Brain Ornithine Decarboxylase Research Articles

Opiate withdrawal increases ornithine decarboxylase activity which is otherwise unaltered in brains of dependent chicken fetuses

We have used the developing chicken to determine if ornithine decarboxylase (ODC) activity is altered in fetuses chronically exposed to the opiate N-desmethyl-l-α-acethylmethadol (NLAAM) or rendered abstinent by acute injection of naloxone (Nx). Exposure to NLAAM from day 3 of embryogenesis did not significantly change brain ODC activity in 15, 17 or 19-day-old fetuses. Acute treatment of 17-day-old fetuses with a motility suppressant dose of NLAAM did not differentially affect ODC activity in NLAAM-dependent fetuses, but an additional treatment with Nx, which precipitated withdrawal, resulted in a significant increase in ODC activity in this group. We conclude that withdrawal can alter fetal ODC activity which otherwise appears normal, even though fetuses have been chronically exposed to and dependent upon an opiate.

Developmental changes in mouse brain polyamine metabolism.

Mouse brain ornithine decarboxylase (ODC) activity is high at the time of birth, whereas S-adenosyl-L-methionine decarboxylase (SAM-DC) activity is low. ODC activity, and putrescine, spermidine and spermine concentrations decline rapidly during postnatal development to the low level characteristic of mature brains, while SAM-DC activity behaves in the opposite manner. The fluctuations in mouse brain polyamine metabolism are in accord with those found in the rat. The apparent Km values of ODC and SAM-DC for their substrates decline parallel with the decrease of substrate and product concentrations during ontogeny suggesting substrate and/or product dependent regulation of polyamine synthesis in the developing brain.

Ornithine decarboxylase activity in maternal and fetal tissues during inanition in pigs.

The relationships between maternal liver and fetal brain and liver ornithine decarboxylase (ODC) activity and porcine fetal development were investigated. Yorkshire gilts were subjected to prolonged inanition (40 days; 0 kcal/day; water only) from Day 50 to Day 90 of gestation and, on Day 90, either hysterectomized or realimentated to a full diet and allowed to advance to term; controls received a full diet (7,028 kcal/day) until hysterectomy at Day 90 or throughout pregnancy. ODC activity was determined in maternal liver tissue collected from 6 experimental and 6 control gilts on Days 50, 70, 89 and 91. Furthermore, ODC activity of Day 90 fetal brain and liver tissue was determined in 6 fetuses from each of 3 additional experimental and control dams (36 fetuses). Prolonged inanition of gilts during late pregnancy had a marked effect upon maternal liver ODC activity. Liver ODC activity in full-fed guts remained constant across days, with a mean activity of 59 (pmol CO3 released per 60 mm per mg soluble protein). ODC activity before inanition (Day 50) in experimental gilts was similar to that of controls, but by Day 70 and continuing to Day 89 (during inanition), was reduced greater than 7-fold. In contrast, after 1 day realimentation (Day 91), ODC activity had increased by greater than 10-fold to levels similar to controls. Day 90 fetal brain ODC activity in inanition gifts was greater than the activity observed in control gilts, and fetal brain weights were similar in all dams, suggesting that ODC may play a role in maintenance of normal fetal brain development. ODC activity of Day 90 fetal liver tissue was decreased in inanition as compared with control gilts, as were fetal liver weights. Reproductive performance, as determined by fetal survival rates, body weight, litter weight and size, was similar in inanition and control gilts. These data indicate that changes in ODC activity may play a role in compensatory responses of the porcine dam and fetus during periods of severe nutrient deprivation to allow normal fetal survival and dev#{231}lopment.

Ornithine decarboxylase induction by glucocorticoids in brain and liver of adrenalectomized rats.

Ornithine decarboxylase (ODC), the rate-limiting enzyme in the biosynthesis of polyamines, was measured in the brain and the liver of adrenalectomized rats after an acute s.c. treatment with glucocorticoids. The effects of corticosterone and dexamethasone were compared in three brain areas, the cerebral cortex, hippocampus, and cerebellum. These structures have similar concentrations of cytosolic glucocorticoid receptor, as measured by an in vitro exchange assay using a specific glucocorticoid ligand, [3H]RU 26988, but contain different amounts of mineralocorticoid receptor. Corticosterone and dexamethasone increased ODC activity in the liver and brain areas in a dose-dependent manner, dexamethasone being more active than corticosterone in all tissues. Moreover, estradiol, progesterone, and testosterone were inactive. Aldosterone, at high doses, increased brain ODC activity. Glucocorticoids, selected for their weak binding, or lack of binding to the mineralocorticoid receptor, were tested and found to be highly active in inducing brain and liver ODC, thus showing that ODC induction by steroids is specific for glucocorticoids. These results are among the first to suggest biochemically a central action of glucocorticoids following an acute treatment and confirm that the brain is a glucocorticoid target organ.

