Metal toxicity poses a potential global threat to the environment and living beings. Their numerous agricultural, medical, industrial, domestic, and technological applications result in widespread distribution in the environment which raises concern on the potential effects of metals in terms of health hazards and environmental pollution. Chelation therapy has been the preferred medical treatment for metal poisoning. The chelating agent bounds metal ions to form complex cyclic structures known as 'chelates' to intensify their excretion from the body. The main disadvantage of synthetic chelators is that the chelation process removes vital nutrients along with toxic metals. Natural compounds are widely available, economical, and have minimal adverse effects compared to classical chelators. Herbal preparations can bind to the metal, reduce its absorption in the intestines, and facilitate excretion from the body. Curcumin, a bioactive substance in turmeric, is widely used as a dietary supplement. Most studies have shown that curcumin protects against metal-induced lipid peroxidation and mitigates adverse effects on the antioxidant system. This review article provides an analysis to show that curcumin imparts promising metal toxicity-ameliorative effects that are related to its intrinsic antioxidant activity.

Nutraceutical agents and food supplements are commonly used as treatment adjuncts in neuropsychiatric disorders. Curcumin, a bioactive agent obtained from the rhizome of Curcuma longa, with its antioxidant and anti-inflammatory properties, has gained much research attention in the last few decades. In this narrative review, we intend to summarize the evidence available for curcumin as an add-on agent in the management of schizophrenia. We searched PubMed/EBSCO for both human and animal trials utilizing curcumin in the management of schizophrenia. We obtained ten articles (five preclinical and five clinical) from the focused literature search. Clinical research utilizing curcumin in schizophrenia is limited to negative and cognitive symptoms. Available preclinical studies suggest curcumin's utility in ameliorating extrapyramidal and metabolic side effects when given as an adjunct with antipsychotics. Curcumin, as an add-on agent, appears promising to improve the negative and cognitive symptoms of schizophrenia. Notably, curcumin was tolerable and safe in all the randomized human clinical trials. The poor oral bioavailability is, however, a limiting factor in its widespread use.

Turmeric has been used in traditional medicine for centuries to treat a range of ailments. Its primary active constituent curcumin, can influence an array of biological activities. Many of these, such as its anti-inflammatory, antioxidant, neuroprotective, and monoaminergic effects are dysregulated in several neuropsychiatric disorders. In this systematic review, in vitro, animal, and human studies investigating the potential of curcumin as a treatment for neuropsychiatric disorders such as major depressive disorder, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), bipolar disorder, psychotic disorders, and autism are reviewed, and directions for future research are proposed. It is concluded that curcumin is a promising, natural agent for many of these conditions, however, further research utilising robust, clinical designs are essential. The problem associated with the poor oral bioavailability of standard curcumin also requires consideration. Currently the greatest support for the efficacy of curcumin is for the treatment of major depressive disorder.

Tardive dyskinesia (TD) is a serious side effect of long-term administration of typical neuroleptics, such as haloperidol. The pathophysiology of TD remains unclear, but the experimental evidence suggests that free radical-induced neuronal apoptosis in the basal ganglia may play an important role.

This study was to investigate changes in Bax and Bcl-2 expression levels in TD-associated brain regions and the effects of the antioxidant EGb761 on Bax and Bcl-2 levels in an animal model of TD.

Thirty-two rats were randomly divided into four study groups: saline control (saline), haloperidol-alone (haloperidol), EGb761-haloperidol (EGb), and alpha-tocopherol-haloperidol (vitamin E). Rats were treated with daily intraperitoneal haloperidol injections (2 mg/kg/day) for 5 weeks. EGb761 (50 mg/kg/day) and alpha-tocopherol (20 mg/kg/day) were then administered for another 5 weeks during the withdrawal period. Behavioral assessments were performed, and Bax and Bcl-2 protein expression levels were immunohistochemically analyzed in four brain regions, including the prefrontal cortex, striatum, substantia nigra, and globus pallidum.

We found that increased vacuous chewing movements (VCMs) were associated with increased proapoptotic Bax protein expression, decreased antiapoptotic Bcl-2 protein expression, and an increased Bax/Bcl-2 ratio. EGb761 and alpha-tocopherol treatment reversed the increase in VCMs, decreased Bax expression, increased Bcl-2 expression, and decreased the Bax/Bcl-2 ratio.

These results demonstrate that long-term haloperidol administration may affect Bcl-2 protein family expression and promote neuronal apoptosis in the basal ganglia. In combination with their antioxidant capacity, EGb761 and alpha-tocopherol's antiapoptotic effects through Bcl-2 might account for the symptom improvement observed in haloperidol-induced TD rats.

First- and second-generation antipsychotics (FGAs and SGAs, respectively), both inhibit cholesterol biosynthesis and impair the intracellular cholesterol trafficking, leading to lipid accumulation in the late endosome/lysosome compartment. In this study we examined if curcumin, a plant polyphenol that stimulates exosome release, can alleviate antipsychotic-induced intracellular lipid accumulation.

