Vitamin D3 and zinc supplements augment the antimanic efficacy of lithium and olanzapine treatments in an animal model of mania.

Objective: Bipolar disorder (BD) is a challenging psychiatric disorder and a complex disease. The associated reduction in serum vitamin D3 (VitD3) levels in BD patients and the contribution of zinc (Zn) to the treatment, along with the severe side effects of lithium (Li) treatment, were encouraging to assess the efficacy of different correlated combinations of therapeutic/nutraceutical treatments such as olanzapine (Oln), VitD3, and Zn against Li. Methods: Mania was induced in C57BL/6 mice by administering methylphenidate (MPH) for 14 consecutive days. On the 8th day of MPH injection, different treatment regimens were administered, Li, Oln, VitD3/Zn, VitD3/Zn/Oln, VitD3 + Zn + Oln + Li50mg/kg (C50), and VitD3 + Zn + Oln + Li100mg/kg (C100). Both VitD3 (850 IU/kg) and Zn (180 mg/kg) were supplied with food for 2 weeks before starting the induction of mania, which continued until the end of MPH administration. Behavioral, brain oxidative stress, thyroid hormones, VitD3, Zn, GsK-3ß, and Bcl2 levels, as well as brain histopathological alterations, were assessed. Results: Manic mice exhibited alterations in all tested parameters, and the histopathological examination of the cortex and hippocampus confirmed these results. The VitD3/Zn/Oln, C50, and C100 treatment regimens reversed most of the behavioral and pathophysiological alterations; however, the C50 treatment regimen was the most efficient. Conclusions: This study emphasizes the importance of combining different antimanic medications like Li and Oln with nutraceutical supplements to increase their antimanic efficacy, reduce their adverse effects, and, ideally, improve the BD patient's quality of life.

Probing the chemoprevention potential of the antidepressant fluoxetine combined with epigallocatechin gallate or kaempferol in rats with induced early stage colon carcinogenesis.

The enhanced chemopreventive action against 1,2 Dimethylhydrazine (DMH)-induced preneoplastic lesion in rats could be achieved via simultaneous administration of the antidepressant fluoxetine (FLX) with two natural polyphenolic compounds viz., kaempferol (KMP) and/or epigallocatechin-gallate (EGCG). The obtained results revealed that single FLX pre-treatment possess a significant apoptotic effect by increasing the activity of serum and colon tissue caspase 3. It also attenuated the DMH driven increase in, colon tissue MDA, NO, PCNA and COX-2 expression as well as serum and colon tissue ß-catenin, with a decrease in the multiplicity of ACF and number of MPLs. The combination of FLX with either KMP or EGCG improved the antioxidant, anti-inflammatory and antiproliferating activities but with higher apoptotic activity in case of KMP. Eventually, histopathological assessment of colon tissues exposed that while sole pre-treatment can improve DMH-induced hyperplasia with only moderate inflammatory infiltration, tissues from the combined pre-treatment regimens groups exhibited almost a normal colonic architecture with slight submucosal edema. The study proved that single FLX administration prior to DMH exerts a chemopreventive effect and that the investigated combined pre-treatment regimens demonstrated more potent chemopreventive and antiproliferative actions.

Chemopreventive effect of sulindac in combination with epigallocatechin gallate or kaempferol against 1,2-dimethyl hydrazine-induced preneoplastic lesions in rats: A Comparative Study.

A systematic investigation of the chemopreventive effect of sulindac (SL) in combination with either epigallocatechin gallate (EGCG) or kaempferol similar (KMP) has been carried out 1,2-dimethyl hydrazine-treated rats (DMH). Those SL combinations with KMP and EGCG have enhanced the SL activity producing greater antioxidant, anti-inflammatory, antiproliferating, and apoptotic activities in both combinations than SL alone. The chemopreventive effects of SL with both EGCG and KMP were demonstrated by a decrease in thiobaribituric acid reactive substances level, tissue nitric oxide (NO), serum, and tissue ß-catenin as well as a reduction in the multiplicity of aberrant crypt foci (ACF) with alleviation in the dysplastic changes that resulted from DMH administration. Down-regulation of proliferating cell nuclear antigen (PCNA) and cyclooxygenase-2 (COX-2) were also confirmed by immunohistochemical staining. The current study paves the way for the use of sulindac combination with kaempferol or EGCG as potential chemopreventive agents against colon cancer with more effect in combination with EGCG.

