The intersection of astrocytes and the endocannabinoid system in the lateral habenula: on the fast-track to novel rapid-acting antidepressants.

Despite attaining significant advances toward better management of depressive disorders, we are still facing several setbacks. Developing rapid-acting antidepressants with sustained effects is an aspiration that requires thinking anew to explore possible novel targets. Recently, the lateral habenula (LHb), the brain's "anti-reward system", has been shown to go awry in depression in terms of various molecular and electrophysiological signatures. Some of the presumed contributors to such observed aberrations are astrocytes. These star-shaped cells of the brain can alter the firing pattern of the LHb, which keeps the activity of the midbrain's aminergic centers under tight control. Astrocytes are also integral parts of the tripartite synapses, and can therefore modulate synaptic plasticity and leave long-lasting changes in the brain. On the other hand, it was discovered that astrocytes express cannabinoid type 1 receptors (CB1R), which can also take part in long-term plasticity. Herein, we recount how the LHb of a depressed brain deviates from the "normal" one from a molecular perspective. We then try to touch upon the alterations of the endocannabinoid system in the LHb, and cast the idea that modulation of astroglial CB1R may help regulate habenular neuronal activity and synaptogenesis, thereby acting as a new pharmacological tool for regulation of mood and amelioration of depressive symptoms.

Opioid system modulation of cognitive affective bias: implications for the treatment of mood disorders.

A significant number of patients (30%) do not adequately respond to commonly prescribed antidepressants (e.g. SSRIs, SNRIs, and TCAs). Opioid receptors and their endogenous peptides have demonstrated a clear role in the regulation of mood in animal models and may offer an alternative approach to augment existing therapies. Nevertheless, there is an urgent need to find better ways to predict a patient's response to drug treatment, to improve overall drug responding, and to reduce the time to symptom remission using novel diagnostic and efficacy biomarkers. Cognitive processes, such as perception, attention, memory, and learning, are impaired in patients with mood disorders. These processes can be altered by emotions, a phenomenon called cognitive affective bias. Negative affective biases are a key feature of major depressive disorder (MDD) and may present concurrently with other cognitive deficits. Importantly, a significant percentage of patients report residual cognitive impairments even after effective drug treatment. This approach offers a new opportunity to predict patient treatment responses, potentially improving residual cognitive symptoms and patient outcomes. This review will (1) describe the underlying neurocircuitry of affective cognition and propose how negative biases may occur, (2) outline the role of opioid receptors in affective cognition, executive function, and MDD, and (3) present evidence from the published literature supporting a modulatory role for opioid drugs on negative affective bias, with a focus on kappa-opioid receptor antagonists, currently in development for clinical use for treatment-resistant MDD.

A COX/5-LOX Inhibitor Licofelone Revealed Anticonvulsant Properties Through iNOS Diminution in Mice.

Licofelone is a COX/5-LOX inhibitor, which recently was approved as an effective treatment for osteoarthritis. Beside its analgesic and anti-inflammatory effects, some reports show neuro-protective properties for this agent in central nervous system. Several lines of evidence declare the involvement of COX or LOX isoenzymes in epileptic disorders. To set the foundation for future research into the neurobiology of licofelone as a potential therapeutic agent, we studied the effect of licofelone in an animal model of epilepsy. Although different neurotransmitters and neuro-modulators like nitric oxide were introduced as suggested targets of licofelone, the underlying mechanisms of central effects of this drug are not still fully understood. We have utilized pentylenetetrazole-induced clonic seizure model to investigate the behavioral consequences of licofelone administration and its possible mechanisms in seizure susceptibility. Licofelone revealed anticonvulsant properties at the dose of 10 mg/kg (i.p) or higher in mice. Pre-treatment with NO (nitric oxide) donor, L-arginine, reversed this anticonvulsant effects dose dependently. L-NAME, as a non-selective nitric oxide synthase (NOS) inhibitor, potentiated the anticonvulsant effects of licofelone. A neuronal NOS inhibitor, 7-NI did not affect seizure threshold alone or in combination with licofelone. Using non-effective doses of selective inhibitors of inducible NOS, aminoguanidine or 1400W, significantly increased the seizure threshold when were accompanied by licofelone in low doses. These data support the involvement of NO as an important role player in the central neuro-protective properties of licofelone. Furthermore, it implies that down regulation of iNOS seems crucial for anticonvulsant properties of this COX/5-LOX inhibitor in seizure susceptibility.

Adjuvant Effect of Biogenic Selenium Nanoparticles Improves the Immune Responses and Survival of Mice Receiving 4T1 Cell Antigens as Vaccine in Breast Cancer Murine Model.

The modification of tumor-associated antigen-based vaccine to elicit a more robust immune response has been addressed in several ways. In the present work, we aimed to investigate the immunomodulatory effect of selenium nanoparticles as an immunoadjuvant in formulation of a tumor-associated antigen-based vaccine in a preventive form. Fortyfive female inbred BALB/c mice five-to-seven weeks old were used and divided into three groups of test and control, each containing fifteen mice. Group one injected by PBS and used as a control. Group two injected by breast tumor cell lysate alone as vaccine. Group three injected by SeNPs with tumor cell lysate as vaccine. All injections were carried out on day fourteen, twentyone and twentyeight of the study. Tumor induction was done at day thirty. Twenty days after tumor induction serum samples were gathered to measure the cytokine assay. Tumor growth and weight of mice as well as delayed type hyper sensitivity (DTH) response were monitored during the study. Results of the present work showed a significant increase in the level of serum IFN-γ, IL-2, IL-12 and decreased TGF-ß in SeNPs/vaccine injected mice as well as lower tumor volume, more potent DTH responses and longer survival rate in comparison to control and tumor lysate vaccine. Taken together, it can be deduced from this work that SeNPs can be considered as an adjuvant in vaccine in triggering robust immune response against breast cancer. But further evaluations are still needed to find the best formula for this agent in antitumor vaccines.

