgical production of a circular craniotomy, attachment of a fluid-filled conduit between the dura overlying the cortex and the outlet port of the fluid percussion device. A fluid pulse is then generated by the free-fall of a pendulum striking a piston on the fluid-filled cylinder of the device. The fluid enters the cranium, producing a compression and displacement of the brain parenchyma resulting in a sharp, high magnitude elevation of intracranial pressure that is propagated diffusely through the brain. This results in an immediate and transient period of traumatic unconsciousness as well as a combination of focal and diffuse damage to the brain, which is evident upon histological and behavioral analysis. Numerous studies have demonstrated that the rat fluid percussion model reproduces a wide range of pathological features associated with human TBI.

Immediately following traumatic brain injury (TBI) and TBI with hypoxia, there is a rapid andpathophysiological increase in extracellula r glutamate, subsequent neuronal damage andultimately diminished moto r and cognitive function. N-acetyl-aspartyl glutamate (NAAG), aprevalent neuropeptide in the CNS, is co-relea sed with glutamate, binds to the presynapticgroup II metabotropic glutamate receptor subtype 3 (mGluR3) and suppresses glutamaterelease. However, the catalytic enzyme glutamate carboxypeptidase II (GCP II) rapidly hydro-lyzes NAAG into NAA and glutamate. Inhibition of the GCP II enzyme with NAAG peptidaseinhibitors reduces the concentration of glutamate both by increasing the duration of NAAGactivity on mGluR3 and by reducing degradation into NAA and glutamate resulting in reducedcelldeathinmodelsofTBIandTBIwithhypoxia. In the following study, rats wereadministered the NAAG peptidase inhibitor PGI-02776 (10 mg/kg) 30 min following TBIcombined with a hypoxic second insult. Over t he two weeks following injury, PGI-02776-treated rats had signi ficantly improved motor function as measured by increased duration onthe rota-rod and a trend toward improved performance on the beam walk. Furthermore, twoweeks post-injury, PGI-02776-treated animals had a signi ficant decrease in latency to find thetarget platform in the Morris water maze as co mpared to vehicle-treated animals. Thesefindings demonstrate that the application o f NAAG peptidase inhibitors can reduce thedeleterious motor and cognitive effects of TBI combined with a second hypoxic insult in theweeks following injury.& 2013 Elsevier B.V. All rights reserved.0006-8993/$-see front matter & 2013 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.brainres.2013.03.043

Traumatic brain injury (TBI) leads to a rapid and excessive glutamate elevation in the extracellular milieu, resulting in neuronal degeneration and astrocyte damage. Posttraumatic hypoxia is a clinically relevant secondary insult that increases the magnitude and duration of glutamate release following TBI. N-acetyl-aspartyl glutamate (NAAG), a prevalent neuropeptide in the CNS, suppresses presynaptic glutamate release by its action at the mGluR3 (a group II metabotropic glutamate receptor). However, extracellular NAAG is rapidly converted into NAA and glutamate by the catalytic enzyme glutamate carboxypeptidase II (GCPII) reducing presynaptic inhibition. We previously reported that the GCPII inhibitor ZJ-43 and its prodrug di-ester PGI-02776 reduce the deleterious effects of excessive extracellular glutamate when injected systemically within the first 30 minutes following injury. We now report that PGI-02776 (10 mg/kg) is neuroprotective when administered 30-minutes post-injury in a model of TBI plus 30 minutes of hypoxia (FiO2 = 11%). 24-hrs following TBI with hypoxia, significant increases in neuronal cell death in the CA1, CA2/3, CA3c, hilus and dentate gyrus were observed in the ipsilateral hippocampus. Additionally, there was a significant reduction in the number of astrocytes in the ipsilateral CA1, CA2/3 and in the CA3c/hilus/dentate gyrus. Administration of PGI-02776 immediately following the cessation of hypoxia significantly reduced neuronal and astrocytic cell death across all regions of the hippocampus. These findings indicate that NAAG peptidase inhibitors administered post-injury can significantly reduce the deleterious effects of TBI combined with a secondary hypoxic insult.

Hypoxia frequently occurs in patients with traumatic brain injury (TBI) and is associated with increased morbidity and mortality. This study examined the effects of immediate or delayed post-traumatic hypoxia (fraction of inspired oxygen [FiO(2)] 11%) on acute neuronal degeneration and long-term neuronal survival in hippocampal fields after moderate fluid percussion injury in rats. In Experiment 1, hypoxia was induced for 15 or 30 min alone or immediately following TBI. In Experiments 2 and 3, 30 min of hypoxia was induced immediately after TBI or delayed until 60 min after TBI. In Experiment 1, acute neurodegeneration was evaluated in the hippocampal fields 24 h after insults using Fluoro-Jade staining and stereological quantification. During hypoxia alone, or in combination with TBI, mean arterial blood pressure was significantly reduced by approximately 30%, followed by a rapid return to normal values upon return to pre-injury FiO(2). Hypoxia alone failed to cause hippocampal neuronal degeneration when measured at 24 h after insult. TBI alone resulted in neuronal degeneration in each ipsilateral hippocampal field, predominantly in CA2-CA3 and the dentate gyrus. Compared to TBI alone, TBI plus immediate hypoxia for either 15 or 30 min significantly increased neuronal loss in most ipsilateral hippocampal fields and in the contralateral hilus and dentate gyrus. In Experiment 2, TBI plus hypoxia delayed 30 min significantly increased degeneration only in ipsilateral CA2-CA3. In Experiment 3, 30 min of immediate hypoxia significantly reduced the numbers of surviving neurons in the CA3 at 14 days after TBI. The greatly increased vulnerability in all hippocampal fields by immediate 30 min post-traumatic hypoxia provides a relevant model of TBI complicated with hypoxia/hypotension. These data underscore the significance of the secondary insult, the necessity to better characterize the range of injuries experienced by the TBI patient, and the importance of strictly avoiding hypoxia in the early management of TBI patients.

Traumatic brain injury (TBI) frequently leads to epilepsy. The process of epileptogenesis - the development of that seizure state - is still poorly understood, and effective antiepileptogenic treatments have yet to be identified. The ketogenic diet (KD) has been shown to be effective as an antiepileptic therapy, but has not been extensively tested for its efficacy in preventing the development of the seizure state, and certainly not within the context of TBI-induced epileptogenesis. We have used a rat model of TBI - fluid percussion injury (FPI) - to test the hypothesis that KD treatment is antiepileptogenic and protects the brain from neuronal cell loss following TBI. Rats fed a KD had a higher seizure threshold (longer latency to flurothyl-induced seizure activity) than rats fed a standard diet (SD); this effect was seen when KD was in place at the time of seizure testing (3 and 6 weeks following FPI), but was absent when KD had been replaced by SD at time of testing. FPI caused significant hippocampal cell loss in both KD-fed and SD-fed rats; the degree of cell loss appeared to be reduced by KD treatment before FPI but not after FPI. These results are consistent with prior demonstrations that KD raises seizure threshold, but do not provide support for the hypothesis that KD administered for a limited time directly before or after FPI alters later seizure sensitivity; that is, within the limits of this model and protocol, there is no evidence for KD-induced antiepileptogenesis.