HepG2 hepatocarcinoma cells were treated with antipsychotics or placebo and DiI-labelled LDL for 18 h and then exposed to curcumin for the last 2 h. Cells and media were collected separately and used for biochemical analyses, electron microscopy and immunocytochemistry. Exosomes were isolated from the incubation medium by ultracentrifugation.

Curcumin treatment reduced the number of heterolysosomes and shifted their subcellular localization to the periphery, as revealed by electron microscopy, and stimulated the release of lysosomal β-hexosaminidase and exosome markers flotillin-2 and CD63 into the media. The presence of DiI in exosomes released by cells preloaded with DiI-LDL demonstrated the endolysosomal origin of the microvesicles. Furthermore, curcumin increased the secretion of cholesterol as well as LDL-derived DiI and [3H]-cholesterol, in association with a decrease of intracellular lipids. Thus, the disruption of lipid trafficking induced by FGAs or SGAs can be relieved by curcumin treatment. This polyphenol, however, did not mitigate the reduction of cholesterol esterification induced by antipsychotics.

Curcumin stimulates exosome release to remove cholesterol (and presumably other lipids) accumulated within the endolysosomal compartment, thereby normalizing intracellular lipid homeostasis. This action may help minimize the adverse metabolic effects of antipsychotic treatment, which should now be evaluated in clinical trials.

Mood disorders have been recognized by the World Health Organization (WHO) as the leading cause of disability worldwide. Notwithstanding the established efficacy of conventional mood agents, many treated individuals continue to remain treatment refractory and/or exhibit clinically significant residual symptoms, cognitive dysfunction, and psychosocial impairment. Therefore, a priority research and clinical agenda is to identify pathophysiological mechanisms subserving mood disorders to improve therapeutic efficacy. During the past decade, inflammation has been revisited as an important etiologic factor of mood disorders. Therefore, the purpose of this synthetic review is threefold: 1) to review the evidence for an association between inflammation and mood disorders, 2) to discuss potential pathophysiologic mechanisms that may explain this association and 3) to present novel therapeutic options currently being investigated that target the inflammatory-mood pathway. Accumulating evidence implicates inflammation as a critical mediator in the pathophysiology of mood disorders. Indeed, elevated levels of pro-inflammatory cytokines have been repeatedly demonstrated in both major depressive disorder (MDD) and bipolar disorder (BD) patients. Further, the induction of a pro-inflammatory state in healthy or medically ill subjects induces 'sickness behavior' resembling depressive symptomatology. Potential mechanisms involved include, but are not limited to, direct effects of pro-inflammatory cytokines on monoamine levels, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, pathologic microglial cell activation, impaired neuroplasticity and structural and functional brain changes. Anti-inflammatory agents, such as acetyl-salicylic acid (ASA), celecoxib, anti-TNF-α agents, minocycline, curcumin and omega-3 fatty acids, are being investigated for use in mood disorders. Current evidence shows improved outcomes in mood disorder patients when anti-inflammatory agents are used as an adjunct to conventional therapy; however, further research is needed to establish the therapeutic benefit and appropriate dosage.

Despite decades of research, tardive dyskinesia (TD) remains a poorly understood iatrogenic movement disorder with few effective treatments and no known cure. Accordingly, the development of an innocuous strategy to prevent or mitigate antipsychotic (AP)-associated TD would represent an important clinical advance. Supporting evidence for antioxidant (AX)-based treatment regimens can be found in the preclinical literature, where AP-induced vacuous chewing movements (VCMs) in rats are attenuated by the concurrent administration of direct and indirect AXs.

Our aim was to review the preclinical literature examining the role of AX-promoting treatments in the prevention of AP-induced VCMs in rats.

A literature search using Google Scholar and PubMed was performed. Relevant results were qualitatively reviewed.

Studies featuring a variety of naturally occurring and synthetic AX treatments were identified and included in the review. The majority of studies used haloperidol (HAL), a typical AP, to induce VCMs. Studies revealed reduced VCMs in co-treated rats, with favorable changes seen in markers of oxidative stress (OS) and AX status, but were limited by their short durations.

Some preclinical evidence suggests that the inclusion of a naturally occurring and benign AX compound as an adjunct to AP treatment may help guard patients against TD, but additional long-duration studies are needed. This AX-based strategy is further substantiated by accumulating evidence of preexisting OS abnormalities in schizophrenia (SZ).

Converging evidence suggests dysregulation of epigenetics in terms of histone-mediated acetylation/deacetylation imbalance in Parkinson's disease (PD). Targeting histone deacetylase (HDAC) in neuronal survival and neuroprotection may be beneficial in the treatment and prevention of neurodegenerative disorders. Few pharmacological studies use the transgenic model of PD to characterize the neuroprotection actions of a lead compound known to target HDAC in the brain.

