Systemic immune activation leads to neuroinflammation and sickness behavior in mice.

Substantial evidence indicates an association between clinical depression and altered immune function. Systemic administration of bacterial lipopolysaccharide (LPS) is commonly used to study inflammation-associated behavioral changes in rodents. In these experiments, we tested the hypothesis that peripheral immune activation leads to neuroinflammation and depressive-like behavior in mice. We report that systemic administration of LPS induced astrocyte activation in transgenic GFAP-luc mice and increased immunoreactivity against the microglial marker ionized calcium-binding adapter molecule 1 in the dentate gyrus of wild-type mice. Furthermore, LPS treatment caused a strong but transient increase in cytokine levels in the serum and brain. In addition to studying LPS-induced neuroinflammation, we tested whether sickness could be separated from depressive-like behavior by evaluating LPS-treated mice in a panel of behavioral paradigms. Our behavioral data indicate that systemic LPS administration caused sickness and mild depressive-like behavior. However, due to the overlapping time course and mild effects on depression-related behavior per se, it was not possible to separate sickness from depressive-like behavior in the present rodent model.

Mobile app for comprehensive management of orthodontic patients with fixed appliances : Design and use.

OBJECTIVES: This study aimed to design and implement a mobile phone application (app) aiming to enhance the cooperation and oral hygiene of orthodontic patients. METHODS: An orthodontic app named "Labkhand" was designed by a team of orthodontists and programmers according to the needs and scheduled interventions for patients. The aim of this app was to obviate the orthodontic needs of patients by providing educational content in the form of texts and videos, oral hygiene reminders, appointment reminders, and nutrition reminders. It also enabled instant messaging and chatting between patients and dental personnel. In this study, 61 patients were monitored during their orthodontic treatment procedure. All patients were evaluated using a questionnaire with 7 questions before and after a 6-month treatment period. A total of 31 patients were instructed to use the app, while the other 30 patients received treatment without the app. The collected data were analyzed using paired t­test and analysis of covariance (ANCOVA) test. RESULTS: While the control group's questionnaire score remained almost the same (P > 0.05), the mean questionnaire score of patients in the intervention group significantly increased after using the app compared to the baseline scores acquired before using the app (P < 0.001). The greatest improvement was noted in topics related to "reminding of appointments", "general information about orthodontic treatment", and "oral hygiene maintenance and instructions". "Quality of services" and "patient-orthodontist communication" showed the least improvement in patient satisfaction. CONCLUSIONS: The Labkhand orthodontic app has multiple functions and can obviate the needs of orthodontic patients easily and at a low cost.

Efficacy of a mobile phone application for the improvement of oral hygiene of patients undergoing fixed orthodontic treatment : A randomized controlled clinical trial.

OBJECTIVES: This study aimed to assess the efficacy of a mobile phone application (app) to improve oral hygiene of patients undergoing fixed orthodontic treatment. MATERIALS AND METHODS: This randomized controlled clinical trial was conducted with a total of 60 patients undergoing fixed orthodontic treatment in two groups: intervention and control (n = 30 each). A previously designed mobile app (Labkhand) was used by patients in the intervention group. Orthodontic plaque index (OPI) and modified gingival index (MGI) were recorded in the two groups at baseline (first session or T0), and after 1 (T1) and 3 (T2) months. The number of debonded/broken brackets was also recorded, and pain score of the patients was assessed at nine time points. Data were analyzed using the χ2 test, paired t­test, and repeated measures analysis of variance (ANOVA; α = 0.05). RESULTS: The two groups demonstrated no significant difference in OPI and MGI at T0 (P > 0.05). OPI and MGI at T1 and T2 were significantly lower in the intervention group than in the control group (P < 0.05). The number of patients with broken brackets in the intervention group was significantly lower than that in the control group (P = 0.017). The two groups reported no significant difference in pain score (P > 0.05). CONCLUSION: The Labkhand mobile app successfully improved oral hygiene indices of patients undergoing fixed orthodontic treatment, and decreased the frequency of broken brackets after 1 and 3 months of use.

Peripheral Administration of Tumor Necrosis Factor-Alpha Induces Neuroinflammation and Sickness but Not Depressive-Like Behavior in Mice.

Clinical observations indicate that activation of the TNF-α system may contribute to the development of inflammation-associated depression. Here, we tested the hypothesis that systemic upregulation of TNF-α induces neuroinflammation and behavioral changes relevant to depression. We report that a single intraperitoneal injection of TNF-α in mice increased serum and brain levels of the proinflammatory mediators TNF-α, IL-6, and MCP-1, in a dose- and time-dependent manner, but not IL-1ß. Protein levels of the anti-inflammatory cytokine IL-10 increased in serum but not in the brain. The transient release of immune molecules was followed by glial cell activation as indicated by increased astrocyte activation in bioluminescent Gfap-luc mice and elevated immunoreactivity against the microglial marker Iba1 in the dentate gyrus of TNF-α-challenged mice. Additionally, TNF-α-injected mice were evaluated in a panel of behavioral tests commonly used to study sickness and depressive-like behavior in rodents. Our behavioral data imply that systemic administration of TNF-α induces a strong sickness response characterized by reduced locomotor activity, decreased fluid intake, and body weight loss. Depressive-like behavior could not be separated from sickness at any of the time points studied. Together, these results demonstrate that peripheral TNF-α affects the central nervous system at a neuroimmune and behavioral level.