Delays in growth and biochemical development of rat brain caused by maternal methadone administration: are the alterations in synaptogenesis and cellular maturation independent of reduced maternal food intake?

Food consumption of control pregnant and nursing rats was matched to that of methadone-treated dams and the patterns of growth and of biochemical development of the brain in the offspring were compared, using tyrosine hydroxylase activity as a marker for synaptogenesis of catecholamine neurons and the developmental pattern of ornithine decarboxylase activity as an index of delay of cellular maturation. Although body growth was slowed significantly, the degree of deficit was attenuated compared to previously reported experiments with non-pair-fed controls. Reduced brain weight and slowing of synaptogenesis also were evident in the methadone-exposed pups, and in this case, the effect was not attenuated with the use of pair-fed controls. Reduced brain weight and slowing of synaptogenesis also were evident in the methadone-exposed pups, and in this case, the effect was not attenuated with the use of pair-fed controls. Delays in the normal maturational decline of brain ornithine decarboxylase activity were prominent in the methadone group compared to offspring of pair-fed controls, just as reported previously in comparisons using non-pair-fed dams. These results indicate the part of the general growth deficit seen in perinatally-addicted pups is related to maternal undernutrition, but that delays in central synaptogenesis or in the pattern of biochemical maturation of the brain are relatively independent of the nutritional deficit.

Effects of insulin on cultured rat brain cells: stimulation of ornithine decarboxylase activity.

Growth-promoting peptide hormones, including growth hormone and insulin, stimulate rat brain ornithine decarboxylase (ODC; EC 4.1.1.17) activity in vivo (Roger et al., 1974; Roger and Fellows, 1980). To determine if this is a result of a direct action on brain, we have investigated the effect of peptide hormones in primary cell cultures of brain from fetal rats of 20 days gestational age. Significant stimulation of ODC activity was observed 4 h after administration of porcine insulin and bovine growth hormone. On a molar basis, growth hormone was less potent than insulin. By contrast, glucagon, enkephalin, and angiotensin II did not stimulate ODC in this system. At 25 ng/ml, insulin stimulated ODC activity approximately threefold, with maximum stimulation of five- to sevenfold reached at 1 microgram/ml. After a 1-h lag, insulin-stimulated ODC activity increased to a maximum between 5 h and 8 h and returned to basal levels by 24 h. The apparent Km of ODC, 5.66 +/- 1.16 microM, was not significantly altered by insulin treatment, nor was any enzyme activator found in mediating insulin actions. Additional evidence suggests that insulin stimulation of ODC activity involves both de novo synthesis of the enzyme and a prolongation of ODC half-life by 50%. These findings, implicating insulin as a regulator of ODC activity in brain cells, suggest the possible involvement of insulin or an insulin-like peptide in the control of growth and development of the CNS.

Effects of material methadone administration on ornithine decarboxylase in brain and heart of the offspring: Relationships of enzyme activity to dose and to growth impairment in the rat

Administration of 5 mg/kg of methadone daily to pregnant and nursing rats produced substantial retardation of body, brain and heart growth in the offspring; alterations in biochemical development also were present in the methadone-exposed pups, as evidenced by delays in the maturational declines of brain and heart ornithine decarboxylase (ODC) activity. Lowering the dose of methadone to levels which did not affect growth or brain ODC, still resulted in pro-found abnormalities in the developmental pattern of heart ODC. These studies indicate that downward adjustment of maternal methadone dosage to a point where birthweights and body and organ growth rates are normal, does not eliminate all of the biochemical alterations associated with the perinatal opiate syndrome.

Stimulation of ornithine decarboxylase activity by insulin in developing rat brain.

Insulin administered ip or intracisternally (ic) increased the activity of ornithine decarboxylase (ODC) in whole brains and brain parts of neonatal rats. Maximal stimulation of activity occurred 4-5 h after ip administration. At the highest doses, insulin stimulated ODC activity by up to 5- and 8-fold after ip and ic injection, respectively. The same amount of insulin given ic caused greater increases in activity than when given ip. Insulin stimulated ODC activity in 2-day-old and in 17- to 60-day-old rats but not in 5- or 9-day old neonates or 80-day-old adults. When insulin-induced hypoglycemia was prevented by giving dextrose, the stimulation of ODC activity was approximately the same as that in animals receiving insulin without dextrose. This indicates that insulin-induced stimulation of brain ODC activity was not caused by insulin-induced hypoglycemia or physiological responses to hypoglycemia. Since ODC is considered an indicator of growth stimulation, these results suggest that insulin or insulin-like peptides have a role in the regulation of brain development.

Evidence for thyroxine-growth hormone interaction during brain development.

