B.P.F. Adlard

Vulnerability of developing brain. III. Development of four enzymes in the brains of normal and undernourished rats

Abstract The developmental profiles of 4 enzymes representative of different metabolic pathways or subcellular organelles have been determined in the homogenates of whole brains of control and undernourished male rats aged 0–21 days. Undernutrition was achieved by underfeeding the dams during gestation and lactation such that the young (at 21 days) had a deficit in body weight of 66% compared with control animals. The activities (per g wet wt of tissue) of the enzymes examined rose 3- to 5-fold between birth and 21 days in control animals. The development of succinate dehydrogenase (acceptor ferricyanide), fructose diphosphate aldolase and acetylcholinesterase was retarded by undernutrition. The activity deficits at 21 days were respectively 21%, 14% and 11% compared with a deficit in brain weight of 27%. The developmental profile of β- N -acetylglucosaminidase which is probably a lysosomal enzyme, was unaffected by undernutrition. These results are considered to indicate that the control of enzyme maturation in the brain may have both chronological and developmental components. Enzyme maturation in the brain appears to be restricted by undernutrition, though not as much as might be suggested by the reduction in brain weight.

The effect of age, growth retardation and asphyxia on ascorbic acid concentrations in developing brain.

Abstract— The concentration of ascorbic acid in whole rat brain during the first week of postnatal life was up to 100 per cent higher than in adult animals. A progressive fall in concentration occurred between 4 and 30 days of age. Corresponding changes did not occur in liver and adrenal gland, two other organs rich in ascorbic acid. Rats subjected to growth retardation during the fetal and suckling periods had, at 25 days of age, levels of ascorbic acid in the cerebellum and brainstem significantly higher than those of control animals. A period of prolonged asphyxia in 5‐day‐old rats resulted in a significant 4 per cent reduction in whole brain ascorbic acid concentration.

A comparison of the effects of cytosine arabinoside and adenine arabinoside on some aspects of brain growth and development in the rat.

1 Treatment of pregnant rats with cytosine arabinoside (ara‐C, 50 mg/kg, i.p.) at 14 days of gestation severely impaired both prenatal and postnatal whole brain growth in their offspring, although the cerebellum was relatively less affected than whole brain. 2 Rats treated at 5 days of age with ara‐C (250 mg/kg, i.p.) showed an impairment in growth of the cerebellum relative to the rest of the brain. 3 Adenine arabinoside (ara‐A) treatment, either prenatally or postnatally, had negligible effect on brain growth, even at doses considerably higher than those of ara‐C. 4 Adult rats, previously treated with ara‐C (50 mg/kg, i.p.) at 14 days of gestation, showed an impairment in discrimination learning when tested in a water T‐maze. 5 These results are discussed in relation to the proposed use of ara‐C or ara‐A as antiviral agents, particularly against intrauterine infection with cytomegalovirus.

Further Studies of Body Growth and Brain Development in ‘Small-for-Dates’ Rats

Rats were growth-retarded either from conception to 5 postnatal days (FNR or ‘small-for-dates’ group) or from 5 to 25 postnatal days (IR group) by underfeeding their mothers or foster-mothers. All young were fed ad libitum from weaning till they were killed at 15–24 weeks. The body weight of the FNR rats was 36% less than that of controls at 5 days and remained significantly less throughout their lives. Their adult nose-rump and tail lengths were slightly but significantly shorter than those of controls, but they did not differ in total body fat. TR rats weighed less than control and FNR rats from 10 days onwards, and they were leaner than both groups at death. They grew more in nose-rump and tail length between 35 and 115 days than the other groups, but were still significantly shorter than the controls at 115 days. This ‘catch-up’ may be related to their relative skeletal immaturity (assessed radiographically) at the time of the body growth spurt. Brain growth was impaired in both FNR and IR rats, though in different ways. Cerebellar growth was selectively affected in IR but not in FNR rats. Total synaptosomal protein (a probable measure of synapse number) was lower in the brains of both experimental groups in proportion to their brain weight deficits.

An Alternative Animal Model for the Full-Term Small-for-Dates Human Baby

Rats were subjected to growth retardation either from conception to 5 days of postnatal age (FNR group) or during the period 5–25 postnatal days (IR group). The rat at 5 days of age has reached a stag

Growth of suckling rats after treatment with dexamethasone or cortisol. Implications for steroid therapy in human infants.

