Skip to main content
SpringerLink
Log in

A neurochemical study of developmental impairment of the brain caused by the administration of cytosine arabinoside during the fetal or neonatal period of rats

  • Original Articles
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Injection of pregnant rats with cytosine arabinoside (ara-C) (280 mg/kg) on day 15 of gestation caused a significant rise (about two times the control value) in monoamine concentrations (norepinephrine, dopamine, and serotonin) accompanied by a decrease (about 60% of the control) in the brain weight and DNA content in the cerebrum of the offspring at 60 days of age. When neonatal rats were injected with ara-C (30 mg/kg/day) for four consecutive days from the fourth to seventh days after birth, a decrease of DNA content per cerebellum and an elevation of monoamine concentrations in the cerebellum were found. However, the total content of each monoamine per cerebrum or cerebellum showed no difference from the control. These results suggest that monoaminergic neurons may remain intact, with normal monoaminergic synapses compressed into a small brain volume. The neonatal administration of ara-C caused an elevation of 2′, 3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) (EC 3.1.4.37) activity and myelin protein content in the cerebellum, suggesting a relative increase in myelin concentration as a result of hypoplasia of granule cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bobbing, J. 1968. Vulnerable period in developing brain. pages 287–316,in Davison A. N., andDobbing, J. (eds.), Applied Neurochemistry, Oxford Univ. Press, London.

    Google Scholar 

  2. Hicks, S. P., D'. Amato, C. J., andLowe, M. J. 1959. The development of mammalian nervous system. J. Comp. Neurol. 113:435–499.

    Google Scholar 

  3. South, M. A., Tompkins, W. A. F., Morris, C. R., andRawls, W. E. 1969. Congenital malformation of the central nervous system associated with genital type (type 2) herpesvirus. J. Pediatr. 75:13–18.

    Google Scholar 

  4. Kohsaka, S., andTsukada, Y. 1980. Neurochemical correlates of discriminative learning disabilities in experimental phenylketonuric rats and postnatal undernourished rats. Pages 149–164,in Tsukada Y., andAgranoff B. W. (eds.), Neurobiological Basis of Learning and Memory, John Wiley and Sons Inc. Pub.

  5. Reddy, T. S., andHorrocks, L. A. 1982. Effects of neonatal undernutrition on the lipid composition of gray matter and white matter in rat brain. J. Neurochem. 38:601–605.

    Google Scholar 

  6. Matsutani, T., Nagayoshi, M., Tamaru, M., andTsukada, Y. 1980. Elevated monoamine levels in the cerebral hemispheres of microencephalic rats treated prenatally with methylazoxymethanol or cytosine arabinoside. J. Neurochem. 34:950–956.

    Google Scholar 

  7. Beaulieu, M., andCoyle, J. 1982. Fetally-induced noradrenergic hyperinnervation of cerebral cortex results in persistent down-regulation of beta-receptors. Devel. Brain Res. 4:491–494.

    Google Scholar 

  8. Ritter, E. J., Scott, W. J., andWilson, J. G. 1973. Relationship of temporal patterns of cell death and development to manifestation in the rat limb. Possible mechanisms of teratogenesis with inhibition of DNA systhesis. Teratology. 7:219–226.

    Google Scholar 

  9. Kochhar, D. M., andAgnish, N. D. 1977. Chemical surgery as an approch to study Morphogenetic events in embryonic mouse limb. Devel. Biol. 61:388–394.

    Google Scholar 

  10. Chaube, S., andMurphy, M. L. 1965. The teratogenic effects of cytosine arabinoside (CA) on the rat fetus. Proc. Am. Ass. Cancer Res. 6:11.

    Google Scholar 

  11. Percy, D. H. 1975. Teratogenic effects of the pyrimidine analogues 5-iododeoxyuridine and cytosin arabinoside in late fetal mice and rats. Teratology. 11:103–118.

    Google Scholar 

  12. Karnofsky, D. A., andLacon, C. R. 1966. The effects of 1-β-D-arabinofuranosyl-cytosine on the developing chick embryo. Biochemical. Pharmacol. 15:1435–1442.

    Google Scholar 

  13. Fishaut, J. M., Connor, J. D., andLampert, P. W. 1974. Comparative effects of arabinosyl nucleoside upon the postnatal growth and development of the rat. Pediatr. Res. 8:825–829.

    Google Scholar 

  14. Shimada, M., Wakaizumi, S., Kasubuchi, Y., andNakamura, T. 1972. Cerebellar malformation following administration of cytosine arabinoside to newborn mice. Teratology. 6:119–120.

    Google Scholar 

  15. Adlard, B. P. F., Dobbing, J., andSands, J. 1975. A comparison of the effects of cytosine arabinoside and adenine arabinoside on some aspects of brain growth and development in the rat. Br. J. Pharmac. 54:33–39.

    Google Scholar 

  16. Ogura, H., Mikami, T., Takamura, M., Suzuki, Y., andChiba, T. 1980. Development of behavioral function of celebellar hypoplasia rat as induced by cytosine arabinoside (ara-C). Folia pharmacol. Japan. 76:33–44.

    Google Scholar 

  17. Tsuji, M., Iwase, N., Sato, K., Takahashi, S., andShimada, M. 1979. Biochemical and histological studies on the cerebellar hypoplasia induced by cytosine arabinoside in the mice. Shinkei Kagaku. 18:320–323.

    Google Scholar 

  18. Kimball, A. P., andWilson, M. J. 1968. Inhibition of DNA polymerase by β-D-arabinosyl-cytosine and reversal of inhibition by deoxycytidine-5′-triphosphate. Proc. Soc. Exp. Biol. Med. 127:429–432.