Anti-diabetic and renoprotective effects of aliskiren in streptozotocin-induced diabetic nephropathy in female rats.

Since chronic kidney disease due to diabetic nephropathy (DN) is becoming an ever larger health burden worldwide, more effective therapies are desperately needed. In the present study, the anti-diabetic and renoprotective effects of aliskiren have been evaluated in streptozotocin (STZ)-induced DN in rats. DN was induced by a single intraperitoneal injection of STZ (65 mg/kg). Three weeks after STZ, rats were divided into four groups; normal, diabetic, diabetic treated with gliclazide (10 mg/kg/day) for 1 month, and diabetic treated with aliskiren (50 mg/kg/day) for 1 month. At the end of the experiment, mean arterial blood pressure and heart rate were recorded. Rats were then euthanized and serum was separated for determination of glucose, insulin, kidney function tests, superoxide dismutase activity (SOD), adiponectin, and tumor necrosis factor-alpha (TNF-α). One kidney was used for estimation of malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) contents. Other kidney was used for histopathological study and immunohistochemical measurement of caspase-3 and transforming growth factor beta (TGF-ß). In addition, islets of Langerhans were isolated from normal rats by collagenase digestion technique for in vitro study. Aliskiren normalized STZ-induced hyperglycemia, increased insulin level both in vivo and in vitro, normalized kidney function tests and blood pressure, and alleviated STZ-induced kidney histopathological changes. This could be related to the ability of aliskiren toward preserving hemodynamic changes and alleviating oxidative stress and inflammatory and apoptotic markers induced by STZ in rats. However, aliskiren was more effective than gliclazide in relieving STZ-induced DN. These findings support the beneficial effect of aliskiren treatment in DN which could be attributed to its anti-diabetic, renoprotective, antioxidant, anti-inflammatory, and anti-apoptotic effects. Moreover, clinical studies are required to establish the effectiveness of aliskiren treatment in patients suffering from hypertension and diabetes.

Role of interleukin-1beta and nitric oxide in the antiinflammatory dynamics of acetylsalicylic acid in carrageenan-induced paw oedema model.

The present study aimed to analyze the role of interleukin-1beta (IL-1beta) and nitric oxide (NO) in the development of peripheral acute inflammation in carrageenan-induced paw edema model in the presence/absence of acetyl salicylic acid (ASA). A 0.5 ml solution of 0.5%, 1% and 2% carrageenan was administered intraplantarly in right hind paw of adult Swiss mice. ASA was administered in a single dose of 200 mg/kg 1 hour before intraplantar injection of carrageenan. Paw volume, IL-1beta and nitrite levels in plasma and paw infiltrate and the total and differential white blood cells count were determined. Carrageenan administration induced a dose-dependent increase in paw volume, IL-1beta level in paw infiltrate and nitrite content in plasma. ASA exhibited a better anti-inflammatory effect where 2% carrageenan was used as the inflammatory agent. Pre-treatment with ASA resulted in increase in plasma IL-1beta level, decrease in IL-1beta level at the inflammation site and restoring plasma nitrite concentration to its normal range. Our results stressed on the role of IL-1beta and NO in the acute inflammation and suggested that the dose of carrageenan is the major determinant in the response to ASA.

Influence of protein malnutrition on induction and treatment of inflammation in mice.

