, Volume 52, Issue 9, pp 892–899 | Cite as

Synergism between long-acting bromocryptine microcapsules and cyclosporine A in the prevention of various autoimmune diseases in rats

  • M. Neidhart
Research Articles


Pre-treatment of male Sprague-Dawley rats with long-acting bromocryptine microcapsules (CBLA) significantly inhibited the arthritic response to Freund's complete adjuvant and reduced weight loss, thymolysis, splenomegaly and leukocytosis. In the prevention of adjuvant arthritis (AA), the combination of CBLA plus sub-optimal doses of cyclosporine A (CsA) was more efficient than either of the drugs alone. Sub-optimal doses of CsA were 0.1 and 1.0 mg/kg/day s.c. for 5 days. Furthermore, CBLA alone did not decrease the incidence of experimental allergic uveitis (EAU) in the male Lewis rats. Low-dose CsA reduced the incidence of uveitis by 50%, and with the addition of CBLA, 100% of rats were protected. Low-dose CsA was 2 mg/kg/day i.m. for 14 days. Long-term treatment of male Sprague-Dawley rats with CBLA alone reduced the incidence and severity of spontaneous autoimmune periateritis nodosa (PN) in a dose-dependent manner; CsA was less potent than CBLA, and only additive effects were obtained. Finally, for the prevention of spontaneous autoimmune insulin-dependent diabetes (DM), the administration of CBLA did not improve the effect of a low-dose CsA in male BB rats. Nevertheless, a delay in onset of DM could be achieved. A sequential therapy using CsA plus CBLA clearly showed beneficial effects. The dose of CsA was 10 mg/kg p.o. 6 days/week for 21 weeks. Compared with Sprague-Dawley or Lewis male rats, BB male rats showed only weak prolactin suppression after the same doses of CBLA. It is suggested that the use of CBLA may be particularly beneficial in autoimmune disorders. The effectiveness of the combination therapy CBLA plus CsA, however, was dependent on the model considered. Various factors could play a role: (1) the different ways of administering CsA (s.c. in AA, i.m. in EAU and PN, oral in DM); (2) strain-dependency in the capacity of CBLA to suppress Prl secretion; and(3) at least in the BB rats, the transient increase of CsA bioavailibility which was possibly induced by CBLA.

