Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for triglyceride in very low density lipoprotein (VLDL). This process decreases the level of anti-atherogenic HDL cholesterol and increases pro-atherogenic VLDL and low density lipoprotein (LDL) cholesterol, so CETP is potentially atherogenic. On the other hand, CETP could also be anti-atherogenic, because it participates in reverse cholesterol transport (transfer of cholesterol from peripheral cells through the plasma to the liver). Because the role of CETP in atherosclerosis remains unclear, we have attempted to develop a potent and specific CETP inhibitor. Here we describe CETP inhibitors that form a disulphide bond with CETP, and present one such inhibitor (JTT-705) that increases HDL cholesterol, decreases non-HDL cholesterol and inhibits the progression of atherosclerosis in rabbits. Our findings indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential anti-atherogenic drug.

1 This study has investigated the e ects of JTT-501, a peroxisome proliferator-activated receptor (PPAR)-a and PPAR-g agonist, on the pathogenesis of diabetic complications in the Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. Comparison is made with troglitazone, a PPAR-g agonist. 2 The ZDF rats exhibited hyperglycaemia and hyperlipidaemia, and developed diabetic complications such as cataract, nephropathy, and neuropathy. Treatment with JTT-501 from the prediabetic stage controlled glycaemia and lipidaemia, and prevented the development of diabetic complications. Troglitazone was less e ective in controlling serum cholesterol and neuropathy. 3 ZDF rats developed diabetic osteopenia with reduced bone turnover, and this was prevented by JTT-501 and troglitazone, possibly mediated by increased bone turnover and bone formation. 4 Since JTT-501 controlled glycaemia and lipidaemia in ZDF rats and prevented several diabetic complications, it is suggested that treatment with JTT-501, which activates both PPAR-a and PPAR-g, could provide a valuable therapeutic approach against diabetic complications in type 2 diabetes.

The authors investigated the impairment of spatial cognitive performance in rats with chronic focal cerebral ischemia using the Morris maze, and examined the correlation between this deficit and other behavioral changes, such as step-through latency in passive avoidance task and neurologic score, or pathologic changes. The authors focused on the relationship between the damaged brain region and the affected spatial learning behavior. In the Morris maze task at 8 weeks after the middle cerebral artery (MCA) occlusion, escape latency, swimming path length, and percent time spent in goal quadrant of MCA-occluded rats were impaired, which correlated with shrinkage of the cortex involving parietal cortex, but not caudate-putamen (CP). Middle cerebral artery-occluded rats were also impaired in the percent time spent in the outermost annulus and in turning ratio, which significantly correlated with shrinkage of CP, but not cortex. Middle cerebral artery-occluded rats showed two typical search patterns; one was almost the same as that of sham-operated and intact rats, and the other was round shaped and had less turning behavior. Both subgroups of MCA-occluded rats divided by turning ratio had significantly impaired spatial cognitive performance, which indicates that the changes of search pattern did not affect cognitive performance in the Morris maze. The neurologic deficits recovered gradually after MCA occlusion, which correlated with shrinkage of cortex and CP. The step-through latency in passive avoidance task of the MCA-occluded rats was impaired, but did not correlate with shrinkage of cortex or CP. These results suggest that the long-term spatial cognitive deficit of MCA-occluded rats is in part associated with damage to the cortex involving parietal cortex, and that the change of search strategies is associated with damage to CP. These findings support the idea that different brain regions contribute differently to cognitive performance, search strategies, avoidance task, and neurologic performance, and may be useful for estimating the related region of functional disorder in the clinical situation.

We investigated the impairment of retention of spatial memory in rats with chronic focal cerebral ischemia, and examined the correlation between this impairment and pathological outcomes. A preoperative acquisition trial of the Morris water-maze task was performed twice a day for 14 successive days, and then the middle cerebral artery (MCA) was occluded. A retention trial was performed 8 weeks after MCA occlusion. Escape latency and swimming path length to the platform were significantly increased in MCA-occluded rats compared with those of sham-operated rats, and these deficits significantly correlated with massive shrinkage of the brain. Retention latency of a passive avoidance task, which was trained preoperatively, was also significantly shortened in MCA-occluded rats compared with that in sham-operated rats. These results suggest that chronic focal cerebral ischemia causes prolonged spatial memory disturbance in rats and is associated with pathological changes, and that this rat model may be useful for assessing not only anterograde but also retrograde amnesia caused by focal cerebral ischemia.

Summary:It is well known that hemiplegia is frequently ob served in cerebral ischemia. It is important for the pathophysi ologic study and development of drug therapies to establish a precise method investigating impairment of motor function with animal models. To develop a quantitative and objective method for evaluating impairment of motor function, we ex amined an inclined plane test after chronic focal cerebral isch emia in the rat. Standard scoring of neurologic deficits has limitations, including problems with quantification and objec tivity. The purpose of this study was to establish a novel method for evaluating impairment of motor function in middle cerebral artery (MeA) occluded rats. The left MeA was per manently occluded at a proximal site, and sensorimotor per formance was evaluated at the fifth day and every week for 11 weeks thereafter. The ability to maintain body position on an inclined plane was measured when rats were placed on a stain less steel slope in left-headed, right-headed, and up-headed positions. Neurologic examination based on hemiparesis and abnormal posture was also performed. After all behavioral ex aminations were completed, the degree of shrinkage of the left hemisphere to the contralateral was measured. The ability of MeA-occluded rats to maintain position on an inclined plane in It is important for the pathophysiologic study and de velopment of drug therapies of stroke to establish con venient methods, and to evaluate impairment of neuro logic and motor functions in rodent models because muscle weakness is a common complaint after stroke in humans. The rat middle cerebral artery occlusion (MCAO) model developed by Tamura et aI. (Tamura et ai., 1981a; Yamamoto et ai., 1988; Hirakawa et aI., 1994) appears to be a suitable stroke model that induces a relatively constant infarct size. Several investigators