Dose-dependent effect of MK-801 on the levels of neuropeptides processing enzymes in rat brain regions.

The appropriate levels of neuropeptides and their processing enzyme activities are required to continue a normal cell life, and the dysfunction of these peptides and enzymes are responsible for many neuronal abnormalities. Systemic administration of (+) MK-801 (dizocilpine maleate), a noncompetitive N-methyl-[D]-aspartate (NMDA) receptor antagonist, causes both neuroprotective and neurotoxic activities depending on doses and conditions. In the present study, we investigated the dose dependent effect of (+) MK-801 on prolyl endopeptidase (PEP), endopeptidase EC 24.15 (EP 24.15) and beta-D-glucuronidase activities as well as the protein levels of EP 24.15 and neuron specific enolase (NSE) in the posterior cingulate/retrosplenial cortices (PC/RSC), hippocampus, frontal cortex and striatum of female rats 3 days after the treatment. The activity of PEP was significantly increased compared with controls (saline) in the PC/RSC at 1.0 and 5.0 mg/kg doses, and in the frontal cortex at 5.0 mg/kg dose. beta-D-Glucuronidase activity was dose-dependently increased in all brain regions examined. The activity of EP 24.15 was unchanged in all regions after the treatment, whereas the Western blot analysis for EP 24.15 showed the increased protein level in the PC/RSC. These results suggest that a low dose treatment with MK-801 causes neurotoxicity in the PC/RSC and hippocampus, and the high dose treatment causes neurotoxicity in all the brain regions examined.