Inhibition of the second phase of amyloidogenesis in a mouse model by a single-dose colchicine regimen.
Amyloidogenesis consists of two stages. In the first, amyloid enhancing factor (AEF) is generated, and in the second, deposition of amyloid fibrils occurs. Colchicine is a known inhibitor of amyloidosis of familial Mediterranean fever (FMF) and of mouse experimental amyloidosis, but the timing and mechanism of its effect are still unclear. The aim of this study is to determine whether colchicine inhibits the second phase of amyloidogenesis and to study the time correlate of such an effect. To that end, amyloid was induced in Swiss male mice with AEF and AgNO(3) (an inflammatory stimulus), a method that skips the first phase of amyloidogenesis. Two amyloid induction protocols were used: a standard protocol, in which AEF and AgNO(3) were administered concurrently, and a prolonged protocol, in which the administration of AgNO(3) was delayed by 24 hours or 7 days. To study the inhibitory effect of colchicine on the second phase of amyloidogenesis, a single dose of colchicine (30 microg) was injected intravenously before, during, or after administration of AgNO(3) in both the standard and prolonged amyloid induction protocols. The amount of amyloid deposition in the spleens was determined with the crush-and-smear technique and a 5-grade scale. Colchicine was found to inhibit the second phase of amyloidogenesis. Its best effect was achieved when administered 48 hours after initiation of AgNO(3) injections. The pattern of colchicine-inhibition-in-time in the standard and the prolonged amyloid induction protocols was similar, indicating that colchicine exerts inhibition through its effect on the inflammatory stimulus (AgNO(3)). These findings suggest that (1) colchicine suppresses amyloidogenesis in the late (second) stage and that (2) this suppression is possibly related to the anti-inflammatory effect of colchicine.
Shtrasburg
S
S
Heller Institute of Medical Research and Department of Orthopedics, Sheba Medical Center, Tel Hashomer, Israel.
Pras
M
M
Gal
R
R
Salai
M
M
Livneh
A
A
D000686:Amyloidosis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003078:Colchicine / Q000494:pharmacology*; D004195:Disease Models, Animal; D006074:Gout Suppressants / Q000494:pharmacology*; D008297:Male; D051379:Mice; D012835:Silver Nitrate; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D006074:Gout Suppressants; D012835:Silver Nitrate; D003078:Colchicine