Overexpression of spermidine/spermine N-1-acetyltransferase in transgenic mice protects the animals from kainate-induced toxicity

We recently generated a transgenic mouse line with activated polyamine cata bolism through overexpression of spermidine/spermine N-1-acetyltransferase (SSAT). A detailed analysis of brain polyamine concentrations indicated tha t all brain regions of these animals showed distinct signs of activated pol yamine catabolism, e.g. overaccumulation of putrescine (three- to 17-fold), appearance of N-1-acetylspermidine and decreases in spermidine concentrati ons. In situ hybridization analyses revealed a marked overexpression of SSA T-specific mRNA all over the brain tissue of the transgenic animals. The tr ansgenic animals appeared to tolerate subcutaneous injections of high-dose kainate substantially better as their overall mortality was less than 50% o f that of their syngenic littermates. We used the expression of glial fibri llary acidic protein (GFAP) as a marker of brain injury in response to kain ate. In situ hybridization analysis with GFAP oligonucleotide up to 7 days after the administration of sublethal kainate doses showed reduced GFAP exp ression in transgenic animals in comparison with their non-transgenic litte rmates. This difference was especially striking in the cerebral cortex of t he transgenic mice where the exposure to kainate hardly induced GFAP expres sion. The treatment with kainate likewise resulted in loss of the hippocamp al (CA3) neurons in non-transgenic but not transgenic animals. These result s support our earlier findings indicating that elevated concentrations of b rain putrescine, irrespective whether derived from an overexpression of orn ithine decarboxylase, or as shown here, from an overexpression of SSAT, pla y in all likelihood a neuroprotective role in brain injury.