ABSTRACT
BACKGROUND: Cerebrospinal fluid (CSF) levels of soluble amyloid precursor protein (sAPP) and its alpha-secreted form (alpha-sAPP) were investigated as a means to distinguish between individuals with mild cognitive impairment (MCI) and Alzheimer-type dementia (DAT) and those with major depressive episode (MDE) showing secondary memory deficits. METHODS: Twenty-seven patients with MCI, 32 with probable DAT, and 24 with MDE attending a memory clinic were studied. Cerebrospinal fluid levels of sAPP/amyloid precursor-like protein 2 (APLP2) and alpha-sAPP were detected by Western blotting. RESULTS: Patients with MDE had the highest CSF levels of total sAPP/APLP2 as compared with MCI and DAT patients (p < .001); sAPP/APLP2 levels were higher in MCI than in DAT subjects. Whereas alpha-sAPP levels did not differ between the MCI and DAT groups, median levels of this peptide were significantly lower in MCI and DAT versus MDE patients. CONCLUSIONS: Soluble amyloid precursor protein/APLP2 and alpha-sAPP concentrations in CSF can differentiate between DAT and MCI versus MDE, facilitating early ameliorative interventions and appropriate treatment regimens.
Subject(s)
Alzheimer Disease/complications , Alzheimer Disease/diagnosis , Cognition Disorders/etiology , Depressive Disorder, Major/diagnosis , Adult , Aged , Alzheimer Disease/cerebrospinal fluid , Amyloid Precursor Protein Secretases , Amyloid beta-Protein Precursor/cerebrospinal fluid , Amyloid beta-Protein Precursor/classification , Aspartic Acid Endopeptidases , Blotting, Western/methods , Chi-Square Distribution , Cognition Disorders/cerebrospinal fluid , Depressive Disorder, Major/cerebrospinal fluid , Diagnosis, Differential , Endopeptidases/cerebrospinal fluid , Female , Humans , Male , Middle Aged , Nerve Tissue Proteins/cerebrospinal fluidABSTRACT
RATIONALE: The neuropeptide corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. The view that CRH hypersecretion underlies anxiety and mood disorders was recently supported by preclinical and clinical data obtained after application of the CRH receptor (CRH-R1) antagonist NBI30775 (R121919). Despite its therapeutic efficacy, there is only little information about its mechanisms of action on cellular and molecular targets. OBJECTIVE: To identify some of the intracellular substrates mediating the actions of NBI30775 after its acute administration in a stress-independent animal model. RESULTS: Of the different doses of NBI30775 tested (0.5, 1, 5 and 30 mg/kg), the 1-mg/kg dose proved behaviorally active insofar that it reduced anxiety-like behavior in mice under basal conditions. Subsequent analysis of brain tissues revealed NBI30775-induced increases in the nuclear translocation of glucocorticoid receptors (GR) and BAG-1, an upregulation of mRNA transcripts encoding GR, mineralocorticoid receptors (MR) and CRH-R1, and a suppression of the DNA-binding activity of the transcription factor AP-1. These changes were significant at a dose of 1 mg/kg of NBI30775. CONCLUSION: NBI30775 reduces levels of anxiety in mice (under basal conditions) with a steep dose-response curve. Molecules such as GR, MR, BAG-1 and AP-1 have been identified as some of the drug's intracellular targets; interestingly, changes in these molecules have also been seen in response to conventional antidepressants, showing that structurally and mechanistically unrelated anxiolytic and antidepressant drugs can influence common downstream pathways.
Subject(s)
Anti-Anxiety Agents/pharmacology , Pyrimidines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anti-Anxiety Agents/administration & dosage , Anxiety/drug therapy , Anxiety/metabolism , Brain/drug effects , Brain/metabolism , Corticosterone/blood , Dose-Response Relationship, Drug , Gene Expression , Male , Mice , Mice, Inbred DBA , NF-kappa B/biosynthesis , NF-kappa B/genetics , Pyrimidines/administration & dosage , RNA, Messenger/biosynthesis , Receptors, Corticotropin-Releasing Hormone/biosynthesis , Receptors, Corticotropin-Releasing Hormone/genetics , Receptors, Glucocorticoid/biosynthesis , Receptors, Glucocorticoid/genetics , Receptors, Mineralocorticoid/biosynthesis , Receptors, Mineralocorticoid/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factor AP-1/biosynthesis , Transcription Factor AP-1/genetics , Transcriptional Activation , Up-RegulationABSTRACT
The undesired side-effects of haloperidol treatment include a number of extrapyramidal side-effects which have been proposed to result from drug-induced damage to the basal ganglia. The drug also causes irregular movements and locomotor patterns in experimental animals. Here we show that haloperidol treatment in rats is associated with increases in the expression of p53 and the ratio of pro-apoptotic (Bax) to anti-apoptotic (Bcl-2/Bcl-x(L)) proteins in the hippocampus and caudate putamen (CPu). In addition, haloperidol induces the DNA binding activity of the redox-sensitive nuclear factor-kappa B (NF-kappaB) and concomitantly upregulates the levels of the phosphorylated form of IkappaBalpha protein in vivo. Similar responses are observed when a mouse hippocampal cell line (HT-22) is treated with haloperidol and/or vitamin E. Interestingly, all of these biochemical effects of haloperidol are significantly attenuated when animals or cultured cells are pretreated with alpha-tocopherol (vitamin E). Consistent with this, vitamin E is demonstrated to substantially reduce the haloperidol-induced impairment of locomotor activity in rats. Collectively, the data indicate the usefulness of vitamin E as an adjunct to haloperidol treatment and provide initial clues about the underlying molecular mechanisms involved in these effects.
