Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis

OBJECTIVE: Inflammation has been implicated in the risk, pathophysiology, and progression of mood disorders and, as such, has become a target of interest in the treatment of bipolar disorder (BD). Therefore, the objective of the current qualitative and quantitative review was to determine the overall antidepressant effect of adjunctive anti-inflammatory agents in the treatment of bipolar depression. METHODS: Completed and ongoing clinical trials of anti-inflammatory agents for BD published prior to 15 May 15 2015 were identified through searching the PubMed, Embase, PsychINFO, and Clinicaltrials.gov databases. Data from randomized controlled trials (RCTs) assessing the antidepressant effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with standard therapy alone. RESULTS: Ten RCTs were identified for qualitative review. Eight RCTs (n = 312) assessing adjunctive nonsteroidal anti-inflammatory drugs (n = 53), omega-3 polyunsaturated fatty acids (n = 140), N-acetylcysteine (n = 76), and pioglitazone (n = 44) in the treatment of BD met the inclusion criteria for quantitative analysis. The overall effect size of adjunctive anti-inflammatory agents on depressive symptoms was -0.40 (95% confidence interval -0.14 to -0.65, p = 0.002), indicative of a moderate and statistically significant antidepressant effect. The heterogeneity of the pooled sample was low (I² = 14%, p = 0.32). No manic/hypomanic induction or significant treatment-emergent adverse events were reported. CONCLUSIONS: Overall, a moderate antidepressant effect was observed for adjunctive anti-inflammatory agents compared with conventional therapy alone in the treatment of bipolar depression. The small number of studies, diversity of agents, and small sample sizes limited interpretation of the current analysis.

Youth Depression Alleviation-Augmentation with an anti-inflammatory agent (YoDA-A): protocol and rationale for a placebo-controlled randomized trial of rosuvastatin and aspirin

AIM: There is growing support for the role of inflammation and oxidative stress in the pathophysiology of major depressive disorder (MDD). This has led to the development of novel strategies targeting inflammation in the treatment of depression. Rosuvastatin and aspirin have well-documented, anti-inflammatory and antioxidant properties. The aim of the Youth Depression Alleviation: Augmentation with an anti-inflammatory agent (YoDA-A) study is to determine whether individuals receiving adjunctive anti-inflammatory agents, aspirin and rosuvastatin experience a reduction in the severity of MDD compared with individuals receiving placebo. METHODS: YoDA-A is a 12-week triple-blind, randomized controlled trial funded by the National Health and Medical Research Council, Australia. Participants aged 15-25, with moderate-to-severe MDD, are allocated to receive either 10 mg/day rosuvastatin, 100 mg/day aspirin, or placebo, in addition to treatment as usual. Participants are assessed at baseline and at weeks 4, 8, 12 and 26. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: The study is planned to be completed in 2017. At date of publication, 85 participants have been recruited. CONCLUSION: Timely and targeted intervention for youth MDD is crucial. Given the paucity of new agents to treat youth MDD, adjunctive trials are not only pragmatic and 'real-world', but additionally aim to target shortfalls in conventional medications. This study has the potential to first provide two new adjunctive treatment options for youth MDD; aspirin and rosuvastatin. Second, this study will serve as proof of principle of the role of inflammation in MDD.

Flavour as an analytical tool : an anti-inflammatory compound in olive oil

The chemical senses have been underutilised as analytical instruments, although as detectors of chemicals our senses are highly specialised biological machines. This paper reviews the current state of knowledge of the chemical senses. A novel technique was used to isolate and identify a flavour-active non-steroidal antiinflammatory compound in virgin olive oil.

The influence of heat on biological activity and concentration of oleocanthal - a natural anti-inflammatory agent

Background – The olive oil phenolic, oleocanthal is a natural non-steroidal anti-inflammatory compound that irritates the oropharynx in a dose-dependent manner. It has been proposed that the biological activity of oleocanthal is partially responsible for the beneficial health effects of the Mediterranean diet. Virgin olive oil containing oleocanthal is often added as an ingredient in a number of cooked dishes and therefore it is of great importance to understand how best to preserve the putative health promoting benefits of this compound, as olive oil phenolics are
subject to heat degradation.

