Glucocorticoid Effect upon Thymidine Kinase in the Developing Cerebellum

Abstract

ExtractForty-nine litters of eight Sprague-Dawley rat pups were divided into four pups treated with 0.6 mg hydrocortisone acetate on the day of bir.th and four littermate controls. The mean body weight, cerebellar weight, and cerebellar DNA were significantly depressed in treated pups by 3 days of age, with all three of these measurements of growth increasing. in rate around 9 days of age, but remaining well below control values throughout 15 days of age. Body weight and cerebellar DNA were maximally depressed at age 12 days (37.7% and 46.6% of control values, respectively), and cerebellar wet weight was maximally depressed to 5 1.5% of the control value at 9 days of age. The activity of thymidine kinase, a salvage pathway enzyme for pyrimidine biosynthesis, was found t o be depressed t o 80.2% and 74.1% of the control value at 3 and 6 days of age, respectively and elevated to 134% and 158% over control values at ages 12 and 15 days. The depression of thymidine kinase activity by hydrocortisone at ages 3 and 6 days followed by the overshoot of enzyme activity after steroid-induced growth suppression had subsided suggests that the thymidine kinase may be considered as having an essential regulatory function in the rate of DNA synthesis in developing brain. SpeculationExtrapolation of these hormone-enzyme relations in developing rat cerebellum t o the clinical use of glucocorticoids in acceleration of lung maturation in human premature infants suggests the possibility that concomitant effects of the steroid may be detrimental t o the development of brain areas which undergo cell replication at the time the drug is administered.Glucocorticosteroids have been used therapeutically for the last few years in diseases of early childhood including myoclonic seizures of childhood (9) and hypoglycemia (22). More recently, glucocorticoids have been used in animal experimentation in studies on maturation of the lung in lambs and rabbits. Liggins and Howie (18) showed that when labor can be delayed a t least 24 hr in unplanned deliveries of infants under 32 weeks gestation, infusion of P-methasone into the mother can prevent respiratory distress syndrome in the infant. These studies, which reflect the ability of glucocorticoids to accelerate lung maturation and prevent the consequences of surfactant deficiency, will undoubtedly lead t o a greater volume of clinical experimentation regarding the use of glucocorticoids in mothers when premature delivery threatens. Although these recent clinical studies appear promising, little attention has been paid t o possible deleterious effects of steroids on fetal organs other than the lung. Avery (4) has pointed out the possibility of permanent neurologic damage as a consequence of steroid therapy in the developing fetus, but more recently described profound effects of glucocorticoids upon brain development have not heretofore been emphasized in the pediatric literature. The studies of Balhzs and Cotterrell (5) and Cotterrell e t al. (12) on the effects of corticosteroids on the maturat...

Postnatal Maturation Patterns of Serum Corticosterone and Growth Hormone in Rats: Effect of Chronic Thyroxine Administration

“…The lower weight gain in the T4 treated animals was similar to that described in an earlier study (Weichsel 1974a). All pups suckled vigorously throughout the experimental period, and examinations of the stomachs of the sacrificed pups showed no observable differences in milk content between the treated and control animals.…”

“…The single dosage regimen of T4 utilized in tbis study previously has been shown to alter thymidine kin ase (TK) activity, thymidylate synthetase (TS) activity, and DNA synthesis in developing rat cerebellum (Weichsel 1974a;C/ark and Weichsel 1977). Administration of T4 in other dose regimens has been shown to alter the activity of ornithine decarboxylase (ODe) in the developing cerebellum and cortex (Anderson and Schanberg 1975).…”

Longterm Effects of Neonatal Treatment with Cortisol and/or Estrogen in the Female BALB/c Mouse

“…Similar observations have been made in neonatally treated rats and mice (8)(9)(10)(11). However, the longterm effects of perinatal glucocorticoid treatment have received little attention.…”

“…The estrous cycles were normal, and the reproductive organs did not suffer any apparent abnormalities. Treatments with cortisol followed by estrogen or with estrogen alone (days [11][12][13][14][15] altered the estrous cycle by prolonging the period of estrus or by eliminating the cycles altogether (persistent diestrus). The ovaries of these animals lacked corpora lutea and had hypertrophied interstitial tissue.…”

Glucocorticoid Induced Cerebellar Toxicity in the Developing Neonate: Implications for Glucocorticoid Therapy during Bronchopulmonary Dysplasia

“…Therefore, it is not surprising that the ability of GCs to stunt brain development in the rodent was known [14] even before Buckingham et al [15] first suggested this steroid might accelerate lung development. Since then, multiple studies have established that GCs can dramatically effect rodent cerebellar development by decreasing proliferation [16,17,18]. Unfortunately, despite these advances, it was still not clear how this decrease in proliferation is occurring or why such vulnerability would exist to begin with.…”