Triflusal posttreatment inhibits glial nuclear factor-κB, downregulates the glial response, and is neuroprotective in an excitotoxic injury model in postnatal brain

Background and Purpose - Nuclear factor-κB (NF-κB) and the signal transducer and activator of transcription 3 (STAT3) are important transcription factors regulating inflammatory mechanisms and the glial response to neural injury, determining lesion outcome. In this study we evaluate the ability of triflusal (2-acetoxy-4-trifluoromethylbenzoic acid), an antiplatelet agent inhibitor of NF-κB activation, to improve lesion outcome after excitotoxic damage to the immature brain. Methods - Postnatal day 9 rats received an intracortical injection of the excitotoxin N-methyl-D-aspartate (NMDA) and oral administration of triflusal (30 mg/kg) either as 3 doses before NMDA injection (pretreatment) or as a single dose 8 hours after NMDA injection (posttreatment). After survival times of 10 and 24 hours, brains were processed for toluidine blue staining, tomato lectin histochemistry, and glial fibrillary acidic protein, NF-κB, and STAT3 immunocytochemistry. Results - NMDA-lesioned animals that were not treated with triflusal showed activation of NF-κB in neuronal cells at first and in glial cells subsequently. Animals that received pretreatment with triflusal showed a strong downregulation of neuronal and glial NF-κB but a similar development of the glial response and an equivalent lesion volume compared with nontreated animals. In contrast, animals receiving triflusal posttreatment showed increased early neuronal NF-κB but a reduction in the subsequent glial NF-κB, accompanied by important downregulation of the microglial and astroglial response and a drastic reduction in the lesion size. STAT3 activation was not affected by triflusal treatment. Conclusions - Triflusal posttreatment diminishes glial NF-κB, downregulates the glial response, and improves the lesion outcome, suggesting a neuroprotective role of this compound against excitotoxic injury in the immature brain.