Growth-promoting hormones have complementary and synergistic effects on cell growth. In particular, thyroid hormone–growth hormone (GH) interactions are important in the regulation of somatic development1. Although the requirement of thyroid hormone for normal brain development is well established2, the effects of growth-promoting peptide hormones, including GH, nerve growth factor and insulin, on central nervous system development have not been well characterised. To investigate the possibility of a role for GH in normal CNS development, we have measured its effect on the activity of brain ornithine decarboxylase (ODC), a key enzyme in the synthesis of the polyamines, spermidine and spermine3,4. Previously, we reported increased ODC activity in neonatal rat brain after intraperitoneal (i.p.) or intracranial administration of GH and other growth-promoting peptide hormones5, results which have been supported by other data6,7. We now extend our findings to show that GH stimulation of brain ODC activity depends on the presence of thyroid hormone, even though thyroid hormone, by itself, does not stimulate ODC activity in brain. This is in contrast to liver, where GH and thyroid hormones seem to stimulate ODC activity independently. Our results suggest that thyroid hormone selectively alters or modulates the action of GH in mammalian brain and that abnormal brain development observed in hypothyroidism may in part result from decreased expression of GH activity.

The effect of vasopressin on the activity of ornithine decarboxylase in rat brain and liver.

The effect of vasopressin on the activity of ornithine decarboxylase in rat brain and liver.

Selective depression of serum growth hormone during maternal deprivation in rat pups.

Maternal deprivation was associated with a decline in immunoreactive growth hormone in the serum of rat pups. Pups that were returned to the mother showed a rapid reversal in this deprivation-induced decrease. The change in growth hormone concentration was not accompanied by changes in the concentrations of prolactin, thyrotropin, or corticosterone in the serum, but were correlated with alteration in the activity of ornithine decarboxylase in the brain. Treatment of neonatal rat pups with cyprohepatadine, a serotonin antagonist that suppresses growth hormone secretion, resulted in a significant decline in both serum growth hormone concentration and brain ornithine decarboxylase activity. These findings suggest that maternal deprivation elicits a specific suppression of growth hormone release which mediates the decrease in ornithine decarboxylase activity. The study is consistent with clinical findings of impaired growth hormone "responsitivity" in human maternal deprivation syndrome.

The permissive effect of cortical steroids on the induction of brain ornithine decarboxylase by nerve growth factor

The intraventricular administration of nerve growth factor causes a marked increase in the activity of ornithine decarboxylase in rat brain. This increase is much smaller in adrenalectomized rats. Dexamethasone and corticosterone, administered either systemically or intraventricularly, are able to restore the ability of nerve growth factor to induce ornithine decarboxylase. The steroids must be given at least three hours before the nerve growth factor to be fully effective.

Nerve growth factor increases activity of ornithine decarboxylase in rat brain

Intraventricular administration of nanogram quantities of nerve growth factor to adult rats results in a marked increase in the activity of ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) in the brain. The increase occurs in all major brain regions and the activity is maximal by 7.5 hr after administration. The enzyme response to nerve growth factor increases in magnitude during maturation; the relative increase in ornithine decarboxylase activity in adult animals is much greater than that in young. Neither insulin nor bovine growth hormone was able to increase ornithine decarboxylase activity to the same extent as did nerve growth factor. When brain was separated into neuronal- and glial-enriched fractions, induction of ornithine decarboxylase was found in both, but a greater increase was observed in the glial fraction.

Ornithine decarboxylase and adenosylmethionine decarboxylase in mouse brain--effect of electrical stimulation.

Ornithine decarboxylase and adenosylmethionine decarboxylase in mouse brain--effect of electrical stimulation.

Effect of maternal deprivation on polyamine metabolism in preweanling rat brain and heart

Ornithine Decarboxylase (ODC) the first and probably rate-limiting step in polyamine biosynthesis, is usually elevated in tissues with high rates of growth or protein synthesis and in preweanling rat brain is altered by hormones thought to play a role in stress such as thyroxine and cortisol. Maternal deprivation stress was examined for its effect on preweanling rat brain ODC activity. Ten day old rat pups were removed from the maternal cage, then alternately returned to the mother or placed in a warm environment after the method of Hall. Pups taken from the mother for as little as 1 hour show a significant decline in their whole brian ODC activity. The effect peaked at 2–4 hours of deprivation, at which time the brain ODC activity was 60% below that of the equally handled littermate controls. Two hours of deprivation produced a similar effect throughout preweanling development. The effect occurred in all brain regions and also in heart. Return to mother reversed rapidly the deprivation-induced ODC decline, with ODC activity overshooting to 300% of control 2 hours after return, then declining to baseline by 4 hours. Putrescine, the immediate product of the ODC reaction, declined 15% one hour after deprivation, and 50% in brain and heart after 15 hours. These data demonstrate that maternal deprivation alters polyamine metabolism in preweanling rat brain and heart.

