# Hyperlipidemic Rabbit Models for Anti-Atherosclerotic Drug Development
## 3 Hyperlipidemic Rabbit Models for the Development of Drugs
### Probucol  
Probucol was originally synthesized in the 1970s as an anti-oxidant and was subsequently found to have lipid-lowering effects [81]. Although the lipid-lowering effect is relatively mild compared to statins, probucol possesses strong anti-oxidative activity along with HDL-lowering and anti-atherosclerotic effects [82]. Probucol was prescribed in the 1980s before the birth of statin. Since probucol is notorious for its HDL-lowering effect, probucol is now used only in Asian countries such as Japan, Korea, and China. The anti-atherosclerotic effect of probucol has been well characterized in cholesterol-fed and WHHL rabbits. Pharmacological effects of probucol on the lipoprotein profiles and atherosclerosis are summarized in Table 3. [PERSON] et al. reported that probucol reduced LDL-C and HDL-C in WHHL rabbits [83]. [PERSON] et al. and [PERSON] et al. demonstrated an anti-atherosclerotic effect of probucol in WHHL rabbits [84; 85]. Although the reduction in plasma TC levels was quite mild, probucol-treated WHHL rabbits showed a significant reduction in aortic atherosclerosis [84; 85]. [PERSON] et al. tested the anti-atherosclerotic effect of probucol on a cholesterol-fed rabbit model and showed that probucol treatment protected against lesion progression without affecting plasma TC levels [86]. [PERSON] et al. reported that probucol treatment led to the regression of the established aortic atherosclerosis in WHHL rabbits [87]; however, others failed to reproduce the results [88]. We have shown that probucol can also inhibit the initiation of atherosclerosis by reducing monocyte adherence and infiltration into the subintima [89]. Furthermore, probucol reduces coronary atherosclerosis and stabilizes plaques in WHHL rabbits [90]. The anti-atherosclerotic effect of probucol occurs mainly through its anti-oxidative activity on LDL [91]. In fact, 69% of probucol in plasma was distributed on the LDL particles in WHHL rabbits [84]. \begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Rabbit** & **Drug** & **Plasma Lipids** & **Atherosclerosis** & **Findings** & **Reference** \\ \hline \multicolumn{6}{c}{WHHL rabbits (Normal standard diet)} \\ \hline \multirow{6}{*}{(Male and female)} & \multirow{6}{*}{ \begin{tabular}{c} 1\% probucolol \\ in diet \\ (4 weeks) \\ \end{tabular}  } & TC: 24\% \(\downarrow\) & \multirow{6}{*}{-} & \multirow{6}{*}{ \begin{tabular}{c} up-regulation of LDL \\ HDL-C: 53\% \(\downarrow\) \\ (4 weeks vs. \\ pre-treatment) \\ \end{tabular}  } & \multirow{6}{*}{Kita [84]} \\  & & & VLDL-C: 4\% \(\downarrow\) & & \\  & 1\% probucol & IDL-C: 2\% \(\downarrow\) & & \\  & & LDL-C: 36\% \(\downarrow\) & & \\  & & HDL-C: 53\% \(\downarrow\) & & \\  & & (4 weeks vs. \\  & & pre-treatment) & & \\ \hline \multirow{6}{*}{(Male and female)} & \multirow{6}{*}{ \begin{tabular}{c} 1\% probucol \\ in diet \\ (6 months) \\ \end{tabular}  } & TC: 17\% \(\downarrow\) & \multirow{6}{*}{ \begin{tabular}{c} 87\% \(\downarrow\) * \\ (6 months) \\ \end{tabular}  } & \multirow{6}{*}{ \begin{tabular}{c} protective effect of \\ LDL oxidization \\ \end{tabular}  } & \multirow{6}{*}{Kita [84]} \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\ \hline \multirow{6}{*}{(Male)} & \multirow{6}{*}{ \begin{tabular}{c} 1\% probucol \\ in diet \\ (\(\approx\)33 weeks) \\ \end{tabular}  } & TC: 35\% \(\downarrow\) * & \multirow{6}{*}{ \begin{tabular}{c} regression of \\ atherosclerosis \\ \end{tabular}  } & \multirow{6}{*}{[PERSON] [87]} \\  & & VLDL-C: 51\% \(\downarrow\) * & \multirow{6}{*}{ \begin{tabular}{c} regression of \\ atherosclerosis \\ \end{tabular}  } & \multirow{6}{*}{Li [90]} \\  & & IDL-C: 19\% \(\downarrow\) & \(\approx\)39\% \(\downarrow\) * & \\  & in diet & LDL-C: 33\% \(\downarrow\) * & \multirow{6}{*}{ \begin{tabular}{c} (Aorta, gross lesion) \\ (5 months) \\ \end{tabular}  } & \multirow{6}{*}{Oshima [87]} \\  & & HDL-C: 45\% \(\downarrow\) * & & \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\ \hline \multirow{6}{*}{(Male)} & \multirow{6}{*}{