P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer's disease: preliminary observations.

P-glycoprotein (P-gp), part of the blood-brain barrier, limits drug access to the brain and is the target for therapies designed to improve drug penetration. P-gp also extrudes brain amyloid-beta (Aß). Accumulation of Aß is a hallmark of Alzheimer's disease (AD). Aß accumulates in normal aging and in AD primarily due to decreased Aß clearance. This is a preliminary report on the relative protein and messenger RNA expression of P-gp in human brains, ages 20-100 years, including AD subjects. In these preliminary studies, cortical endothelial P-gp expression decreased in AD compared with controls (p < 0.001). Trends in P-gp expression in human aging are similar to aging rats. Microvessel P-gp messenger RNA remained unchanged with aging and AD. Aß plaques were found in 42.8% of normal subjects (54.5% of those older than 50 years). A qualitative analysis showed that P-gp expression is lower than the group mean in subjects older than 75 years but increased if younger. Decreased P-gp expression may be related to Aß plaques in aging and AD. Downregulating P-gp to allow pharmaceuticals into the central nervous system may increase Aß accumulation.

Amyloid-beta accumulation, neurogenesis, behavior, and the age of rats.

The goals of this research were to describe age-related changes in brain biochemistry and behavior, and the relationships between them. The chronological ages of greatest change are particularly important for targeting interventions. In this experiment, 36 Fischer 344/Brown-Norway rats (3, 12, 20, and 30 months old) were trained in lever boxes on temporal discrimination tasks. The greatest response rate decrease and response pattern change occurred between 12 and 20 months. The biochemical results showed that amyloid-beta peptides (Aß40 and Aß42) increased with age. The endothelial expression of the Aß influx transporter (RAGE) also increased, and the expression of Aß efflux transporter (LPR-1) decreased, with age. The greatest change in the biochemical measures also were between 12 and 20 months. Twenty additional rats were analyzed for stem cell proliferation, and neurogenesis decreased with age, particularly between about 12 and 20 months. These early changes in brain, biochemistry, and behavior provide opportunity for new therapies or prophylaxis.

Excrescence of neurotransmitter glutamate from disc material has nociceptive qualities: evidence from a rat model.

BACKGROUND CONTEXT: The authors have previously demonstrated that herniated human lumbar disc is rich in free glutamate from degradation of aggrecan. Prior data have suggested that free glutamate could contribute to a nociceptive state. PURPOSE: Previous behavioral experiments suggested glutamate-related nociception by comparing pre- and postglutamate infusion responses only. This indirectly suggested nociceptive effects of epidural glutamate but was not a definitive evidence. Now, by using larger numbers of subjects, we have demonstrated that lumbar epidural glutamate infusion causes significant left-to-right differences in hind paw response during treatment, demonstrating more directly the focal nociceptive effects of glutamate. STUDY DESIGN: Behavioral studies and immunohistochemistry were used to assess for evidence of a nociceptive state. All researchers were blinded to infusion solution. METHODS: Via an implanted mini osmotic pump, the epidural space of rats was infused with 0.02 mM glutamate or normal saline for 72 hours. Signs of nociception were assessed by von Frey and plantar thermal stimulation testing and by glutamate receptor expression in the corresponding dorsal horn of the spinal cord and dorsal root ganglion. RESULTS: Both von Frey mechanical and plantar thermal stimulations showed differences in hind paw reactivity depending on whether it was on the ipsilateral or contralateral side of glutamate infusion. Saline infusion had no significant behavioral effects. Dorsal horn expression of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid and N-methyl-d-aspartic acid receptors was significantly increased in glutamate-infused animals, further indicative of a nociceptive state related to glutamate infusion. CONCLUSIONS: Elevated epidural glutamate concentrations caused a focal hyperesthetic state. Increased epidural glutamate concentration could be a driving force or "chemical" component of disc-related radiculopathy.

Study of diet-induced changes in lipoprotein metabolism in two strains of Golden-Syrian hamsters.

The objective of this study was to characterize two strains of Golden-Syrian hamsters for use in the study of diet-induced changes in lipoprotein metabolism. In Experiment 1, the time course and response to dietary saturated fat was investigated for serum lipoprotein profiles and aortic lesion formation in Golden-Syrian hamsters from Charles River Laboratories, Wilmington, MA (CR) and Bio Breeders, Watertown, MA (F(1)B). Hamsters were fed a nonpurified diet containing 10 g/100 g saturated fat and 0.1 g/100 g dietary cholesterol. After 12 wk, CR hamsters had significantly lower serum total and non-HDL cholesterol (TC and nHDL-C) levels, but higher aortic cholesteryl ester (CE) than the F(1)B hamsters (P < 0.05). In Experiment 2, CR hamsters were fed a nonpurified diet containing 10 g/100 g saturated fat and 0.1, 0.5 or 1 g/100 g dietary cholesterol. After 10 wk of dietary intervention, TC and nHDL-C levels were significantly higher in the 0.5 and 1.0 g/100 g cholesterol groups than in the 0.1 g/100 g cholesterol group. These levels declined after 20 wk of dietary intervention in all groups, potentially reflecting the toxic effect of high cholesterol intakes. CR hamsters fed a 10 g/100 g saturated fat containing 0.1 g/100 g dietary cholesterol for 10 wk appear to be a good model for investigating diet-induced change in plasma lipids.