Quetiapine attenuates glial activation and proinflammatory cytokines in APP/PS1 transgenic mice via inhibition of nuclear factor-κB pathway.

BACKGROUND: In Alzheimer's disease, growing evidence has shown that uncontrolled glial activation and neuroinflammation may contribute independently to neurodegeneration. Antiinflammatory strategies might provide benefits for this devastating disease. The aims of the present study are to address the issue of whether glial activation and proinflammatory cytokine increases could be modulated by quetiapine in vivo and in vitro and to explore the underlying mechanism. METHODS: Four-month-old amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic and nontransgenic mice were treated with quetiapine (5mg/kg/d) in drinking water for 8 months. Animal behaviors, total Aß levels, and glial activation were evaluated by behavioral tests, enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot accordingly. Inflammatory cytokines and the nuclear factor kappa B pathway were analyzed in vivo and in vitro. RESULTS: Quetiapine improves behavioral performance, marginally affects total Aß40 and Aß42 levels, attenuates glial activation, and reduces proinflammatory cytokines in APP/PS1 mice. Quetiapine suppresses Aß1-42-induced activation of primary microglia by decresing proinflammatory cytokines. Quetiapine inhibits the activation of nuclear factor kappa B p65 pathway in both transgenic mice and primary microglia stimulated by Aß1-42. CONCLUSIONS: The antiinflammatory effects of quetiapine in Alzheimer's disease may be involved in the nuclear factor kappa B pathway. Quetiapine may be an efficacious and promising treatment for Alzheimer's disease targeting on neuroinflammation.

Pain perception in schizophrenia: no changes in diffuse noxious inhibitory controls (DNIC) but a lack of pain sensitization.

BACKGROUND: Pain is a dynamic phenomenon resulting from the activity of both excitatory (e.g. sensitization) and inhibitory endogenous modulation systems. Preliminary experimental studies have shown diminished pain sensitivity in schizophrenia patients. The objective of the study was to investigate the role of excitatory and inhibitory systems on pain perception in schizophrenia. METHODS: Participants were 23 patients with a schizophrenia-spectrum disorder (DSM-IV criteria) and 29 healthy volunteers, who did not differ in age, sex or ethnicity. Excitatory and inhibitory systems were elicited using a temporal summation test (Peltier thermode) administered before and after activation of the diffuse noxious inhibitory control (DNIC) by means of a cold-pressor test. RESULTS: Time was a significant predictor of pain scores in controls, but not in patients. That is, pain ratings increased during the tonic thermal stimulation among controls but not in schizophrenia patients. When correlation coefficients (between time and pain ratings) for patients and controls were compared, the correlation coefficient emerged as significantly weaker in the schizophrenia group (Z=12.04; p=0.0001), suggesting a lack of sensitization in schizophrenia. DNIC was similar in magnitude in both patients and controls. CONCLUSIONS: Diminished pain sensitivity in schizophrenia may be related to abnormal excitatory mechanisms, but not to DNIC. More studies are needed to better characterize the neurophysiological and neurochemical mechanisms involved in the lack of sensitization in schizophrenia.

[On the front line: survey on shared responsibility. General practitioners and schizophrenia]. / Sur la première ligne: sondage pour un partage. Les omnipraticiens et la schizophrénie.

CONTEXT: General practitioners (GP) play a preponderant role in the treatment of patients suffering of schizophrenia. OBJECTIVES: Discovering the number of patients with schizophrenia who are treated by GPs ; the needs and attitudes of GPs, their knowledge concerning diagnosis, and the treatment they provide. METHODOLOGY: A postal survey was conducted with Quebec GPs who were randomly chosen. RESULTS: A total of 1003 GPs have participated in the survey. Among them, a small percentage have to treat an early onset schizophrenia and the GPs have expressed their wish to be more informed on the accessibility of specialized services. Results pertaining to questions on diagnoses and knowledge on treatments are inconsistent. The majority of GPs treat the first psychotic episodes with antipsychotic medication. Only a third of GPs surveyed propose maintaining the treatment after a first psychotic episode, in accordance with international recommendations and the recent Canadian guidelines on practices that recommends at least 6 to 12 months of treatment after a partial or complete clinical response. Time given by male GPs to a first contact varies between 10 and 20 minutes, while 80 % of female GPs spend at least 20 minutes. The adverse effects of antipsychotic medication that raise most concern is weight gain before neurological signs. CONCLUSION: some of this survey's data should be considered by various professional and governmental associations, in order to improve the place of GPs in a health plan destined to treat schizophrenia.

