Changes of Thymidine Kinase in the Developing Rat Brain

Yamagami, Sakae; Mow, K.; Kawakita, Yukio

doi:10.1111/j.1471-4159.1972.tb01346.x

Cited by 58 publications

(17 citation statements)

References 26 publications

(1 reference statement)

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“…Although control of DNA synthesis may involve many factors, our findings are consistent with the concept of Bollum and Potter (8) and Bianchi et al (6) that thymidine kinase may be considered as the essential regulatory control enzyme in the rate of DNA synthesis as demonstrated in regenerating rat liver, and that there may be a similar mechanism during brain development (26,32). Pratt and Aranow (23) observed that, in a study of cultured fibroblasts, inhibition of thymidine incorporation by cortisone may result from inhibition of DNA polymerase.…”

Section: Discussionsupporting

confidence: 79%

“…(32) and Breitman (10) as modified for use in this laboratory in conjunction with other enzyme assays in rat brain tissue.…”

Section: Methodsmentioning

confidence: 99%

“…(32) and Breitman (10) as modified for use in this laboratory in conjunction with other enzyme assays in rat brain tissue. The enzyme reaction mixture contained 0.2 ml Tris-HC1 buffer, pH 8 (0.125 M), 0.05 ml ATP (0.01 M), 0.05 ml 3~-thymidine (250 pCi/pmol) (37), and 0.2 ml tissue homogenate supernatant.…”

Section: Methodsmentioning

confidence: 99%

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Glucocorticoid Effect upon Thymidine Kinase in the Developing Cerebellum

Weichsel

1974

Pediatr Res

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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...

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Section: Discussionsupporting

confidence: 79%

“…(32) and Breitman (10) as modified for use in this laboratory in conjunction with other enzyme assays in rat brain tissue.…”

Section: Methodsmentioning

confidence: 99%

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Glucocorticoid Effect upon Thymidine Kinase in the Developing Cerebellum

Weichsel

1974

Pediatr Res

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“…However, in vivo studies found that TK is required for viral replication in neural tissues (TG and brain), but not in peripheral tissues, of immunocompetent adult mice (4,(11)(12)(13)(14). Therefore, it is generally believed that adult neurons are postmitotic cells that do not express detectable levels of cellular TK, which presumably supports TK Ϫ HSV-1 to replicate in dividing cells (10,15). This notion is supported by our work showing that the replacement of viral tk with cellular tk enables HSV-1 to replicate in TG (16) and that providing TK activity in trans by coinfection with wild-type virus enables the TK Ϫ mutant to replicate in TG (17).…”

mentioning

confidence: 99%

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

Huang

Yao

Wang

et al. 2017

J Virol

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Herpes simplex virus 1 (HSV-1) establishes latency in neural tissues of immunocompetent mice but persists in both peripheral and neural tissues of lymphocyte-deficient mice. Thymidine kinase (TK) is believed to be essential for HSV-1 to persist in neural tissues of immunocompromised mice, because infectious virus of a mutant with defects in both TK and UL24 is detected only in peripheral tissues, but not in neural tissues, of severe combined immunodeficiency mice (T. Valyi-Nagy, R. M. Gesser, B. Raengsakulrach, S. L. Deshmane, B. P. Randazzo, A. J. Dillner, and N. W. Fraser, Virology 199:484 -490, 1994, https://doi.org/10.1006/viro .1994.1150). Here we find infiltration of CD4 and CD8 T cells in peripheral and neural tissues of mice infected with a TK-negative mutant. We therefore investigated the significance of viral TK and host T cells for HSV-1 to persist in neural tissues using three genetically engineered mutants with defects in only TK or in both TK and UL24 and two strains of nude mice. Surprisingly, all three mutants establish persistent infection in up to 100% of brain stems and 93% of trigeminal ganglia of adult nude mice at 28 days postinfection, as measured by the recovery of infectious virus. Thus, in mouse neural tissues, host T cells block persistent HSV-1 infection, and viral TK is dispensable for the virus to establish persistent infection. Furthermore, we found 30-to 200-fold more virus in neural tissues than in the eye and detected glycoprotein C, a true late viral antigen, in brainstem neurons of nude mice persistently infected with the TK-negative mutant, suggesting that adult mouse neurons can support the replication of TK-negative HSV-1.IMPORTANCE Acyclovir is used to treat herpes simplex virus 1 (HSV-1)-infected immunocompromised patients, but treatment is hindered by the emergence of drugresistant viruses, mostly those with mutations in viral thymidine kinase (TK), which activates acyclovir. TK mutants are detected in brains of immunocompromised patients with persistent infection. However, answers to the questions as to whether TKnegative (TK Ϫ ) HSV-1 can establish persistent infection in brains of immunocompromised hosts and whether neurons in vivo are permissive for TK Ϫ HSV-1 remain elusive. Using three genetically engineered HSV-1 TK Ϫ mutants and two strains of nude mice deficient in T cells, we found that all three HSV-1 TK Ϫ mutants can efficiently establish persistent infection in the brain stem and trigeminal ganglion and detected glycoprotein C, a true late viral antigen, in brainstem neurons. Our study provides evidence that TK Ϫ HSV-1 can persist in neural tissues and replicate in brain neurons of immunocompromised hosts.

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“…Thymidine kinase was assayed by a procedure combining the method of Yamagami et al (22) and Breitman (2), as modified for use in our laboratory (19). Other activities were assayed as follows: ATC by a modification of the method described by Bethell et al (I), UK by the Herbst et al (7) modification of the method of Skold (15), and thymidylate synthetase as described by Kawai and Hillcoat (9).…”

Section: Methodsmentioning

confidence: 99%