In our study, we investigated neuroprotective effects of liposomal-formulated curcumin: Lipocurc™ targeting HDAC inhibitor in the DJ-1(Park 7)-gene knockout rat model of PD. Group I (DJ-1-KO-Lipocurc™) received Lipocurc™ 20 mg/kg iv 3× weekly for 8 weeks; Group II: DJ-1 KO controls (DJ-1 KO-PBS) received i.v. phosphate-buffered saline (PBS). Group III: DJ-1-Wild Type (DJ-1 WT-PBS) received PBS. We monitored various components of motor behavior, rotarod, dyskinesia, and open-field behaviors, both at baseline and at regular intervals. Toward the end of the 8 weeks, we measured neuronal apoptosis and dopamine (DA) neuron-specific tyrosine hydroxylase levels by immunohistochemistry methods at post-mortem.

We found that DJ-KO Group I and Group II, as compared with DJ-1 WT group, exhibited moderate degree of motor impairment on the rotarod test. Lipocurc™ treatment improved the motor behavior motor impairment to a greater extent than the PBS treatment. There was marked apoptosis in the DJ-1 WT group. Lipocurc™ significantly blocked neuronal apoptosis: the apoptotic index of DJ-1-KO-Lipocurc™ group was markedly reduced compared with the DJ-KO-PBS group (3.3 vs 25.0, p<0.001). We found preliminary evidence Lipocurc™ stimulated DA neurons in the substantia nigra. The ratio of immature to mature DA neurons in substantia nigra was statistically higher in the DJ-1-KO-Lipocurc™ group (p<0.025).

We demonstrated for the first time Lipocurc™'s anti-apoptotic and neurotrophic effects in theDJ-1-KO rat model of PD. Our promising findings warrant randomized controlled trial of Lipocurc™ in translating the novel nanotechnology-based epigenetics-driven drug discovery platform toward efficacious therapeutics in PD.

Schizophrenia is a mental illness characterized by a breakdown in cognition and emotion. Over the years, drug treatment for this disorder has mainly been compromised of orthosteric ligands that antagonize the active site of the dopamine D2 receptor. However, these drugs are limited in their use and often lead to the development of adverse movement and metabolic side effects. Allosteric modulators are an emerging class of therapeutics with significant advantages over orthosteric ligands, including an improved therapeutic and safety profile. This study investigates our newly developed allosteric modulator, PAOPA, which is a specific modulator of the dopamine D2 receptor. Previous studies have shown PAOPA to attenuate schizophrenia-like behavioral abnormalities in preclinical models. To advance this newly developed allosteric drug from the preclinical to clinical stage, this study examines the pharmacokinetic behavior and toxicological profile of PAOPA. Results from this study prove the effectiveness of PAOPA in reaching the implicated regions of the brain for therapeutic action, particularly the striatum. Pharmacokinetic parameters of PAOPA were found to be comparable to current market antipsychotic drugs. Necropsy and histopathological analyses showed no abnormalities in all examined organs. Acute and chronic treatment of PAOPA indicated no movement abnormalities commonly found with the use of current typical antipsychotic drugs. Moreover, acute and chronic PAOPA treatment revealed no hematological or metabolic abnormalities classically found with the use of atypical antipsychotic drugs. Findings from this study demonstrate a better safety profile of PAOPA, and necessitates the progression of this newly developed therapeutic for the treatment of schizophrenia.

Haloperidol (HP) is a widely prescribed antipsychotic drug used for the treatment of mental disorders. However, while providing therapeutic benefits, this drug also causes serious extrapyramidal side effects, such as tardive dyskinesia (TD). Upon chronic administration, HP causes behavioural supersensitivity to dopamine D2 receptor agonists, as well as the development of vacuous chewing movements (VCMs), in an animal model of human TD. Currently, a prevailing hypothesis to account for these behavioural abnormalities implicates oxidative stress. This study was undertaken to examine whether the free radical trapping agent, α-phenyl-N-tert-butylnitrone (PBN), can prevent the development of behavioural supersensitivity to dopamine D2 receptor agonists and the development of VCMs. Additionally, the study examined whether increased synthesis of apoptosis inducing factor (AIF) can result from HP-induced oxidative stress. Male Sprague-Dawley rats were treated with HP in conjunction with PBN, or its vehicle, for 4weeks. After a 24-hour washout period, behavioural observations were recorded along with the estimation of lipid peroxidation and antioxidant enzyme activities. The free radical trapping agent, PBN, prevented the development of behavioural supersensitivity, reduced lipid peroxidation and prevented the reduction of antioxidant enzyme activities. AIF concentrations at the mRNA and protein levels remained unchanged; therefore increased AIF gene expression is unlikely to be involved in HP-induced oxidative stress. The findings of the present study suggest the involvement of striatal free radicals in the development of behavioural supersensitivity, and free radical trapping agents, such as PBN, as possible options for the treatment of extrapyramidal side effects in humans.