[Differences and similarities in perception of schizophrenia between physicians and the general population in Quebec]. / Différences et similitudes dans la perception de la schizophrénie entre les omnipraticiens et la population générale québécoise.

This paper presents results concerning the perceptions and attitudes of Quebec physicians towards patients with schizophrenia and compares data obtained from a previous poll to data drawn from answers of five common questions asked to the general population. A short questionnaire with 5 items selected earlier from a broader questionnaire submitted to the general population, has been distributed to Quebec physicians. These items inquired about the perceptions and attitudes of physicians towards schizophrenia. A randomized sample of physicians was performed. Three thousand and five hundred (3 500) physicians were selected and distributed questionnaires. A response rate of 29 %, a little more than one thousand (1003 responses) was observed, 46 % women and 54 % men. The authors have found significant differences between physicians and the general population in the tendency of wanting to offer help to those suffering from schizophrenia (physicians = 58 % versus general population : 45 %). Also, a higher percentage of physicians (72 %) have expressed feelings of compassion towards patients with schizophrenia versus 27 % in the general population. Results indicate that physicians, with a family member suffering from schizophrenia, are less comfortable discussing openly about the family member's illness (26 % versus 48 %). With regards to preconception of the severity of schizophrenia, in the field of health, and more specifically mental health, there are no differences observed amongst the physicians and the general population.

Therapeutic effects of quetiapine on memory deficit and brain ß-amyloid plaque pathology in a transgenic mouse model of Alzheimer's disease.

Our previous study has shown the preventive effects of quetiapine, an atypical antipsychotic drug, on memory impairment and brain pathological changes in a mouse model of Alzheimer's disease (AD). The aim of the present study was to evaluate the therapeutic effects of quetiapine on memory deficit and neuropathology in an amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mouse model of AD. The APP/PS1 mice started to have detectable brain ß-amyloid (Aß) at 3 months of age. Non-transgenic and transgenic mice were treated with quetiapine (0, 2.5, or 5 mg/(kg day)) in drinking water from the age of 4 months. After 8 months of continuous quetiapine administration, memory deficit was reversed and brain Aß plaque pathology was attenuated in the AD mice. Quetiapine also decreased the soluble Aß peptide levels in brain and cerebrospinal fluid (CSF), and attenuated the decreased synaptic protein levels in the AD mice. Furthermore, quetiapine normalized the abnormal activity of glycogen synthase kinase-3ß (GSK-3ß), an AD-involved kinase, in the AD mice. These results suggest that quetiapine can treat and alleviate the neuropathology in an APP/PS1 transgenic mouse model of AD, and indicate that quetiapine may have therapeutic effects in the treatment of AD.

Quetiapine modulates conditioned anxiety and alternation behavior in Alzheimer's transgenic mice.

