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Extremely high dose pravastatin may suppress amyloidogenesis in a mouse model
  1. S Shtrasburg,
  2. M Pras,
  3. M Lidar,
  4. A Livneh
  1. Heller Institute of Medical Research, Sheba Medical Centre, Tel-Hashomer, Israel
  1. Correspondence to:
    Dr S Shtrasburg, Heller Institute of Medical Research, Sheba Medical Centre, Tel Hashomer 52621, Israel;

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Pravastatin is a cholesterol lowering agent,1 recently reported to have anti-inflammatory properties.2 It was suggested that the prevention and regression of atherosclerosis by pravastatin is partially related to its anti-inflammatory effect,2 probably mediated by inhibition of proinflammatory cytokines.3 Pravastatin's anti-inflammatory effect is associated with, and probably reflected by, reduced levels of the acute phase reactants, C reactive protein and serum amyloid A (SAA).2 The N-terminal fragment of the SAA is amyloid A (AA), which is deposited in a fibrillar form in the tissues of up to 30% of patients with a variety of chronic infectious and chronic inflammatory disorders, leading to reactive amyloidosis.4

Because prevention and treatment of AA amyloidosis are currently unsatisfactory and reactive amyloidosis is a potentially lethal complication, it is important to find out whether pravastatin affects amyloidogenesis.

The effect of pravastatin on amyloidogenesis was studied in several groups of male Swiss mice 7–17 weeks old, which were subjected to amyloid induction, using intravenous amyloid enhancing factor (1 μg in 0.5 ml phosphate buffered saline on day 0) and subcutaneous AgNO3 (0.5 ml 2% daily, on days 0, 1, and 2), according to our published protocol.5 Two groups of study mice (groups I and II) received intraperitoneal pravastatin 0.4 mg/day in 0.5 ml saline, and two other groups (III and IV) received intraperitoneal pravastatin 10 mg/day. The human oral dose analogous to these regimens is 0.5 mg/kg and 12.5 mg/kg respectively (assuming a 20-fold increase in drug catabolism in mice as compared with man). The experiments lasted for 72 hours (groups I and III) or 96 hours (groups II and IV). The 72 hour interval, during which the amount of amyloid deposits is still low, allows the detection of a mild inhibition. All experiments were controlled by mice of the same strain, sex, and age, which received the same amyloid induction regimen, but 0.5 ml saline intraperitoneally instead of pravastatin. The amount of amyloid deposition in the spleen was studied by the crush and smear technique and a five grade score, estimated by polarised microscopy.6 All experiments were repeated two to three times.

Amyloidosis in mice receiving pravastatin was somewhat less abundant and developed in fewer animals than in controls (table 1). This trend was noted only in animals receiving 10 mg/day and only in the short term experiments, but the statistical significance obtained was inconsistent (table 1). No amyloid inhibition by pravastatin was seen in any of the other experiments, either when a lower pravastatin dose (0.4 mg/day) was used or when mice were subjected to a longer (96 hours) amyloidogenic stimulus.

These findings suggest that pravastatin in a very high dose may have a mild amyloid protecting effect and thus increases the spectrum of drugs with a possible tangible amyloid preventive effect. Further studies are warranted to determine underlying mechanisms and to see whether other statins also have anti-amyloidogenic qualities.

Table 1

High dose pravastatin may suppress amyloidogenesis


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