Effects of gestational or neonatal treatment with alpha-difluoromethylornithine on ornithine decarboxylase and polyamines in developing rat brain and on adult rat neurochemistry

Abstract

Pregnant rats were treated for five consecutive days during gestation with s.c. injections of the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine (DFMO). Treatment beginning at gestational days 13 or 14 was effective in inhibiting ODC and altering polyamine levels, and resulted in relatively small decreases in body and forebrain weight, but not in significant differences in adult neurochemistry. Neonatal rats were treated with DFMO from postnatal day 0 (PD 0) to PD 24. In addition to some somatic effects (decreased body weight, delayed eyelid opening and delayed fur growth) the postnatal treatment resulted in a permanent decrease in brain weight, which was mainly due to a dramatic decrease in cerebellar size. During treatment, and 3 days after the end of it, the levels of putrescine and spermidine, but not those of spermine, were consistently lower in the cerebellum and forebrain of DFMO-treated rats than in controls. On the other hand, ODC appeared strongly inhibited only during the first phase of the treatment and showed recovery, and also rebound of the activity, during the second part of the treatment. A screening of neurochemical markers related to cholinergic, GABAergic and glutamatergic neurons, as well to astrocytes and oligodendrocytes was performed in several brain regions (cerebellum, olfactory bulbs, cortex, striatum, hippocampus) of some of these rats once they became adults. Significant alterations for all the parameters tested, with the exception of the marker for the glutamatergic transmission, were measured in the undersized cerebellum of the neonatally DFMO-treated rats. A shorter neonatal treatment with DFMO (from PD 1 to 6) resulted, in the adult, in decreased cerebellar size and in neurochemical alterations, both very similar to those occurring after the prolonged treatment. In the other brain regions a few minor differences were noticed. The present results show that: (1) the brain polyamine system is differently regulated in foetuses with respect to newborns; (2) the effects of chronic ODC blockade are different on prenatally or postnatally proliferating neurons, due either to a lower sensitivity of gestationally proliferating neurons or to a subsequent recovery; and (3) chronic postnatal ODC inhibition has a strong effect on proliferating neurons, but little effect on further maturation of postmitotic neurons.

Delayed Administration of Alpha-Difluoromethylornithine Prevents Hippocampus-Dependent Cognitive Impairment after Single and Combined Injury in Mice

“…Once neuronal cells have matured and proliferation has ceased, polyamine levels drop. We recognize that there is considerable data available showing that DFMO depletes polyamine levels (42–44). However, it was not the objective of this study to do an in-depth investigation into whether the observed differences in cognition were directly attributed to alerted levels of polyamines.…”

Difluoromethylornithine (DFMO) reduces deficits in isolation-induced ultrasonic vocalizations and balance following neonatal ethanol exposure in rats

“…This dose has also been shown to reduce the severity of EtOH withdrawal behaviors (Davidson and Wilce, 1998). DFMO was administered only on a single day because of concern regarding the important role that polyamines play in CNS development and because repeated injections of DFMO itself can cause reductions in cerebellar size (Schweitzer et al, 1989; Sparapani et al, 1996). This resulted in six treatments groups: Intubated Control/Saline, Intubated Control/DFMO, Intubated EtOH /Saline, Intubated EtOH /DFMO and Non-intubated Control/Saline and Non-intubated Control/ DFMO.…”

The Polyamine Inhibitor Alpha-Difluoromethylornithine Modulates Hippocampus-Dependent Function after Single and Combined Injuries

“…The present study represented a proof of concept study to determine if DFMO would modify the behavioral consequences of single insults or RCI. Considerable data are available showing that DFMO depletes PA levels [37]–[39], but for this study we focused exclusively on how DFMO affects factors associated with cognition.…”