Objective – To investigate if oleocanthal is thermally degraded or its biological activity reduced during cooking.

Design – One extra virgin olive oil containing 54mg/kg oleocanthal was heated at varying temperatures (100°C, 170°C and 240°C) for set time periods (0, 1, 5, 20, 60, 90 min). Oleocanthal concentrations were quantified using HPLC and its biological activity determined with a taste bioassay measuring the intensity of throat irritation.

Outcomes – Results demonstrated that oleocanthal was heat stable compared with other olive oil phenolics, with a maximum loss of 16% as determined by HPLC analysis. In contrast, there was a significant decrease of up to 38% (p<0.05) in the biological activity of oleocanthal as determined by the taste bioassay.

Conclusions – Minimal degradation of oleocanthal concentration was observed upon heating however a significant decrease in the biological activity of this compound was noted with extended heating time. This has important implications for health in that, consumers may be unable to reap all of the putative health benefits associated with oleocanthal when adding virgin olive oil as an ingredient to dishes requiring prolonged heat treatment.

Oleocanthal, a natural anti-Inflammatory compound in extra virgin olive oil

Recent research on the olive oil phenolic, oleo canthal has led to speculation that it may confer some of the health benefits associated with a traditional Mediterranean diet. Oleocanthal produces a peppery, stinging sensation at the back of the throat similar to that of the non-steroidal anti-inflammatory drug (NSAID), ibuprofen. This led to the hypothesis that the perceptual similarity between oleocanthal and ibuprofen may indicate similar pharmacological properties. Subsequent studies have proved the hypothesis and oleocanthal was shown not only to inhibit inflammation in the same way as ibuprofen does, but it was found to be substantially more potent than this NSAID. It is important to note that inflammation has been demonstrated to playa significant role in the development of a number of chronic diseases, such as cardiovascular disease (CVD) and certain types of cancers. Therefore, as a result of dietary feeding with olive oil as a part of the traditional Mediterranean diet, a reduction in inflammation produced by oleocanthal is speculated to be the potential mechanism that is partially responsible for the health benefits associated with this dietary pattern. This review summarizes the current knowledge on oleocanthal, in tenns of its physiological and sensory properties, as well as a discussion on the factors that have the ability to affect oleocanthal concentrations in extra virgin olive oils (EVOOs).

Molecular mechanisms of inflammation : anti-inflammatory benefits of virgin olive oil and the phenolic compound oleocanthal

Chronic inflammation is a critical factor in the pathogenesis of many inflammatory disease states including cardiovascular disease, cancer, diabetes, degenerative joint diseases and neurodegenerative diseases. Chronic inflammatory states are poorly understood, however it is known that dietary habits can evoke or attenuate inflammatory responses. Popular methods to deal with inflammation and its associated symptoms involve the use of non steroidal anti-inflammatory drugs, however the use of these drugs are associated with severe side effects. Therefore, investigations concerned with natural methods of inflammatory control are warranted. A traditional Mediterranean diet has been shown to confer some protection against the pathology of chronic diseases through the attenuation of proinflammatory mediators and this has been partially attributed to the high intake of virgin olive oil accompanying this dietary regime. Virgin olive oil contains numerous phenolic compounds that exert potent anti-inflammatory actions. Of interest to this paper is the recently discovered phenolic compound oleocanthal. Oleocanthal is contained in virgin olive oil and possesses similar anti-inflammatory properties to ibuprofen. This pharmacological similarity has provoked interest in oleocanthal and the few studies conducted thus far have verified its anti-inflammatory and potential therapeutic actions. A review of the health benefits of the Mediterranean diet and antiinflammatory properties of virgin olive oil is presented with the additional emphasis on the pharmacological and anti-inflammatory properties of the phenolic compound oleocanthal.

The perceptual and anti-Inflammatory effects of oleocanthal, an olive oil phenolic

 Oleocanthal a virgin olive oil phenolic produces varying intensities of irritation in the oropharanx in individuals and is also a naturally occuring NSAID effective in reducing inflammatory markers and increasing protein synthesis in skeletal muscle cells. There may be a link between the variation in throat sensitivity to oleocanthal and its effects on muscle growth processes and inflammation.

A 'polypill' for acute tendon pain in athletes with tendinopathy?