Quetiapine, an atypical antipsychotic drug, is effective in treating the behavioral and psychological symptoms in Alzheimer's disease (AD). However, it is presently unclear whether quetiapine has beneficial effects on memory and whether the effects of quetiapine on psychological symptoms are associated with its effect on memory in AD. The present study was designed to examine the effect of chronic administration of quetiapine on the conditioned (generalized) anxiety that is related to learning experience of open arm exposure in the elevated T-maze (ETM) test in an amyloid precursor protein (APP)/presenilin 1 (PS1) double transgenic mouse model of AD. In a 2nd experiment, the effect of quetiapine on memory per se was investigated in a Y-maze test in AD mice. Non-transgenic and transgenic mice were treated with quetiapine in drinking water from the age of 2 months. After continuous treatment with quetiapine (5 mg/kg/day) for 10 months, mice were tested for conditioned anxiety on the ETM task. After ETM testing, the expression of brain-derived neurotrophic factor (BDNF), a neuroprotective protein, was examined by immunohistochemistry in the basolateral amygdala (BLA) and hippocampus. In the 2nd experiment, the effect of quetiapine (2.5 or 5 mg/kg/day) on the short-term memory in AD mice was tested in a Y-maze test. After 10 months of administration, quetiapine prevented the decrease of conditioned anxiety and cerebral BDNF in AD mice. In addition, quetiapine also prevented memory impairment in the Y-maze test in AD mice. These findings suggest that the therapeutic mechanism of quetiapine on anxiety in AD may be associated with its beneficial effect on memory and its neuroprotective effect on cerebral BDNF expression.

Serum ß-amyloid peptide levels spike in the early stage of Alzheimer-like plaque pathology in an APP/PS1 double transgenic mouse model.

Serum levels of ß-amyloid (Aß) peptides may represent an early biomarker in the diagnosis of Alzheimer's disease (AD). In the present study, we investigated the temporal kinetic changes in the levels of serum Aß 1-42 and 40 in an amyloid precursor protein (APP)/presenilin (PS)1 double transgenic mouse model of AD. Serum Aß peptide levels in 2-, 3-, 6-, 9- and 18-month old, and liver Aß 1-40 level in 6-month old mice were measured using enzyme-linked immunosorbent assay (ELISA) kits. Results revealed that serum Aß levels peaked in 3-month old transgenic mice, and the Aß level in non-transgenic and transgenic mice is comparable in liver. Compared to the 6-month old transgenic mice, Congo red staining showed that the 3-month old transgenic mice had minimum brain Aß plaques, corresponding to the early stage of Alzheimer-like plaque pathology, and confocal microscope images showed that the deposition of Aß in their cerebral vessels was minimal. Furthermore, results of the water maze test, showed that memory was normal for the 3- month old transgenic mice when compared to age-matched non-transgenic mice. These results suggest that serum Aß peptide levels may be peaked during the early stage of AD. Monitoring serum Aß peptide levels in the potential AD population may provide an early diagnosis of AD prior to the appearance of clinical symptoms.

Beneficial effects of quetiapine in a transgenic mouse model of Alzheimer's disease.

Previous studies have suggested that quetiapine, an atypical antipsychotic drug, may have beneficial effects on cognitive impairment, and be a neuroprotectant in treating neurodegenerative diseases. In the present study, we investigated the effects of quetiapine on memory impairment and pathological changes in an amyloid precursor protein (APP)/presenilin-1 (PS-1) double transgenic mouse model of Alzheimer's disease (AD). Non-transgenic and transgenic mice were treated with quetiapine (0, 2.5, or 5mg/(kg day)) for 1, 4, and 7 months in drinking water from the age of 2 months. After 4 and 7 months of continuous quetiapine administration, memory impairment was prevented, and the number of beta-amyloid (Abeta) plaques decreased in the cortex and hippocampus of the transgenic mice. Quetiapine also decreased brain Abeta peptides, beta-secretase activity and expression, and the level of C99 (an APP C-terminal fragment following cleavage by beta-secretase) in the transgenic mice. Furthermore, quetiapine attenuated anxiety-like behavior, up-regulated cerebral Bcl-2 protein, and decreased cerebral nitrotyrosine in the transgenic mice. These findings suggest that quetiapine can alleviate cognitive impairment and pathological changes in an APP/PS1 double transgenic mouse model of AD, and further indicate that quetiapine may have preventive effects in the treatment of AD.