The aim of this study was to assess and quantitate topographically the effects of posttraumatic intravenous magnesium sulphate (MgSO4) on neuronal perikaryal APP antigen and messenger RNA (mRNA) expression in sheep brains 2 h after a controlled focal head impact. The percentage brain area with APP immunoreactive neuronal perikarya was 71, 56, 27.5 and 5.5%, respectively, in MgSO4-treated head-injured animals, head-injured animals without any treatment, MgSO4 treated nonimpacted animals, and nontreated nonimpacted control sheep. Although there was no statistically significant difference in APP immunoreactive neuronal perikarya in the MgSO4-treated HI group (mean 71%) compared to the HI group without any treatment (mean 56%), northern analysis showed that there was a 2.3-+/-0.2-fold increase in APP mRNA in the thalamus of treated impacted animals compared to untreated impacted animals (p < 0.005). However, MgSO4 treated nonimpacted control animals also showed a 1.6-+/-0.1-fold increase in APP mRNA compared to untreated nonimpacted controls (p < 0.005). MgSO4 therapy results in upregulation of neuronal APP mRNA and APP expression that is quantitatively greater following a focal head impact.