    Google Scholar 

  19. Karasawa, T., Furukawa, K., Yoshida, K., andShimizu, M. 1975. A double column procedure for the simultaneous estimation of norepinephrine, normethanephrine, dopamine, 3-methoxytyramine, and 5-hydroxytryptamine in brain tissue. Japan. J. Pharmacol. 25:727–736.

    Google Scholar 

  20. Tsukada, Y., Nagai, K., andSuda, H. 1980. A rapid micromethod for 2′, 3′-cyclic nucleotide 3′-phosphohydrolase assay using micro high performance liquid chromatography. J. Neurochem. 34:1019–1022.

    Google Scholar 

  21. Norton, W. T., andPoduslo, S. E. 1973. Myelination in the rat brain: method of myelin isolation. J. Neurochem. 21:749–757.

    Google Scholar 

  22. Lowry, O. H., Rosebrough, N. J., Farr, A., andRandall, R. J. 1951. Protein determination with the Folin phenol reagent. J. Biol. Chem. 193:265–275.

    Google Scholar 

  23. Schmidt, G., andThannhauser, S. J. 1945. Method for determination of deoxyribonucleic, ribonucleic acid, and phosphoproteins on animal tissue. J. Biol. Chem. 161:83–89.

    Google Scholar 

  24. Fleck, A., andMunro, H. N. 1962. The precision of ultraviolet absorption measurements in the Schmidt-Thannhauser procedure for nucleic acid estimation. Biochem. Biophys. Acta. 55:571–583.

    Google Scholar 

  25. Burton, K. 1956. A study of the conditions and for colorimetric estimation of deoxyribonucleic acid. Biochem. J. 62:315–323.

    Google Scholar 

  26. Zamenhof, S., Bursztyn, H., andZamenhof, P. 1964. The determination of deoxyribonucleic acid and of cell number in brain. J. Neurochem. 11:505–509.

    Google Scholar 

  27. Das, G. D. 1977. Experimental analysis of embryogenesis of cerebellum in rat. I. Subnormal growth following X-ray irradiation on day 15 of gestation. J. Comp. Neurol. 176:419–434.

    Google Scholar 

  28. Ashwal, S., Finegold, M., Fish, I., Budzilovich, G., andBrunell, P. A. 1974. Effect of antiviral drug, Cytosine arabinoside, on the developing nervous system. Pediatr. Res. 8:949–950.

    Google Scholar 

  29. Grondin, G., Sharkey, T., Jones, M., Sculthorpe, A., andTaylor, W. 1975. Postnatal cerebellar hypoplasea and dysfunction following methylazoxymethanol acetate treatment. Pro. Soc. Exp. Biol. Med. 148:156–159.

    Google Scholar 

  30. Lai, H., Quock R. M., Makous, W., Horita, A., andJen, L. S. 1978. Methylaz-oxymethanol acetate: Effect of postnatal injection on brain amines and behavior. Pharmacol. Biochem. Behav. 8:251–257.

    Google Scholar 

  31. Jakobson, M. 1978. Histogenesis and morphogenesis of the central nervous system. Pages 57–114,in Jakobson, M. (ed.) Developmental Neurobiology 2nd ed, Plenum Press. New York and London.

    Google Scholar 

  32. Fujita, S., Shimada, M., andNakamura, T. 1966.3H-Thymidine autoradiographic studies on the cell proliferation and differentiation in the external and internal granular layers of the mouse cerebellum. J. Comp. Neurol. 128:191–208.

    Google Scholar 

  33. Lauder, J. M., andBloom, F. E. 1974. Ontogeny of monoamine neurons in the locus coerleus, raphe nuclei and substantia nigra of the rat. I. Cell differentiation. J. Comp. Neurol. 155:469–482.

    Google Scholar 

  34. Das, G. D. 1977. Gliogenesis during embryonic development in the rat. Experientia. 33:1648–1649.

    Google Scholar 

  35. Yamano, T., Shimada, M., Nakao, K., Nakamura, T., Wakaizumi, S., andKusunoki, T. 1978. Maturation of purkinje cells in mouse cerebellum after neonatal administration of cytosine arabinoside. Acta. Neuropath. (Berl.) 44:41–45.

    Google Scholar 

  36. Mikoshiba, K. 1979. Animal models for ataxia: Mutants with cerebellar malformation. (weaver, staggerer, reeler, nervous, and pcd). Advances in Neurological Sciences. 23:918–936.

    Google Scholar 

  37. Nagaike, K. 1981. Neurochemical studies on myelin formation in cultured cerebellar tissues from rodent. Keio-Igaku. 58:85–106.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Developmental Physiology Institute for Comprehensive Medical Sciences, Fujita-Gakuen University School of Medicine, Aichi, Japan

    T. Matsutani, M. Tamaru, Y. Hayakawa, M. Nagayoshi & T. Nakahara

  2. Department of Physiology, KEIO University School of Medicine, Tokyo, Japan

    Y. Tsukada

Authors
  1. T. Matsutani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Tamaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y. Hayakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Nagayoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. Nakahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. Tsukada
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matsutani, T., Tamaru, M., Hayakawa, Y. et al. A neurochemical study of developmental impairment of the brain caused by the administration of cytosine arabinoside during the fetal or neonatal period of rats. Neurochem Res 8, 1295–1306 (1983). https://doi.org/10.1007/BF00963999

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00963999

Keywords

Search

Navigation