Acute tendon pain in athletes is a condition that is difficult to manage. There are few treatment options that give adequate pain relief and have a theoretical basis for efficacy. We report the use of a novel “polypill” for tendon pain, and provide evidence for the basis for its use. We present it to stimulate discussion and research into a new area of tendinopathy.

A gene expression signature for insulin resistance

Insulin resistance is a heterogeneous disorder caused by a range of genetic and environmental factors, and we hypothesize that its aetiology varies considerably between individuals. This heterogeneity provides significant challenges to the development of effective therapeutic regimes for long-term management of type 2 diabetes. We describe a novel strategy, using large-scale gene expression profiling, to develop a Gene Expression Signature (GES) that reflects the overall state of insulin resistance in cells and patients. The GES was developed from 3T3-L1 adipocytes that were made ‘insulin resistant’ by treatment with tumour necrosis factor-alpha (TNFα) and then reversed with aspirin and troglitazone (‘re-sensitized’). The GES consisted of five genes whose expression levels best discriminated between the insulin resistant and insulin re-sensitized states. We then used this GES to screen a compound library for agents that affected the GES genes in 3T3- L1 adipocytes in a way that most closely resembled the changes seen when insulin resistance was successfully reversed using aspirin and troglitazone. This screen identified both known and new insulin sensitizing compounds including non-steroidal anti inflammatory agents, β-adrenergic antagonists, beta-lactams and sodium channel blockers. We tested the biological relevance of this GES in participants in the San Antonio Family Heart Study (n = 1,240) and showed that patients with the lowest GES scores were more insulin resistant (according to HOMA_IR and fasting plasma insulin levels, P < 0.001). These findings show that GES technology can be used for both the discovery of insulin sensitizing compounds and the characterization of patients into subtypes of insulin resistance according to GES scores, opening the possibility of developing a personalized medicine approach to type 2 diabetes.

A comparative assessment of a-lipoic acid N-phenylamides as non-steroidal androgen receptor antagonists both on and off gold nanoparticles

A group of α-lipoic acid N-phenylamides were synthesized employing a variety of amide coupling protocols utilizing electron deficient anilines. These compounds were then assessed for their ability to block androgen-stimulated proliferation of a human prostate cancer cell line, LNCaP. These structurally simple compounds displayed anti-proliferative activities at, typically, 5–20 μM concentrations and were comparable to a commonly used anti-androgen Bicalutamide®. The inclusion of a disulfide (RS-SR) moiety, serving as an anchor to several metal nanoparticle systems (Au, Ag, Fe₂O₃, etc.), does not impede any biological activity. Conjugation of these compounds to a gold nanoparticle surface resulted in a high degree of cellular toxicity, attributed to the absence of a biocompatible group such as PEG within the organic scaffold.

Sensory characterization of the irritant properties of oleocanthal, a natural anti-inflammatory agent in extra virgin olive oils

Oleocanthal is an olive oil phenolic possessing anti-inflammatory activity. Anecdotal evidence suggests that oleocanthal elicits a stinging sensation felt only at the back of the throat (oropharynx). Due to this compound possessing potentially health-benefiting properties, investigation into the sensory aspects of oleocanthal is warranted to aid in future research. The important link between the perceptual aspects of oleocanthal and health benefits is the notion that variation in sensitivity to oleocanthal irritation may relate to potential differences in sensitivity to the pharmacologic action of this compound. The current study assessed the unique irritant attributes of oleocanthal including its location of irritation, temporal profile, and individual differences in the perceived irritation. We show that the irritation elicited by oleocanthal was localized to the oropharynx (P < 0.001) with little or no irritation in the anterior oral cavity. Peak irritation was perceived 15 s postexposure and lasted over 180 s. Oleocanthal irritation was more variable among individuals compared with the irritation elicited by CO₂ and the sweetness of sucrose. There was no correlation between intensity ratings of oleocanthal and CO₂ and oleocanthal and sucrose (r = –0.15, n = 50, P = 0.92 and r = 0.17, n = 84, P = 0.12, respectively), suggesting that independent mechanisms underlie the irritation of CO₂ and oleocanthal. The unusual spatial localization and independence of acid (CO₂) sensations suggest that distinct nociceptors for oleocanthal are located in the oropharyngeal region of the oral cavity.