Considerable evidence suggests that protein malnutrition (PM) impairs immune function especially cytokine and interferes with the toxicopharmacology of some non-steroidal anti-inflammatory drugs. The present study tries to assess whether PM will affect induction and treatment of inflammation. The study was performed on adult male Swiss mice using the carrageenan-air pouch model. Animals were fed either protein sufficient 20% or protein deficient 8% casein diet starting 3wks before induction of air pouch, 6-days after which the pouch was administered with 1ml carrageenan (2%). Treatment with aspirin (200 mg/kg, p.o.) or diclofenac (20 mg/kg im.) was conducted one hour before the challenge with carrageenan. Six hours after the challenge, the local exudates were collected and subjected for total leukocyte infiltration count and IL-12 assessment. IL-1 beta and nitrate content were estimated in both plasma and air pouch infiltrate. The obtained results showed a reduction in leukocytes and decrease in IL-1 beta level in PM mice. In conclusion, PM slows the inflammatory reaction, and influences the inflammatory process differently especially in the presence of another stimulus.

Effects of IL-7 and dexamethasone: induction of CD25, the high affinity IL-2 receptor, on human CD4+ cells.

Since we have previously shown that dexamethasone (Dex) enhances the proportion of murine Treg cells, we tested the effect of IL-7, a promoter of T cell survival, together with Dex on human CD4+CD25+ Treg cells in an in vitro setting. The results showed that IL-7 in concert with Dex markedly augmented the generation of CD4+CD25+ T cells. To discern the origin of the induced CD4+CD25+ T cells, MACS-purified CD4+CD25-, and CD4+CD25+ cells were cultured in the presence of Dex and/or IL-7 for 4 days. Although two thirds of CD4+CD25- T cells became CD4+CD25+ T cells, they had no suppressive activity. In contrast, the original CD4+CD25+ T cells maintained suppressive activity after Dex/IL-7 treatment, however, there was not a significant expansion in their cell number. Dex and IL-7 did not induce additional Treg cells, but additively induced the expression of the activation marker CD25 by CD4+CD25- T cells. This combination may provide a novel means of priming CD4 T cells to respond to IL-2 and may prove useful in up-regulation of normal immune responses in immune deficient diseases.

Effects of diclofenac, piroxicam and alpha-tocopherol on monoaminelymphopoietic interfacing in mice.

The non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac (CAS 15307-79-6) and piroxicam (CAS 36322-90-4) were shown in previous works to induce bone marrow lymphopoiesis. The present work aimed at evaluating the extent to which lymphopoietic effects of the above mentioned drugs as well as their interactions with alpha-tocopherol (CAS 10191-41-0) may be reflected in changes in the tissue levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT). The study was performed in male adult mice. The doses were given once daily for 7 days. The evaluations were performed in 2 phases. First, dose-response relationships of each of diclofenac, piroxicam and alpha-tocopherol were evaluated using bone marrow lymphocytes counts and monoamines levels in plasma, brain and spleen. Then, interactions of alpha-tocopherol (10 mg/kg) with diclofenac (20 mg/kg) and piroxicam (3 mg/kg), respectively, were evaluated. The interaction evaluations included effects on bone marrow lymphocytes count, monoamines levels in plasma, brain, spleen and thymus, as well as spleen weight. The obtained findings revealed that diclofenac, piroxicam and alpha-tocopherol decreased NE and DA levels in plasma, brain and spleen. There was some correlation between the decrease in plasma NE and the bone marrow lymphopoiesis. Pre-administration of alpha-tocopherol failed to maintain monoamines levels at the range of normal values in plasma, brain and spleen of NSAIDs-treated mice except splenic DA levels. In addition, the decrease in NE level induced by administration of piroxicam or diclofenac, either alone or together with a-tocopherol, corresponded to the increase in bone marrow lymphopoiesis. The present work suggests that the diclofenac- and piroxicam-induced bone marrow lymphopolesis as well as their respective interactions with alpha-tocopherol are associated with parallel changes in monoamines levels, especially those of NE and 5-HT.