Effects of late prenatal or early postnatal ethanol exposure on ornithine decarboxylase activity in brain and heart of developing rats

Pregnant rats were kept on a liquid diet containing ethanol (6.8% v/v) from the 18th day of gestation, and the developmental pattern of ornithine decarboxylase (ODC) activity was determined for the brain and heart of the offspring. In neonates exposed to ethanol throughout development, both brain and heart ODC activities increased but then declined to normal or subnormal levels; brain weights were not different from controls but heart weights were depressed. Withdrawal from ethanol at birth produced alterations in heart ODC activity similar to those in pups exposed to ethanol continuously. Neonatal withdrawal resulted in no deviations from normal ODC development in brain minus the cerebellum, but in the cerebellum, ODC levels were increased consistently. Postnatal exposure of pups to ethanol caused a decrease in heart weight and ODC activity but no significant change in brain weight or its ODC activity. These data suggest that exposure to ethanol during development produces alterations in polyamine metabolism and organ weight which are dependent upon the duration and age period of exposure.

Effect of maternal ethanol ingestion on neonatal rat brain and heart ornithine decarboxylase

Perinatal exposure of developing rats to ethanol caused an alteration in the developmental pattern of ornithine decarboxylase (ODC) activity in heart and brain which was different for the two tissues. In brain, an initial decrease in ODC activity was followed by normal or Supranormal levels before declining again, whereas heart ODC activity initially was increased but then declined to the low levels of activity characteristic of adult heart tissue. Withdrawal from ethanol at birth or at 3 and 5 days postnatally produced alterations in brain and heart ODC activity that were different from those seen in pups exposed to ethanol continuously throughout development, indicating that the biochemical changes are dependent on the duration of exposure as well as the time at which withdrawal is initiated. The altered ODC developmental patterns in the brain and heart are consistent with the hypothesis that maternal ethanol administration exerts significant effect on fetal polyamine metabolism and ultimately upon the growth and development of these tissues.

Apparent kinetic differences between brain and liver ornithine decarboxylase

Kinetic studies of ornithine decarboxylase activity in homogenates of rat brain and liver indicate that rat brain ornithine decarboxylase has a higher affinity for substrate L-ornithine and competitive inhibitor putrescine. These data suggest different forms of ornithine decarboxylase may exist in these tissues.

Effect of thyroxine and cortisol on brain ornithine decarboxylase activity and swimming behavior in developing rat

Thyroxine and cortisol were tested to determine their effects on the ontogenetic pattern of ornithine decarboxylase (ODC) (EC 4.1.1.17) activity in rat brain. The effects of both hormones were significant, but varied with the brain region studied and with the age of the rat. Thyroxine (1 μg/g body wt/day injected i.p. × 3) altered ODC activity in all brain regions studied, if given during the first 10 postnatal days The overall effect was to compress the time course in which ODC activity passed through its ontogenetic pattern; both the peak in activity and the drop to the characteristic low adult activity level occurred earlier and were accelerated. The magnitude of the response to thyroxine was greater in the cerebellum, followed by the cerebrum and brainstem respectively. Cortisol, when given on the first postnatal day (0.5 mg i.p. × 1), initially depressed ODC activity and subsequently prolonged the time required to reach the low level of activity found normally in adult brain. The magnitude of the response to cortisol generally was greater than that of thyroxine, except in the cerebellum. The effects of these hormones on the ontogenetic pattern of ODC activity are consistent with previously observed effects in rats both on biochemical parameters, e.g. polyamine content and nucleic acid synthesis, and behavioral parameters, e.g. development of swimming ability. Our data are consistent with the hypothesis that thyroxine and cortisol, when administered to the neonate, may exert some of their effects on nucleic acid metabolism and ultimately growth, development and behaviour via their effects on polyamine metabolism.

Growth and lactogenic hormone stimulation of ornithine decarboxylase in neonatal rat brain.

Bovine growth hormone (bGH), bovine prolactin (bPRL), human placental lactogen (hPL) and nerve growth factor (NGF) were administered intracisternally (ic) and intraperitoneally (ip) to 16–18-day-old rats, and ornithine decarboxylase (ODC) activity in brain and liver was determined. All four hormones stimulated brain ODC activity when injected ic: bGH caused a 458% increase of activity compared to controls while bPRL, hPL and NGF were about half as potent as bGH. When injected ip, bGH and bPRL, but not hPL or NGF, stimulated brain ODC activity. bGH and bPRL, but not hPL, stimulated liver ODC activity after both ic and ip administration. A fragment derived from bGH by cleavage with cyanogen bromide (fragment A) had 40% of the activity of intact bGH on brain ODC activity when given ic. The results suggest that GH may be involved in the regulation of CNS development through its effects on polyamine synthesis. The finding that when injected intracisternally hPL and NGF, as well as bGH and bPRL, are capable of ...