| 1 | Neuropsychopharmacology 2013 Nov 38: 2446-55 |
|---|---|
| PMID | 23748226 |
| Title | Administration of the Y2 receptor agonist PYY3-36 in mice induces multiple behavioral changes relevant to schizophrenia. |
| Abstract | Functional changes in neuropeptide Y (NPY) signaling at the Y2 receptor subtype have been widely implicated in stress-related neuropsychiatric illnesses such as depression and anxiety disorders. Altered Y2 receptor signaling may also play a role in the precipitation of behavioral and cognitive symptoms associated with schizophrenia. To seek preclinical evidence for this possibility, we explored the functional consequences of treatment with the selective Y2 receptor agonist PYY(3-36) using translational tests for the assessment of schizophrenia-relevant behavioral and cognitive deficits in mice. We found that acute systemic administration of PYY(3-36) at a low dose (1??g/100?g body weight) or high dose (20??g/100?g body weight) profoundly impaired social interaction without affecting innate anxiety. PYY(3-36) treatment at the high dose further led to a disruption of sensorimotor gating in the form of prepulse inhibition deficiency. This effect was fully antagonized by acute treatment with the preferential dopamine D2 receptor antagonist haloperidol, but not with clozapine. In addition, both doses of PYY(3-36) impaired selective associative learning in the latent inhibition paradigm and spatial working memory in a matching-to-position water maze test. The wide range of abnormalities induced by PYY(3-36) suggests that signaling at the Y2 subtype of NPY receptors is critical for a number of behavioral and cognitive functions, some of which are highly relevant to schizophrenia and related psychotic disorders. At least some of the behavioral deficits induced by augmentation of Y2 receptor signaling may involve increased dopaminergic activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 287-94 |
| PMID | 23085507 |
| Title | Immune system and glucose metabolism interaction in schizophrenia: a chicken-egg dilemma. |
| Abstract | Impaired glucose metabolism and the development of metabolic syndrome contribute to a reduction in the average life expectancy of individuals with schizophrenia. It is unclear whether this association simply reflects an unhealthy lifestyle or whether weight gain and impaired glucose tolerance in patients with schizophrenia are directly attributable to the side effects of atypical antipsychotic medications or disease-inherent derangements. In addition, numerous previous studies have highlighted alterations in the immune system of patients with schizophrenia. Increased concentrations of interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-?) appear to be state markers, whereas IL-12, interferon-gamma (IFN-?), tumor necrosis factor-alpha (TNF-?), and soluble IL-2 receptor (sIL-2R) appear to be trait markers of schizophrenia. Moreover, the mononuclear phagocyte system (MPS) and microglial activation are involved in the early course of the disease. This review illustrates a "chicken-egg dilemma", as it is currently unclear whether impaired cerebral glucose utilization leads to secondary disturbances in peripheral glucose metabolism, an increased risk of cardiovascular complications, and accompanying pro-inflammatory changes in patients with schizophrenia or whether immune mechanisms may be involved in the initial pathogenesis of schizophrenia, which leads to disturbances in glucose metabolism such as metabolic syndrome. Alternatively, shared underlying factors may be responsible for the co-occurrence of immune system and glucose metabolism disturbances in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Twin Res Hum Genet 2014 Apr 17: 108-20 |
| PMID | 24556202 |
| Title | Copy number variation distribution in six monozygotic twin pairs discordant for schizophrenia. |