Examining dopamine D3 receptor occupancy by antipsychotic drugs via [3H]7-OH-DPAT ex vivo autoradiography and its cross-validation via c-fos immunohistochemistry in the rat brain.

Dopamine D3 receptors are a major target for drug discovery programs related to psychiatric disorders such as schizophrenia. The ability of a compound to occupy significant levels of D3 receptors is important for achieving therapeutic efficacy in both pre-clinical and clinical settings. Here we attempt to characterise antipsychotic drug-effects at D3 receptors by measuring receptor occupancy via ex-vivo [3H]7-OH-DPAT autoradiography, and further validating this outcome via analysis of Fos-like immunoreactivity (Fos-LI) in the rat major islands of Calleja (ICjM), a brain structure with high D3 expression. Rats were treated subcutaneously with haloperidol (0.04 mg/kg), clozapine (20 mg/kg) and olanzapine (0.63 mg/kg), the selective D2 antagonist L-741626 (2.5 mg/kg) and the selective D3 antagonist SB-277011-A (10 mg/kg). Doses were based on levels of D2 occupancy considered clinically relevant (60-80%). When measuring D3 occupancy, clozapine and SB-277011-A displayed meaningful levels of occupancy (60% and 77%, respectively), haloperidol and olanzapine showed limited occupancy (16% and 27%, respectively), whereas L-741626 showed no occupancy. There were no significant changes in ICjM Fos-LI after L-741626 and haloperidol treatment, minor but significant increases after olanzapine treatment, whereas highly significant increases were seen with SB-277011-A and clozapine. Additionally, pre-treating clozapine with the D1 antagonist SCH23390 caused a significant, albeit non-complete, reduction in Fos-LI, highlighting the D1 agonist property of clozapine. In conclusion, it appears that drugs occupying >50% D3 receptors produce robust increases in ICjM Fos-LI. This study may help to identify the appropriate D3 receptor antagonists that have the potential to be tested in the clinic.

Hyperphagia and increased meal size are responsible for weight gain in rats treated sub-chronically with olanzapine.

RATIONALE: Atypical antipsychotic-induced weight gain is a significant impediment in the treatment of schizophrenia. OBJECTIVES: In a putative model of antipsychotic drug-induced weight gain, we investigated the effects of sub-chronic olanzapine on body weight, meal patterns, the expression of genes encoding for hypothalamic feeding-related neuropeptides and the contribution of hyperphagia to olanzapine-induced weight gain in rats. MATERIALS AND METHODS: In experiment 1, female rats received either olanzapine (1 mg/kg, p.o.) or vehicle, twice daily for 7 days, while meal patterns were recorded. At the end of the treatment regimen, we measured the levels of hypothalamic messenger RNAs (mRNAs) encoding neuropeptide-Y (NPY), hypocretin/orexin (HCRT), melanin concentrating hormone and pro-opiomelanocortin. NPY and HCRT mRNA levels were also assessed in a separate cohort of female rats treated acutely with olanzapine (1 mg/kg, p.o.). In experiment 2, we investigated the effect of a pair-feeding paradigm on sub-chronic (1 mg/kg, p.o.) olanzapine-induced weight gain. RESULTS: In experiment 1, sub-chronic olanzapine increased body weight, food intake and meal size. Hypothalamic neuropeptide mRNA levels were unchanged after both acute and sub-chronic olanzapine treatment. In experiment 2, the restriction of food intake to the level of vehicle-treated controls abolished the sub-chronic olanzapine-induced increase in body weight. CONCLUSIONS: Hyperphagia mediated by drug-induced impairments in satiety (as evidenced by increased meal size) is a key requirement for olanzapine-induced weight gain in this paradigm. However, olanzapine-induced hyperphagia and weight gain may not be mediated via alterations in the expression of the feeding-related hypothalamic neuropeptides examined in this study.

Comparative effects of olanzapine and ziprasidone on hypophagia induced by enhanced histamine neurotransmission in the rat.

Atypical antipsychotic drugs (AAPDs), such as olanzapine, are associated with weight gain and hyperphagia in both humans and rodents. This side effect, however, is absent or reduced for AAPD such as ziprasidone. The increased levels of appetite seen in rodents may be related to drug interactions with brain histamine systems involved in appetite control. We demonstrate a significant interaction of olanzapine treatment with histamine neurotransmission in a rat-feeding paradigm measuring the consumption of a palatable fat emulsion. This interaction was identified using the H3 receptor antagonist thioperamide, which by blocking autoreceptor control of histaminergic neurons enhances release of hypothalamic histamine, causing hypophagia. We challenged this effect of thioperamide with olanzapine, which among its pharmacological actions is a potent H1 receptor antagonist. Olanzapine pretreatment significantly attenuated thioperamide-induced hypophagia. Pretreatment of thioperamide with ziprasidone, an AAPD with negligible H1 receptor affinity, however, failed to have this effect. Although thioperamide may also increase levels of neurotransmitters other than histamine, the potent H1 antagonist property of olanzapine is likely to result in the suppression of thioperamide-induced hypophagia. We conclude that olanzapine may be directly modulating histaminergic neurotransmission associated with the regulation of feeding behaviour.