Hyperactivity in a mouse model of the antiphospholipid syndrome

Abstract

In the antiphospholipid syndrome (APS), antibodies to a complex of phospholipids and beta2-glycoprotein I (β₂-GPI) are associated with recurrent thromboembolic events, spontaneous abortions, thrombocytopenia and central nervous system (CNS) disturbances. Animals immunized with b2-GPI develop the systemic manifestations of APS but the involvement of the (CNS) in these animals has not been studied. The objective of the present study was to examine mice with induced experimental APS for behavioral changes. Female Balb/C mice were immunized once with β₂-GPI in complete Freund's adjuvant (CFA) or with CFA alone. Four months after immunization the mice were tested in the staircase apparatus and the following two variables were measured: (1) number of rears; and (2) number of stairs climbed by the mice. Immunization with β₂-GPI resulted in elevated levels of circulating anti-negatively charged phospholipids and anti-β₂-GPI antibodies. The APS mice exhibited hyperactive behavior as reflected by more frequent rears (P < 0.023) and higher number of stairs climbed (P < 0.019) by the mice in 3 min. This simple test demonstrated that experimental APS animals are significantly hyperactive and may serve as a marker for CNS involvement in this model.

Keywords

antiphospholipid syndrome β2-glycoprotein-I (apolipoprotein H)animal model staircase test behavior

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References

Hughes GRV . The antiphospholipid syndrome: ten years on . Lancet 1993; 342: 341–344 .

Petri M . Pathogenesis and treatment of the antiphospholipid antibody syndrome . Med Clin N Am 1997; 81: 151–177 .

Asherson RA , Khamashta MA , Ordi-Ros J et al. The ‘primary’ antiphospholipid syndrome: major clinical and serological features . Medicine 1989; 68: 366–374 .

Asherson RA , Cervera R , Piette J-C , Shoenfeld Y . The Antiphospholipid Syndrome. CRC Press: Boca Raton, FL , 1996, p 368.-368

Levine SR , Welch KMA . The spectrum of neurologic disease associated with antiphospholipid antibodies . Lupus anticoagulants and anticardiolipin antibodies. Arch Neurol 1987; 44: 876–883 .

Asherson RA , Khamashta MA , Gill A et al. Cerebrovascular disease and antiphospholipid antibodies in systemic lupus erythematosus, lupus-like disease, and the primary antiphospholipid syndrome . Am J Med 1989; 86: 391–399 .

Inzelberg R , Bornstein NM , Reider I , Korczyn AD . The lupus anticoagulant and dementia in non-SLE patients . Dementia 1992; 3: 140–145 .

Mosek A , Yust I , Treves TA et al. Dementia and antiphospholipid antibodies . Dement Geriatr Cogn Disord 2000; 11: 36–38 .

Galli M , Comfurius P , Maassen C et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor . Lancet 1990; 335: 1544–1547 .

10.

McNeil HP , Simpson RJ , Chesterman CN , Krilis SA . Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-Glycoprotein I (apolipoprotein H) . Proc Natl Acad Sci USA 1990; 87: 4120–4124 .

11.

Valesini G , Shoenfeld Y . A new player in the antiphospholipid syndrome: the beta 2 glycoprotein I cofactor . Autoimmunity 1992; 14: 105–110 .

12.

Cabiedes J , Cabral AR , Alarcon-Segovia D . Clinical manifestations of the antiphospholipid syndrome in patients with systemic lupus erythematosus associate more strongly with anti-b2-glycoprotein-I than with antiphospholipid antibodies . J Rheumatol 1995; 22: 1899–1906 .

13.

Gharavi AE , Sammaritano LR , Wen J , Elkon KB . Induction of antiphospholipid autoantibodies by immunization with b2 glycoprotein I (apolipoprotein H) . J Clin Invest 1992; 90: 1105–1109 .

14.

Pierangeli SS , Harris EN . Induction of phospholipid-binding antibodies in mice and rabbits by immunization with human beta 2 glycoprotein I or anticardiolipin antibodies alone . Clin Exp Immunol 1993; 93: 269–272 .

15.

Blank M , Faden D , Tincani A et al. Immunization with anticardiolipin cofactor (beta-2-glycoprotein I) induces experimental antiphospholipid syndrome in naive mice . J Autoimmun 1994; 7: 441–455 .

16.

Aron AL , Cuellar ML , Brey RL et al. Early onset of autoimmunity in MRL/+ + mice following immunization with beta 2 glycoprotein I . Clin Exp Immunol 1995; 101: 78–81 .

17.

Garcia CO , Kanbour-Shakir A , Tang H et al. Induction of experimental antiphospholipid antibody syndrome in PL/J mice following immunization with beta 2 GPI . Am J Reprod Immunol 1997; 37: 118–124 .

18.

Pick CG , Peter Y , Terkel J , Gavish M , Weizman R . Effect of the neuroactive steroid alpha-THDOC on staircase test behavior in mice . Psychopharmacology 1996; 128: 61–66 .

19.

Blank M , Palestine A , Nussenblatt R , Shoenfeld Y . Down-regulation of autoantibody levels of cyclosporine and bromocriptine treatment in patients with uveitis . Clin Immunol Immunopathol 1990; 54: 87–97 .

20.

George J , Blank M , Levy Y et al. Differential effects of anti-beta2-glycoprotein I antibodies on endothelial cells and on the manifestations of experimental antiphospholipid syndrome . Circulation 1998; 97: 900–906 .

21.

Ziporen L , Shoenfeld Y , Levy Y , Korczyn AD . Neurological dysfunction and hyperactive behavior associated with antiphospholipid antibodies . A mouse model. J Clin Invest 1997; 100: 613–619 .

22.

Sakic B , Szechtman H , Keffer M et al. A behavioral profile of autoimmune lupus-prone MRL mice . Brain Behav Immunol 1992; 6: 265–285 .

23.

Brey RL , Cote S , Barohn R et al. Model for the neuromuscular complications of systemic lupus erythematosus . Lupus 1995; 4: 209–212 .

24.

Brey RL , Sakic B , Szechtman H , Denburg JA . Animal models for nervous system disease in systemic lupus erythematosus . Ann NY Acad Sci 1997; 823: 97–106 .

25.

Smith HR , Hansen CL , Rose R , Canoso RT . Autoimmune MRL-lpr/lpr mice are an animal model for the secondary antiphospholipid syndrome . J Rheumatol 1990; 17: 911–915 .

26.

Cohen PL , Eisenberg RA . Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease . A Rev Immunol 1991; 9: 243–269 .