Kappa opioid activation changes protein profiles in different regions of the brain relevant to depression.

Depression is a widespread disorder with a significant burden on individuals and society. There are various available treatments for patients with depression. However, not all patients respond adequately to their treatment. Recently, the opioid system has regained interest in depression studies. Research in animals and humans suggest that blocking the kappa opioid receptor (KOR) may potentially alleviate the symptoms of depression. The mechanism behind this effect is not fully understood. Stress and alterations in hypothalamic-pituitary-adrenal axis (HPA-axis) activity are thought to play a crucial role in depression. This study aimed to characterize stress hormones and stress-related protein expression following activation of KOR using a selective agonist. The longitudinal effect was investigated 24 h after KOR activation using the selective agonist U50,488 in Sprague Dawley rats. Stress-related hormones and protein expression patterns were explored using multiplex bead-based assays and western blotting. We found that KOR activation caused an increase in both adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in serum. Regarding protein assays in different brain regions, phosphorylated glucocorticoid receptors also increased significantly in thalamus (THL), hypothalamus (HTH), and striatum (STR). C-Fos increased time-dependently in THL following KOR activation, extracellular signal-regulated kinases 1/2 (ERK1/2) increased significantly in STR and amygdala (AMG), while phosphorylated ERK1/2 decreased during the first 2 h and then increased again in AMG and prefrontal cortex (PFC). This study shows that KOR activation alters the HPA axis and ERK signaling which may cause to develop mood disorders.

Involvement of PPAR receptors in the anticonvulsant effects of a cannabinoid agonist, WIN 55,212-2.

Cannabinoid and PPAR receptors show well established interactions in a set of physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study aimed to evaluate the roles of the PPAR-gamma, PPAR-alpha and CB1 receptors on the anticonvulsant effects of WIN 55,212-2 (WIN, a non selective cannabinoid agonist). The clonic seizure thresholds after intravenous administration of pentylenetetrazole (PTZ) were assessed in mice weighing 23-30 g. WIN increased the seizure threshold dose dependently. Pretreatment with pioglitazone, as a PPARγ agonist, potentiated the anticonvulsant effects of WIN, while PPARγ antagonist inhibited these anticonvulsant effects partially. On the other hand PPARα antagonist reduced the anticonvulsant effects of WIN significantly. Finally the combination of CB1 antagonist and PPARα antagonist could completely block the anticonvulsant properties of WIN. Taken together, these results show for the first time that a functional interaction exists between cannabinoid and PPAR receptors in the modulation of seizure susceptibility.

Effect of Oral Supplementation of Biogenic Selenium Nanoparticles on White Blood Cell Profile of BALB/c Mice and Mice Exposed to X-ray Radiation.

BACKGROUND: Radiation therapy is an effective method used for treatment of many types of cancers. However, this method can cause unwanted side effects such as bone marrow suppression. In this study, the effect of oral administration of biogenic selenium nanoparticles (SeNPs) on total and differentiated white cells profile of BALB/c mice exposed to X-ray radiation was investigated and compared with non-irradiated mice. METHODS: Sixty female BALB/c mice between six to eight weeks olds were divided into 4 test and control groups in two categories of normal and irradiated mice. In normal mice SeNPs administration was started from the day 0 and followed for a month. Irradiated mice were divided into three groups and were exposed to doses of 2, 4 and 8 Gy. After 72 hr of irradiation, the SeNPs treatment was started and continued for a month. Total and differentiated blood cells counts of both irradiated and non-irradiated groups were monitored during 30 days and the obtained results were compared. Also, the deposition of Se in different tissues and blood serum of normal mice was determined in normal mice after 30 days period of supplementation. RESULTS: In normal mice an increase in the count of neutrophils was observed after 30 days of supplementation. In irradiated mice, SeNPs supplementation led to increase in both lymphocytes and neutrophils counts especially in mice exposed to 2 and 4 Gys radiation. CONCLUSION: Radiotherapy is categorized as an invasive method which can cause tissue damage and suppress the host immune defense. A restore of lymphocytes which was observed after SeNPs supplementation in irradiated mice can be highly interesting and provide cellular immunity against malignant diseases or other bacterial or fungal infections after radiotherapy.

The immunostimulatory effect of biogenic selenium nanoparticles on the 4T1 breast cancer model: an in vivo study.

Selenium salts as well as elemental selenium nanoparticles are attracting the attention of researchers due to their excellent biological properties. The aim of the present work was to study immunomodulation by applying elemental Se NPs to stimulate the immune response of mice bearing 4 T1 breast cancer tumors. Six- to 8-week-old female inbred BALB/c mice were divided into two groups of test and control, each containing 15 mice. Every day, for 2 weeks prior to tumor induction, selenium nanoparticles were orally administered to the mice at a dose of 100 µg/day. Then, 1 × 10(6) cells from a 4 T1 cell line were injected subcutaneously to each mouse. Oral nanoparticle administration was continued daily for 3 weeks after tumor induction. Different immunological parameters were then evaluated including cytokine level, delayed type hypersensitivity (DTH) response as well as tumor growth and the survival rates in all treated or nontreated animals. The production of Th1 cytokines, such as IFN-γ and IL-12, in spleen cell culture was increased in the test mice-administered selenium nanoparticles. The DTH response of test mice also showed a significant increase when compared to the control mice. The survival rate was notably higher for the selenium nanoparticle-treated mice compared to the control mice. Our results suggest that selenium nanoparticle administration can result in considerable induction of the Th1 platform of immune response through the elevation of IFN-γ and IL-12 and may be a cause for better prognosis in mice with tumors.