glucagon-like-peptide-1 and Schizophrenia

Glucagon-like peptide 1 (GLP-1) agonists are among the agents that can be used to treat type 2 diabetes mellitus, and they have also been reported to have neuroprotective effects. This study examined the effects of GLP-1 agonist Liraglutide on CREB, BDNF, Trk-B expression and emotional/cognitive behaviors in an experimental schizophrenia-like behavior model induced by MK-801. MK-801 (0.25 mg/kg, 0.1 ml/kg body weight) and/or Liraglutide (300 mcg/kg) were injected intraperitoneally once a day for 7 weeks into 8-10 weeks old male Balb/c mice (n = 78). Mice were randomly divided into 5 groups: Saline+Saline, MK-801 +Saline, Liraglutide+Saline, MK-801 +Liraglutide co-treatment, and Liraglutide+MK-801 co-treatment. A Morris water maze test, an elevated plus maze test, and an open field test were performed after injection. Western blots were performed on mice' hippocampus and PFC for BDNF, Trk-B, CREB, and p-CREB expression. Our study found that MK-801 impaired emotional and cognitive functions in mice. MK-801 administration did not affect Liraglutide's positive effects on spatial learning and memory activity in the Liraglutide+MK-801 group. Liraglutide administration (Liraglutide+MK-801 group) improved the BDNF/Trk-B and p-CREB/CREB ratio in the hippocampus, and the p-CREB/CREB ratio in the PFC to the control group level. The negative effects of MK-801 on cognitive behavior were not reversed by Liraglutide in the MK-801 +Liraglutide group. In conclusion, Liraglutide does not affect NMDA receptor blockade-induced emotional and cognitive behaviors. However, it has a protective effect against cognitive impairment. Furthermore, it is possible that the GLP-1 receptors in the hippocampus and PFC are involved in the modulation of NMDA receptor activity through CREB activation/deactivation.

Topics: Animals; Brain-Derived Neurotrophic Factor; Diabetes Mellitus, Type 2; Dizocilpine Maleate; Glucagon-Like Peptide 1; Hippocampus; Liraglutide; Male; Mice; Mice, Inbred BALB C; Prefrontal Cortex; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Topics: Adult; Antipsychotic Agents; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Middle Aged; Obesity; Schizophrenia

Schizophrenia is among the top half of the 25 leading causes of disabilities worldwide with a 10-20 year decrease in life expectancy. Ineffective pharmacotherapy in the management of cognitive deficits and weight gain are known to be significant contributors; therefore interventions that may mitigate one, or both, of these parameters would be highly beneficial. Manipulation of the gut microbiome using dietary supplements such as prebiotics may be one such intervention. Preclinical studies have shown that a 2-4 week dietary supplementation with a prebiotic has beneficial effects on learning and memory, and prevents pro-inflammatory signals that are detrimental to cognitive processes. Furthermore, prebiotics influence metabolism, and in obesity they increase the expression of anorexigenic gut hormones such as peptide tyrosine tyrosine, glucagon-like peptide 1 and leptin, as well as decrease levels of orexigenic hormones such as ghrelin. Despite compelling evidence for the pro-cognitive and neuroprotective effects of prebiotics in rodents, their ability to alleviate cognitive deficits or enhance cognition needs to be evaluated in humans. Here we suggest that important symptoms associated with schizophrenia, such as cognitive impairment and weight gain, may benefit from concurrent prebiotic therapy.

Topics: Cognition; Dietary Supplements; Gastrointestinal Microbiome; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Obesity; Peptide YY; Prebiotics; Schizophrenia; Weight Gain

Schizophrenia appears to be linked to higher incidence of metabolic syndrome even in the absence of antipsychotic treatment. Atypical antipsychotics substantially differ in their propensity to induce metabolic alterations. Aripiprazole is considered to represent an antipsychotic drug with low risk of metabolic syndrome development. The aim of this study was to evaluate metabolic phenotype of neurodevelopmental polyI:C rat model and assess metabolic effects of chronic aripiprazole treatment with regard to complex neuroendocrine regulations of energy homeostasis. Polyinosinic:polycytidylic acid (polyI:C) was administered subcutaneously at a dose of 8 mg/kg in 10 ml on gestational day 15 to female Wistar rats. For this study 20 polyI:C and 20 control adult male offspring were used, randomly divided into 2 groups per 10 animals for chronic aripiprazole treatment and vehicle. Aripiprazole (5 mg/kg, dissolved tablets, ABILIFY

Topics: Administration, Oral; Animals; Antipsychotic Agents; Aripiprazole; Body Weight; Cytokines; Disease Models, Animal; Ghrelin; Glucagon-Like Peptide 1; Leptin; Male; Metabolic Syndrome; Poly I-C; Random Allocation; Rats, Wistar; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Liraglutide; Middle Aged; Obesity; Receptors, Glucagon; Schizophrenia; Weight Loss

Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia.Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes between schizophrenia and overweight patients.. Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed.. We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted.

Topics: Antipsychotic Agents; Glucagon-Like Peptide 1; Humans; Obesity; Schizophrenia; Weight Gain

The atypical antipsychotic drug olanzapine induces weight gain and defects in glucose metabolism in patients. Using a rat model we investigated the effects of acute and long term olanzapine treatment on weight gain, food preference and glucose metabolism. Olanzapine treated rats fed a chow diet grew more slowly than vehicle controls but olanzapine treated animals fed a high fat/sugar diet grew faster than control animals on the same diet. These changes in weight were paralleled by changes in fat mass. Olanzapine also induced a strong preference for a high fat/high sugar diet. Acute exposure to olanzapine rapidly induced severe impairments of glucose tolerance and increased insulin secretion but did not impair insulin tolerance. These results indicate the defect in glucose metabolism induced by acute olanzapine treatment was most likely due to increased hepatic glucose output associated with a reduction in active GLP-1 levels and correspondingly high glucagon levels.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Diet, High-Fat; Food Preferences; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Liver; Male; Obesity; Olanzapine; Rats; Schizophrenia; Weight Gain