ABSTRACT
gamma-Secretase inhibitors are one promising approach to the development of a therapeutic for Alzheimer's disease (AD). gamma-Secretase inhibitors reduce brain beta-amyloid peptide (Abeta), which is believed to be a major contributor in the etiology of AD. Transgenic mice overexpressing the human beta-amyloid precursor protein (APP) are valuable models to examine the dynamics of Abeta changes with gamma-secretase inhibitors in plaque-free and plaque-bearing animals. BMS-299897 2-[(1R)-1-[[(4-chlorophenyl)sulfony](2,5-difluorophenyl)amino]ethyl]-5-fluorobenzenepropanoic acid, a gamma-secretase inhibitor, showed dose- and time dependent reductions of Abeta in brain, cerebrospinal fluid (CSF), and plasma in young transgenic mice, with a significant correlation between brain and CSF Abeta levels. Because CSF and brain interstitial fluid are distinct compartments in composition and location, this correlation could not be assumed. In contrast, aged transgenic mice with large accumulations of Abeta in plaques showed reductions in CSF Abeta in the absence of measurable changes in plaque Abeta in the brain after up to 2 weeks of treatment. Hence, CSF Abeta levels were a valuable measure of gamma-secretase activity in the central nervous system in either the presence or absence of plaques. Transgenic mice were also used to examine potential side effects due to Notch inhibition. BMS-299897 was 15-fold more effective at preventing the cleavage of APP than of Notch in vitro. No changes in the maturation of CD8(+) thymocytes or of intestinal goblet cells were observed in mice treated with BMS-299897, showing that it is possible for gamma-secretase inhibitors to reduce brain Abeta without causing Notch-mediated toxicity.
Subject(s)
Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Brain Chemistry/drug effects , Brain Chemistry/genetics , Endopeptidases/physiology , Protease Inhibitors/pharmacology , Aging/metabolism , Amyloid Precursor Protein Secretases , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Aspartic Acid Endopeptidases , Blotting, Western , Cell Separation , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Immunoprecipitation , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Plaque, Amyloid/pathology , Receptors, Notch , T-Lymphocytes/metabolismABSTRACT
Administration of neuropeptide Y (NPY) into hypothalamic areas or into the cerebral ventricles induces marked increases in food consumption in satiated rats. Since monoamines have been suggested to be involved in NPY-induced feeding, we investigated the effects of NPY and [D-Trp32]NPY, a putative NPY antagonist, on extracellular levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), 3,4-dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole-3-acetic acid (5-HIAA) in the hypothalamus, including the paraventricular hypothalamic nuclei (PVN), during feeding behavior. Intracerebroventricular (i.c.v.) injections of NPY (20 microg) significantly increased extracellular NE (1.5-fold), DA (2.5-fold), DOPAC (2-fold) and HVA (3-fold), and did not change 5-HT or 5-HIAA levels. This dose of NPY significantly increased food intake over a 2 h period. The putative NPY antagonist [D-Trp32]NPY (40 microg, i.c.v.) produced similar neurochemical changes to NPY: it increased dialysate levels of NE (1.7-fold), DA (2.5-fold), DOPAC (1.6-fold) and HVA (2.2-fold) and did not change 5-HT or 5-HIAA levels. [D-Trp32]NPY also produced a significant increase in food intake. I.c.v. administration of [D-Trp32]NPY 5 min before NPY did not significantly change the increase in NE, DA, HVA and DOPAC induced by NPY. In these animals, food consumption was also significantly increased. These data indicate that NPY-induced feeding is associated with activation of the hypothalamic monoaminergic system and that [D-Trp32]NPY, at the dose given, acts as an agonist and not as an antagonist at NPY receptors in vivo.
Subject(s)
Biogenic Monoamines/metabolism , Feeding Behavior/drug effects , Hypothalamus/drug effects , Neuropeptide Y/analogs & derivatives , Neuropeptide Y/pharmacology , 3,4-Dihydroxyphenylacetic Acid/metabolism , Analysis of Variance , Animals , Dopamine/metabolism , Homovanillic Acid/metabolism , Hydroxyindoleacetic Acid/metabolism , Hypothalamus/metabolism , Male , Microdialysis , Norepinephrine/metabolism , Rats , Rats, Wistar , Serotonin/metabolismABSTRACT
Interactions between melatonin and serotonin type 2A (5-HT2A) receptors in the regulation of the sleep-wakefulness cycle in the rat have been reported. We studied the acute effects of melatonin and related agonists on 5-HT2A neurotransmission as reflected in behavioral (head shake) and biochemical [phosphoinositide (PI) hydrolysis] responses to 5-HT2A receptor stimulation. Like 5-HT1A agonists and antidepressants, acute administration of melatonin and related agonists inhibited the 5-HT2A-mediated (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-induced head shake in a dose-dependent manner. Consistent with these behavioral findings, in vitro incubation of cortical slices with melatonin agonists robustly inhibited 5-HT2A receptor-mediated PI hydrolysis in a noncompetitive manner. 2-Iodomelatonin-induced reductions in 5-HT2A-stimulated PI hydrolysis were blocked by preincubation with the melatonin antagonist N-acetyltryptamine. Further, pretreatment of rats in vivo with melatonin and related agonists reduced the cortical PI hydrolysis response to the 5-HT2A agonist alpha methyl-5-HT but did not alter cortical 5-HT2A receptor density. The present data support an interaction between melatonin and 5-HT2A receptors in the central nervous system.
