Epigenetic regulation of the transcriptional activity of genes mediating the neuroprotective activity of ceftriaxone in the brain in a rat model of sporadic Alzheimer disease: the involvement of histone deacetylase 1.

Histone deacetylases (HDACs) are enzymes that provide transcriptional repression, while HDAC inhibitors are considered to be potential drugs in the treatment of Alzheimer disease (AD). Earlier we found that ceftriaxone (CEF), an antibiotic with neuroprotective activity, augmented mRNA levels of Ide and Mme, encoding enzymes involved in the catabolism of amyloid beta in the amygdala of OXYS rats, a model of sporadic AD. On the other hand, disturbances of neurotrophic factors (BDNF in particular) play an important role in AD pathogenesis. Moreover, HDACs of class I (HDAC1) are involved in the regulation of Bdnf transcriptional activity. The study was aimed to assess the effects of CEF on HDAC1 enrichment at Mme, Ide, and Bdnf gene promoters in the amygdala of OXYS rats and on Bdnf mRNA levels in the amygdala of OXYS and Wistar rats. Chromatin immunoprecipitation and qPCR were utilized for epigenetic analysis and assay of Bdnf mRNA levels, respectively. Neither significant HDAC1 enrichment, nor its alteration under CEF treatment at the Mme or Ide promoters were found, whereas CEF attenuated HDAC1 binding at Bdnf promoter IV. This is a novel mechanism of transcription regulation by CEF in the brain, which may be involved in its neuroprotective activity. In 5-month-old OXYS rats, it seems to play a minor role, as CEF did not change Bdnf transcript 5 (containing exons IV and IX) levels. We were first to demonstrate the transcript-specific regulation of Bdnf transcription by CEF. CEF significantly increased the levels of Bdnf transcript 6 (containing exons VII, VIII, and IX). The results of our study can be taken into account in AD treatment.