Influence of heat on biological activity and concentration of oleocanthal : a natural anti-inflammatory agent in virgin olive oil

The olive oil phenolic oleocanthal is a natural nonsteroidal anti-inflammatory compound that irritates the oral pharynx in a dose-dependent manner. It has been proposed that the biological activity of oleocanthal is partially responsible for the beneficial health effects of the Mediterranean diet. Virgin
olive oil containing oleocanthal is often added as an ingredient in a number of cooked dishes, and therefore it is of great importance to understand how best to preserve the putative health-promoting benefits of this compound, as olive oil phenolics are subject to degradation upon heating in general. One extra virgin olive oil containing 53.9 mg/kg oleocanthal was heated at various temperatures (100, 170, and 240 °C) for set time periods (0, 1, 5, 20, 60, and 90 min). Oleocanthal concentrations were quantified using HPLC, and its biological activity was determined with a taste bioassay measuring the intensity of throat irritation. Results demonstrated that oleocanthal was heat stable compared with other olive oil phenolics, with a maximum loss of 16% as determined by HPLC analysis. However, there was a significant decrease of up to 31% (p < 0.05) in the biological activity of oleocanthal as determined by the taste bioassay. Although there was minimal degradation of leocanthal concentration, there was a significant decrease in the biological activity of oleocanthal upon extended heating time, indicating a possible loss of the putative health -benefiting properties of oleocanthal. Alternatively, the difference in the concentration and biological activity of oleocanthal after heat treatment could be a result of an oleocanthal antagonist forming, decreasing or masking the biological activity of oleocanthal.

Gut health immunomodulatory and anti-inflammatory functions of gut enzyme digested high protein micro-nutrient dietary supplement-Enprocal

Background: Enprocal is a high-protein micro-nutrient rich formulated supplementary food designed to meet the nutritional needs of the frail elderly and be delivered to them in every day foods. We studied the potential of Enprocal to improve gut and immune health using simple and robust bioassays for gut cell proliferation, intestinal integrity/permeability, immunomodulatory, anti-inflammatory and anti-oxidative activities. Effects of Enprocal were compared with whey protein concentrate 80 (WPC), heat treated skim milk powder, and other commercially available milk derived products.

Results: Enprocal (undigested) and digested (Enprocal D) selectively enhanced cell proliferation in normal human intestinal epithelial cells (FHs74-Int) and showed no cytotoxicity. In a dose dependent manner Enprocal induced cell death in Caco-2 cells (human colon adencarcinoma epithelial cells). Digested Enprocal (Enprocal D: gut enzyme cocktail treated) maintained the intestinal integrity in transepithelial resistance (TEER) assay, increased the permeability of horseradish peroxidase (HRP) and did not induce oxidative stress to the gut epithelial cells. Enprocal D upregulated the surface expression of co-stimulatory (CD40, CD86, CD80), MHC I and MHC II molecules on PMA differentiated THP-1 macrophages in coculture transwell model, and inhibited the monocyte/lymphocyte (THP-1/Jurkat E6-1 cells)-epithelial cell adhesion. In cytokine secretion analyses, Enprocal D down-regulated the secretion of proinflammatory cytokines (IL-1β and TNF-α) and up-regulated IFN-γ, IL-2 and IL-10.

Conclusion: Our results indicate that Enprocal creates neither oxidative injury nor cytotoxicity, stimulates normal gut cell proliferation, up regulates immune cell activation markers and may aid in the production of antibodies. Furthermore, through downregulation of proinflammatory cytokines, Enprocal appears to be beneficial in reducing the effects of chronic gut inflammatory diseases such as inflammatory bowel disease (IBD). Stimulation of normal human fetal intestinal cell proliferation without cell cytotoxicity indicates it may also be given as infant food particularly for premature babies.

Effect of exercise and protein on skeletal muscle inflammatory mediators

Intense exercise results in muscular inflammation. Molecular techniques were used to identify novel inflammatory proteins in human muscle. Males and females displayed different levels of exercise-induced inflammatory proteins. Interestingly, dairy protein supplements reduced these inflammatory proteins post-exercise. Increased dietary red meat consumption, with training, had no impact on muscle inflammation, although strength gain was improved.