De Souza, S. W., and Adlard, B. P. F. (1973). Archives of Disease in Childhood, 48, 519. Growth of suckling rats after treatment with dexamethasone or cortisol: implications for steroid therapy in human infants. Immature rats were treated with a single dose of dexamethasone (1 mg/kg or 20 mg/kg body weight). At both dose levels the subsequent growth of whole body, brain, and thymus was markedly impaired. Cortisol had smaller but similar effects. These results are discussed in the context of possible glucocorticoid therapy in newborn infants.

Nutritionally Small-for-Dates Rats: Their Subsequent Growth, Regional Brain 5-Hydroxytryptamine Turnover, and Behavior

Extract: Rats were subjected to nutritional growth retardation either from conception to 5 postnatal days of age (fetal and neonatal restriction (FNR) group), or from 5 to 25 postnatal days of age (infantile restriction (IR) group). The FNR group may serve as a model for the human small-for-dates baby.At 20 weeks of age cerebellum, midbrain, and cerebrum were significantly reduced in weight by 4%, 5%, and 4%, respectively, in FNR animals when compared with controls. Only cerebellum and midbrain were affected in IR rats of the same age, but in both regions the percentage deficits (8% and 9%, respectively) were greater than in FNR animals. Both cerebellum and midbrain weighed significantly less in IR than in FNR rats.The timing of nutritional growth retardation appeared to be of little consequence to the regional brain turnover of 5-hydroxytryptamine in adulthood. The rate of synthesis in the hippocampus of both FNR and IR animals was significantly faster (67% and 75%, respectively) than in controls. The increased turnover could perhaps represent “overactivity” of those 5-hydroxytryptaminergic neurons terminating in the hippocampus.Some differences in the behavior of the previously undernourished adult animals were also evident. On the fifth day of testing, control rats were most venturesome in the open field. Eighteen control rats left the edge zone within 2 min, whereas only 8 FNR and 11 IR rats did so. Most animals froze immediately after a 7-sec exposure to a loud electric bell. The delay before moving about again differentiated the three groups. FNR rats took longest to move out of the area in which they froze.Speculation: Lasting changes have been shown here in rats undernourished at a stage of development commonly implicated in the growth retardation of many human small-for-dates infants. It would therefore be unwise at this stage to conclude that such babies emerge unscathed from intrauterine growth retardation.

Maze Learning by Adult Rats after Inhibition of Neuronal Multiplication in Utero

Extract: Rats whose mothers received hydroxyurea (HU, 1 or 2 g/kg) at 14 days of gestation had a 30% deficit in both brain and body weight at birth, when compared with controls. Number of brain cells at birth (mainly neurons) was reduced by 33–34%. A severe reduction in postnatal whole brain growth (31–33% in adulthood) was observed, but the cerebellum was relatively spared. In the Hebb-Williams maze text in adulthood HU animals made 28% more errors than controls over 12 problems. The differences were much more marked on certain problems and for HU animals with particularly small brains. In a T-maze spatial discrimination test in adulthood HU rats learned the initial response normally but, when required to reverse this response, showed a significant tendency to make more perseverative errors than controls.Speculation: Rats exposed to an inhibitor of cell division at the beginning of the major period of brain neurogenesis showed deficits in learning ability in adulthood. The large number of mentally retarded human children whose handicap is without known etiology may have suffered a similar early loss of neurons, and if so, this preparation could provide a useful animal model.

Permanent changes in the activity and subcellular distribution of acetylcholinesterase and lactate dehydrogenase in adult rat cerebellum after X-irradiation in infancy

Abstract The activity of acetylcholinesterase and lactate dehydrogenase was examined in subcellular fractions of the cerebellum from normal adult rats and adult rats receiving one dose of X-rays (600 R) to the head at 6 days of age. Acetylcholinesterase activity was significantly elevated in the irradiated animals, the effect being most marked in the crude mitochondrial and cytoplasmic fractions. Similarly, lactate dehydrogenase activity was slightly elevated in the cytoplasmic fraction. The results are discussed in comparison with available histological data on radiation effects on developing cerebellum. It is suggested that the increased acetylcholinesterase concentration after early irradiation represents a relative sparing of cholinergic neurons.

Influence of Asphyxia and of Dexamethasone on ATP Concentrations in the Immature Rat Brain

Five-day-old rats subjected to prolonged asphyxia (at 37 °C) to the point of death showed an approximately 50-percent loss of brain ATP and a rise in ADP and AMP. Brain energy charge was reduced from 0.86 to 0.64. Recovery of ATP levels to normal was virtually complete 20 min after beginning resuscitation. Rats treated with dexamethasone (20 mg/kg body weight) showed, during asphyxia, a fall in brain ATP which was significantly less than in those animals asphyxiated without steroid. Possible implications for the use of glucocorticoid therapy in asphyxia neonatorum are discussed.