| Abstract | We have evaluated copy number variants (CNVs) in six monozygotic twin pairs discordant for schizophrenia. The data from Affymetrix® Human SNP 6.0 arrays? were analyzed using Affymetrix® Genotyping Console?, Partek® Genomics Suite?, PennCNV, and Golden Helix SVS?. This yielded both program-specific and overlapping results. Only CNVs called by Affymetrix Genotyping Console, Partek Genomics Suite, and PennCNV were used in further analysis. This analysis included an assessment of calls in each of the six twin pairs towards identification of unique CNVs in affected and unaffected co-twins. Real time polymerase chain reaction (PCR) experiments confirmed one CNV loss at 7q11.21 that was found in the affected patient but not in the unaffected twin. The results identified CNVs and genes that were previously implicated in mental abnormalities in four of the six twin pairs. It included PYY (twin pairs 1 and 5), EPHA3 (twin pair 3), KIAA1211L (twin pair 4), and GPR139 (twin pair 5). They represent likely candidate genes and CNVs for the discordance of four of the six monozygotic twin pairs for this heterogeneous neurodevelopmental disorder. An explanation for these differences is ontogenetic de novo events that differentiate in the monozygotic twins during development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Pharmacopsychiatry 2014 Jul 47: 169-73 |
| PMID | 24936806 |
| Title | Serum levels of PYY(1-36) peptide in patients with schizophrenia on clozapine monotherapy. |
| Abstract | The present study was undertaken to determine if patients with schizophrenia on clozapine monotherapy have lower serum levels of peptide YY [PYY(1-36)], which is an endogenous inhibitor of food intake, comparing to healthy controls. Data for 24 patients (mean age 38.8 years) with paranoid schizophrenia on clozapine monotherapy and 24 healthy subjects (gender- and age-matched; mean age 39.9 years) were analyzed. Fasting serum levels of PYY(1-36) were lower in the clozapine group (178.4±138.4 vs. 277.4±218.1?pg/mL, p=0.034). In the whole study sample PYY(1-36) levels were lower in subjects with body mass index?25?kg/m(2) (p=0.03) and in subjects with abdominal obesity defined using International Diabetes Foundation criteria (p=0.04). There were no significant differences for metabolic syndrome, smoking, impaired fasting glucose, dyslipidemia, and homeostatic model assessment (HOMA) defined insulin resistance. RESULTS suggest that weight is asso-ciated with levels of PYY. Patients on clozapine had higher body mass index, but not fat mass index or body weight, therefore lower levels of PYY(1-36) in patients taking clozapine may result from clozapine-induced weight gain and central -obesity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Neuropeptides 2016 Jun 57: 21-34 |
| PMID | 26988064 |
| Title | Identifying neuropeptide Y (NPY) as the main stress-related substrate of dipeptidyl peptidase 4 (DPP4) in blood circulation. |
| Abstract | Dipeptidyl peptidase 4 (DPP4; EC 3.4.14.5; CD26) is a membrane-bound or shedded serine protease that hydrolyzes dipeptides from the N-terminus of peptides with either proline or alanine at the penultimate position. Substrates of DPP4 include several stress-related neuropeptides implicated in anxiety, depression and schizophrenia. A decline of DPP4-like activity has been reported in sera from depressed patient, but not fully characterized regarding DPP4-like enzymes, therapeutic interventions and protein. Sera from 16 melancholic- and 16 non-melancholic-depressed patients were evaluated for DPP4-like activities and the concentration of soluble DPP4 protein before and after treatment by anti-depressive therapies. Post-translational modification of DPP4-isoforms and degradation of NPY, Peptide YY (PYY), Galanin-like peptide (GALP), Orexin B (OrxB), OrxA, pituitary adenylate cyclase-activating polypeptide (PACAP) and substance P (SP) were studied in serum and in ex vivo human blood. N-terminal truncation of biotinylated NPY by endothelial membrane-bound DPP4 versus soluble DPP4 was determined in rat brain perfusates and spiked sera. Lower DPP4 activities in depressed patients were reversed by anti-depressive treatment. In sera, DPP4 contributed to more than 90% of the overall DPP4-like activity and correlated with its protein concentration. NPY displayed equal degradation in serum and blood, and was equally truncated by serum and endothelial DPP4. In addition, GALP and rat OrxB were identified as novel substrates of DPP4. NPY is the best DPP4-substrate in blood, being truncated by soluble and membrane DPP4, respectively. The decline of soluble DPP4 in acute depression could be reversed upon anti-depressive treatment. Peptidases from three functional compartments regulate the bioactivity of NPY in blood. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |