Differential effects of difluoromethylornithine on basal and induced activity of cerebral ornithine decarboxylase and mRNA

Abstract

Summary-The induction of the activity of cerebral ornithine decarboxylase (EC 4.1.1.17) and mRNA by electrical stimulation exhibits regional differences. The effects of the enzyme inhibitor difluoromethylornithine on these regional variations was examined. Administration of this inhibitor resulted in pronounced depression of both basal and induced activity of ornithine decarboxylase in the hippocampus. Basal activity of the enzyme in the neocortex and the cerebellum appeared to be resistant to difluoromethylornithine but the induced enzyme activity was sensitive to the effects ofthis inhibitor. Susceptibility to difluoromethylornithine may be directly correlated with a slower turnover rate for ornithine decarboxylase. These results suggest that ornithine decarboxylase in the hippocampus may possess a longer half-life than its counterparts in other regions of the brain. Pretreatment with difluoromethylornithine had no effect on the induced ornithine decarboxylase mRNA in the neocortex. Thus, elevated activity of ornithine decarboxylase enzyme, due to electrical stimulation, appears to not have any effect on either the transcription or the decay rate of the induced ornithine decarboxylase mRNA. These findings support the concept of region-specific regulation of cerebral ornithine decarboxylase.

Activation of rat brain ornithine decarboxylase by GTP

“…The ability of GTP to activate brain ODC was greatest for the enzyme from the cerebellum, where the level of activity of the enzyme was lowest, while GTP activation of ODC from the hippocampus was smallest. The absolute level of activity of ODC in the hippocampus, in contrast, was the highest of all brain regions, in agreement with an earlier report from Zawia et al [25]. A GTPactivatable ODC isoform has been found in mouse skin tumours Table 5 Irreversibility of the activation of ODC by GTP Identical aliquots of rat midbrain and hypothalamic ODC from Sephadex chromatography were preincubated with L-ornithine (1.25 mM) or with L-ornithine plus GTP (0.1 mM) for 30 min at 37°C, followed by extensive dialysis (4000 vol.…”

“…However, under the gel filtration conditions that we used, the GTP-activatable ODC isoform could not be separated from the other possible ODC isoforms (Figure 1). The partial resistance of the brain ODC to the potent irreversible inhibitor DFMO is consistent with the observations of other [25]. Furthermore, it could explain why DFMO only inhibits mouse brain ODC at toxic dose levels [8].…”

“…Since it was known from the previous work of Zawia et al [25] that the basal activity of the ODC in the neocortex and the cerebellum was resistant to inactivation by DFMO, we determined the effect of DFMO on the enzyme activity from the rat brain regions. DFMO inhibited around 60 % of the ODC activity from all brain regions (Table 2).…”

“…DL-a-Difluoromethylornithine (DFMO) is a potent irreversible inhibitor of mammalian ODC [23,24]. However, it has been reported that mouse brain ODC could not be inhibited by doses of DFMO that did not result in side effects [8], and that the basal activity ofODC in the neocortex and the cerebellum ofthe rat was resistant to DFMO in vivo [25]. Also, the ODC of cutaneous tumours of both mouse and human origin has been reported to be resistant to irreversible inactivation by DFMO [26,27].…”

Expression of the Genes Coding for Ornithine Decarboxylase and Its Regulatory Protein Antizyme in the Developing Rat Brain

“…[12][13][14][15][16][17]. Changes in the rate of transcription or transla tion and changes in mRNA and protein stability have been implicated in the modulation of ODC catalytic activity [18][19][20][21]. An important regulator of ODC activ ity is the polyamine-inducible protein, antizyme [20,22,231.…”