Inhibition of SRC family kinases protects hippocampal neurons and improves cognitive function after traumatic brain injury.

Traumatic brain injury (TBI) is often associated with intracerebral and intraventricular hemorrhage. Thrombin is a neurotoxin generated at bleeding sites fater TBI and can lead to cell death and subsequent cognitive dysfunction via activation of Src family kinases (SFKs). We hypothesize that inhibiting SFKs can protect hippocampal neurons and improve cognitive memory function after TBI. To test these hypotheses, we show that moderate lateral fluid percussion (LFP) TBI in adult rats produces bleeding into the cerebrospinal fluid (CSF) in both lateral ventricles, which elevates oxyhemoglobin and thrombin levels in the CSF, activates the SFK family member Fyn, and increases Rho-kinase 1(ROCK1) expression. Systemic administration of the SFK inhibitor, PP2, immediately after moderate TBI blocks ROCK1 expression, protects hippocampal CA2/3 neurons, and improves spatial memory function. These data suggest the possibility that inhibiting SFKs after TBI might improve clinical outcomes.

NAAG peptidase inhibitor improves motor function and reduces cognitive dysfunction in a model of TBI with secondary hypoxia.

Immediately following traumatic brain injury (TBI) and TBI with hypoxia, there is a rapid and pathophysiological increase in extracellular glutamate, subsequent neuronal damage and ultimately diminished motor and cognitive function. N-acetyl-aspartyl glutamate (NAAG), a prevalent neuropeptide in the CNS, is co-released with glutamate, binds to the presynaptic group II metabotropic glutamate receptor subtype 3 (mGluR3) and suppresses glutamate release. However, the catalytic enzyme glutamate carboxypeptidase II (GCP II) rapidly hydrolyzes NAAG into NAA and glutamate. Inhibition of the GCP II enzyme with NAAG peptidase inhibitors reduces the concentration of glutamate both by increasing the duration of NAAG activity on mGluR3 and by reducing degradation into NAA and glutamate resulting in reduced cell death in models of TBI and TBI with hypoxia. In the following study, rats were administered the NAAG peptidase inhibitor PGI-02776 (10mg/kg) 30 min following TBI combined with a hypoxic second insult. Over the two weeks following injury, PGI-02776-treated rats had significantly improved motor function as measured by increased duration on the rota-rod and a trend toward improved performance on the beam walk. Furthermore, two weeks post-injury, PGI-02776-treated animals had a significant decrease in latency to find the target platform in the Morris water maze as compared to vehicle-treated animals. These findings demonstrate that the application of NAAG peptidase inhibitors can reduce the deleterious motor and cognitive effects of TBI combined with a second hypoxic insult in the weeks following injury.

Evaluation of metric, topological, and temporal ordering memory tasks after lateral fluid percussion injury.

Impairments in learning and memory occur in as many as 50% of patients following traumatic brain injury (TBI). Similar impairments occur in rodent models of TBI, and the development of new memory testing procedures provides an opportunity to examine how TBI affects memory processing in specific neural memory systems. Specifically, metric, topological, and temporal ordering tasks are object-based tests for memory of spatial orientation and temporal sequencing working memory developed for use in rodents. Previous studies demonstrated that specific lesions of the dentate gyrus/CA3 of the hippocampus and the parietal cortex resulted in deficits in the metric and topological spatial orientation tasks, respectively. Lesions of the CA1 impaired a rat's ability to recall the temporal order of odors. The purpose of the following study was to determine whether moderate lateral fluid percussion TBI would generate deficits in these working memory tasks, and whether observed deficits were associated with cell loss in the CA2/3 and/or CA1 of the hippocampus. Two weeks following a moderate lateral fluid percussion TBI, adult rats demonstrated significant deficits in both the metric and temporal ordering tasks (p<0.05) but not in the topological task. Stereological analysis identified a significant reduction in neurons in the CA2/3 (p<0.05) but not the CA1 of the hippocampus. These data demonstrate the utility of three object-based tasks to expand our understanding of how different neural memory systems are affected by TBI.