Key words

Adjuvant arthritis experimental allergic uveitis periarteritis nodosa diabetes mellitus prolactin bromocryptine cyclosporine A 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Pearson C. M. (1979) Arthritis in animals. In: Arthritis and Allied Conditions: A Textbook of Rheumatology, pp. 308–319, McCarty D. J. (eds.), Lea & Febiger, PhiladelphiaGoogle Scholar
  2. 2.
    Neidhart M. and Larson D. F. (1990) Freund's complete adjuvant induced ornithine decarboxylase activity in the central nervous system of male rats and triggered the release of pituitary hormones. J. Neuroimmun.26: 97–105Google Scholar
  3. 3.
    Neidhart M. and Flückiger E. W. (1992) Hyperprolactinemia in hypophysectomized or intact male rats and the development of adjuvant arthritis. Immunology77: 449–455PubMedGoogle Scholar
  4. 4.
    Berczi I., Nagy E., Asa S. L. and Kovacs K. (1984) The influence of pituitary hormones on adjuvant arthritis. Arthritis Rheum.27: 682–688PubMedGoogle Scholar
  5. 5.
    Neidhart M. (1989) Bromocriptine microcapsules inhibit ornithine decarboxylase activity induced by Freund's complete adjuvant in lymphoid tissues of male rats. Endocrinology125: 2846–2852PubMedGoogle Scholar
  6. 6.
    Russell D. H. (1985) Ornithine decarboxylase: a key regulatory enzyme in normal and neoplastic growth. Drug Metab. Rev.16: 1–88PubMedGoogle Scholar
  7. 7.
    Nussenblatt R. B., Rodrigues M. M., Wacker W. B., Cevario S. J., Salinas-Carmona M. C. and Gery I. (1981) Cyclosporin A: inhibition of experimental autoimmune uveitis in Lewis rats. J. Clin. Invest.67: 1228–1231PubMedGoogle Scholar
  8. 8.
    Nussenblatt R. B., Caspi R. R., Dinning W. J., Palestine A. G., Hiestand P. and Borel J. (1986) A comparison of the effectiveness of cyclosporine A, D and G in the treatment of experimental autoimmune uveitis in rats. J. Immunopharmacol.8: 427–435PubMedGoogle Scholar
  9. 9.
    Palestine A. G., Muellenberg-Coulombre C. G., Kim M. K., Gelato M. C. and Nussenblatt R. B. (1987) Bromocriptine and low dose cyclosporine in the treatment of experimental autoimmune uveitis in the rat. J. Clin. Invest.79: 1078–1081PubMedGoogle Scholar
  10. 10.
    Hedner L. P. and Bynke G. (1985) Endogenous iridocyclitis relieved during treatment with bromocryptine. Am. J. Ophthalmol.100: 618–619PubMedGoogle Scholar
  11. 11.
    Weber G., Neidhardt M., Frey H., Galle K. and Geiger A. (1981) Treatment of psoriasis with bromocriptin. Arch. Dermatol. Res.271: 437–439PubMedGoogle Scholar
  12. 12.
    Wigley R. D. (1970) The aetiology of Polyartheritis nodosa: a review. N. Z. Med. J.71: 151–158PubMedGoogle Scholar
  13. 13.
    Cutts J. H. (1966) Vascular lesions resembling polyarteritis nodosa in rats undergoing prolonged stimulation with oestrogen. Br. J. Exp. Path.47: 401–404Google Scholar
  14. 14.
    Griffith, R. W. (1977) Bromocriptine and uterine neoplasia. Br. J. Med.2: 1605Google Scholar
  15. 15.
    Mahon J. L., Gunn H. C., Stobie K., Gibson C., Dupre J. and Stiller C. R. (1988) The effect of bromocryptine and cyclosporine on spontaneous diabetes in BB rats. Transplant. Proc.3/Suppl.4: 197–200Google Scholar
  16. 16.
    Zierhut M., Thiel H. J., Pleyer U., Waetjen R. and Weidle E. G. (1991) Bromocriptine in therapy of chronic recurrent anterior uveitis. Fortschr. Ophthalmol.88: 161–164PubMedGoogle Scholar
  17. 17.
    Blank M., Palestine A., Nussenblatt R. and Shoenfeld Y. (1990) Down-regulation of autoantibody levels of cyclosporine and bromocryptine treatment in patients with uveitis. Clin. Immunol. Immunopathol.54: 87–97PubMedGoogle Scholar
  18. 18.
    Neidhart M. (1996) Elevated serum prolactin or elevated prolactin/cortisol ratio are associated with autoimmune processes in systemic lupus erythematosus and other connective tissue diseases. J. Rheumatol.23: 476–481PubMedGoogle Scholar
  19. 19.
    Hawkins T. A., Gala R. R. and Dunbar J. C. (1994) Prolactin modulates the incidence of diabetes in male and female NOD mice. Autoimmunity18: 155–162PubMedGoogle Scholar
  20. 20.
    Klaus G. G. B. and Chisholm P. M. (1986) Does cyclosporine act in vivo as it does in vitro?. Immunol. Today7: 101–103Google Scholar
  21. 21.
    Atkison P. R., Mahon J. L., Dupre J., Stiller C. R., Jenner M. R., Paul T. L. and Momah C. I. (1990) Interaction of bromocryptine and cyclosporine in insulin dependent diabetes mellitus: results from the Canadian open study. J. Autoimmun.3: 793–799PubMedGoogle Scholar
  22. 22.
    Hiestand P. C., Mekler P., Nordmann R., Grieder A. and Permmongkol C. (1986) Prolactin as a modulator of lymphocyte responsiveness provides a possible mechanism of action for cyclosporine. Proc. Natl. Acad. Sci. USA83: 2599–2603PubMedGoogle Scholar
  23. 23.
    Russell D. H., Larson D. F., Cardon S. B. and Copeland J. G. (1984) Cyclosporine inhibits prolactin induction of ornithine decarboxylase in rat tissues. Mol. Cell. Endocrinol.35: 159–166PubMedGoogle Scholar
  24. 24.
    Gore-Langton R. E. (1985) Cyclosporine directly affects steroid production by rat granulosa cells. Endocrinology116 (Suppl.): 352Google Scholar
  25. 25.
    Cardon S. B., Larson D. F. and Russell D. H. (1984) Rapid elevation of rat serum prolactin concentration by cyclosporine, a novel immunosuppressive drug. Biochem. Biophys. Res. Commun.120: 614–618PubMedGoogle Scholar
  26. 26.
    Morikawa K., Oseko F. and Morikawa S. (1994) Immunosuppressive activity of bromocryptine on human T lymphocyte function in vitro. Clin. Exp. Immunol.95: 514–518PubMedGoogle Scholar
  27. 27.
    Ptachcinski R. J., Burckart G. J. and Venkataramanan R. (1986) Cyclosporine concentration determinations for monitoring and pharmacokinetic studies. J. Clin. Pharmacol.26: 358–366PubMedGoogle Scholar
  28. 28.
    Lemaire M., Maurer G. and Wood A. J. (1986) Cyclosporin. Pharmacokinetics and metabolism. Prog. Allergy38: 93–107PubMedGoogle Scholar
  29. 29.
    Peyronneau M. A., Delaforge M., Riviere R., Renaud, J. P. and Mansuy D. (1994) High affinity of ergopeptides for cytochromes P450 3A: improtance of their peptide moiety for P450 recognition and hydroxylation of bromocryptine. Eur. J. Biochem.223: 947–956PubMedGoogle Scholar
  30. 30.
    Collier S. J., Calne R. Y., White D. J. G., Winters S. and Thiru S. (1986) Blood levels and nephrotoxicity of cyclosporin A and G in rats. Lancet1: 216PubMedGoogle Scholar
  31. 31.
    Kahan B. D., Ried M. and Newberger J. (1983) Pharmacokinetics of cyclosporine in human renal transplantation. Transplant. Proc.15: 446–453Google Scholar

Copyright information

© Birkhäuser Verlag 1996

Authors and Affiliations

  • M. Neidhart
    • 1
  1. 1.Department of RheumatologyUniversity Hospital ZurichZurich(Switzerland)

Personalised recommendations