Abstracts

Rationale: The objective of the study was to evaluate the effect of levetiracetam (LEV) on functional recovery and gene expression in a rat model of traumatic brain injury (TBI). LEV has antiepileptogenic effects in animal models and has been proposed as a neuroprotectant after TBI. In addition, the use of LEV to prevent acute post traumatic seizures is increasing, replacing phenytoin prophylaxis. Therefore, in addition to determining a neuroprotectant effect, it is also important to determine whether or not LEV causes detrimental effects after a TBI.Methods: Male rats were randomly assigned to either TBI + vehicle (saline), TBI + LEV or Sham (uninjured). A moderate to severe unilateral parietal injury was induced using controlled cortical impact (CCI). At 4 h post-TBI, LEV was administered as a 50 mg/Kg i.p. loading dose followed by a 14 mg/h/kg s.c. infusion designed to provide clinically relevant concentrations (30-60 mg/L) for 7 days. In one group of animals, motor function was assessed using the locomotor placing task, the rotor-rod task and a photobeam activity monitoring system and cognitive function was assessed using the Morris water maze. For the gene expression studies, 5 animals from each treatment group were euthanized at 24 h, 72 h and 7 days after TBI. RNA samples passed stringent quality control, were processed and submitted to microarray analysis using Affymetrix GeneChip Rat Gene 1.0 ST arrays. Microarray data analysis was performed with the Bioconductor packages limma and gene ontology analysis (GOA) was used to identify relevant biological pathways.Results: There was no significant effect on motor or cognitive function compared to vehicle treatment. The number of differentially expressed genes (>1.5-fold up or down, p<0.05) at 24 h, 72h and 7 days is given in Table 1. Specifically, LEV decreased expression of dopamine receptors, Drd1 and Drd2 by 0.40 and 0.44 respectively compared to vehicle 24 h post-TBI and >70% pathways identified by GOA involved an effect of LEV on dopamine pathways; i.e. dopamine transport, synaptic transmission and metabolic process and dentate gyrus, forebrain and hippocampus development. At all 3 times points, LEV altered expression of cholinergic receptors. GOA pathways identified at 7 days including regulation of catecholamine secretion and amine transport, smooth muscle contraction, membrane depolarization and protein heterooligomerization.Conclusions: Treatment with LEV did not result in neuroprotection in a CCI rat model; however there was no evidence of any detrimental effects from the LEV treatment. The effect of LEV on gene expression suggests a primary effect on dopaminergic and cholinergic pathways after TBI without altering motor or cognitive function. The research was supported by a grant from the NIH/NICHD R01 HD061944-01 and NIH/NIEHS P30ES007033.