Triflusal posttreatment inhibits glial nuclear factor-kappaB, downregulates the glial response, and is neuroprotective in an excitotoxic injury model in postnatal brain.
OBJECTIVE
Nuclear factor-kappaB (NF-kappaB) 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-kappaB 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-kappaB, and STAT3 immunocytochemistry.


RESULTS
NMDA-lesioned animals that were not treated with triflusal showed activation of NF-kappaB 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-kappaB 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-kappaB but a reduction in the subsequent glial NF-kappaB, 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-kappaB, downregulates the glial response, and improves the lesion outcome, suggesting a neuroprotective role of this compound against excitotoxic injury in the immature brain.
Acarin
L
L
Unit of Histology, School of Medicine, Department of Cell Biology, Physiology, and Immunology, Autonomous University of Barcelona, Bellaterra, Spain. lacarin@servet.uab.es
González
B
B
Castellano
B
B
D000284:Administration, Oral; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004334:Drug Administration Schedule; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008845:Microinjections; D016202:N-Methylaspartate / Q000008:administration & dosage; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D051381:Rats; D020318:Rats, Long-Evans; D050796:STAT3 Transcription Factor; D012459:Salicylates / Q000008:administration & dosage*; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010975:Platelet Aggregation Inhibitors; D050796:STAT3 Transcription Factor; D012459:Salicylates; C494088:Stat3 protein, rat; D015534:Trans-Activators; C016167:triflusal; D016202:N-Methylaspartate