Epilepsy treatment requires anti-seizure medical formulations; available medications have various painful side effects and penetrate the brain–blood barrier poorly. A promising method is the use of natural clay nanocontainers for drug delivery through this membrane barrier. Halloysites (Hly) are biocompatible, 50-nm diameter tubes with a positively charged, hollow inner lumen and negatively charged outer shell and are available naturally. These characteristics enable them to be versatile as drug loaded ‘nano-torpedoes’ effectively penetrating cell membranes. The endothelial cells are a major cell type in the blood–brain barrier that provides for the selective permeability separating the circulating blood and allowing only the passage of glucose, water, and amino acids, but not traditional drug formulations. Nanotubes encapsulating rhodamine isothiocyanate and ionomycin penetration through the rat-brain microvascular endothelial cells followed by a prolonged 24-h drug release was demonstrated. A model membrane was set up across 0.4-μm-pore polystyrene transwell supports covered by seeding endothelial and astrocyte cells to mimic the blood–brain barrier in vivo. This barrier demonstrated a dual permeation mechanism (inter-cell accumulation and through-passing) for loaded Hlys, exploiting the potential of this nanoclay in the trans-membrane delivery of drugs. Use of Hly nanotubes as drug carriers to penetrate the brain microvascular endothelial barrier and to deliver the payload displayed a new approach for the treatment of brain diseases such as epilepsy.

The golden spice turmeric with its main bioactive component curcumin is one of the most popular and extensively studied nutraceuticals. Despite numerous pre-clinical studies reporting positive pharmacodynamics of turmeric extracts and curcumin, the main issues in translating the pharmacological effects to clinical efficacy have been to overcome its poor pharmacokinetics and to deliver significant amounts of the biologically relevant forms of the actives to various tissues. This review is aimed at providing a first critical evaluation of the current published literature with the novel curcumagalactomannoside (CGM) formulation of curcumin using fenugreek galactomannan dietary fibre, specifically designed to address curcumin poor pharmacokinetics. We describe CGM and its technology as a food-grade formulation to deliver ‘free’ unconjugated curcuminoids with enhanced bioavailability and improved pharmacokinetic properties. The therapeutic relevance of improving bioavailability of ‘free’ curcuminoids and some of the technical challenges in the measurement of the ‘free’ form of curcuminoids in plasma and tissues are also discussed. A total of twenty-six manuscripts are reviewed here, including fourteen pre-clinical and twelve clinical studies that have investigated CGM pharmacokinetics, safety and efficacy in various animal models and human conditions. Overall current scientific evidence suggests CGM formulation has improved bioavailability and tissue distribution of the biologically relevant unconjugated forms of turmeric actives called ‘free’ curcuminoids that may be responsible for the superior clinical outcomes reported with CGM treatments in comparison with unformulated standard curcumin across multiple studies.

The blood-brain barrier (BBB) is an important internal barrier. Herein, the electron microscope examination of duck BBB was performed during the brain development. Meanwhile, the genes/proteins of tight junctions (TJs) including zonula occludens-1, occludin, and claudin-5 in the duck brain were detected by Q-PCR and immunohistochemistry. The results showed the density of capillaries in the brain gradually increased during the embryonic period. The generation of the BBB and the specialization of its components occurred mainly in the embryonic stage. During this period, the endothelial cells (ECs) became thinner and pinocytic vesicles decreased; the TJs between EC membranes became longer and more electron-dense; the basement membrane surrounding ECs and pericytes gradually thickened; and the astrocyte foot processes appeared to wrap around the vessels. By the day of hatching (P1), the whole set of duck BBB structures was completely assembled and gradually improved in the subsequent growth process. Interestingly, compared with the cerebrum and cerebellum, the maturity level of the midbrain BBB was earlier seen during the embryonic stage. The expression of TJs increased during the embryonic period and remained stable by post-hatching. The study systematically investigated the histochemical and ultrastructural features of duck BBB during development and explored the corresponding relationship between structure and function.

With growing and ageing populations, the incidence of dementia is expected to triple globally by 2050. In the absence of effective drugs to treat or reverse the syndrome, dietary approaches which prevent or delay disease onset have considerable population health potential. Prospective epidemiological studies and mechanistic insight from experimental models strongly support a positive effect of a high fish and long chain n-3 fatty acid (EPA and DHA) intake on a range of cognitive outcomes and dementia risk, with effect sizes equivalent to several years of ageing between the highest and lowest consumers. As reviewed here, an effect of EPA and DHA on neuroinflammation and oxylipin production is likely to in part mediate the neurophysiological benefits. However, randomised controlled trials (RCTs) with EPA and DHA supplementation have produced mixed findings. Insight into the likely modulators of response to intervention and factors which should be considered for future RCTs are given. Furthermore, the impact of APOE genotype on disease risk and response to EPA and DHA supplementation is summarised. The prevalence of dementia is several-fold higher in APOE4 females (about 13% Caucasian populations) relative to the general population, who are emerging as a subgroup who may particularly benefit from DHA intervention, prior to the development of significant pathology.

The past decade has seen a surge of reports and investigations into cases of autoimmune-mediated encephalitis. The increasing recognition of these disorders is especially of relevance to the fields of neurology and psychiatry. Autoimmune encephalitis involves antibodies against synaptic receptors, neuronal cell surface proteins and intracellular targets. These disorders feature prominent symptoms of cognitive impairment and behavioural changes, often associated with the presence of seizures. Early in the clinical course, autoimmune encephalitis may manifest as psychiatric symptoms of psychosis and involve psychiatry as an initial point of contact. Although commonly associated with malignancy, these disorders can present in the absence of an inciting neoplasm. The identification of autoimmune encephalitis is of clinical importance as a large proportion of individuals experience a response to immunotherapy. This review focuses on the current state of knowledge on n-methyl-d-aspartate (NMDA) receptor-associated encephalitis and limbic encephalitis, the latter predominantly involving antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, the γ-aminobutyric acid (GABA)B receptor and leucine-rich glioma-inactivated 1 (LGI1) protein. In addition, we briefly describe anti-dopamine D2 receptor encephalitis. A summary of the literature will focus on common clinical presentations and course, diagnostic approaches and response to treatment. Since a substantial proportion of patients with autoimmune encephalitis exhibit symptoms of psychosis, the relevance of this disorder to theories of psychosis and schizophrenia will also be discussed.

Studies show that vitamin D (vit-D) (25(OH)D), the bioactive metabolite (1,25(OH)2D3) and vit-D receptors (vit-D receptor; protein disulphide isomerase, family A member 3) are expressed throughout the brain, particularly in regions pivotal to learning and memory. This has led to the paradigm that avoiding vit-D deficiency is important to preserve cognitive function. However, presently, it is not clear if the common clinical measure of serum 25(OH)D serves as a robust surrogate marker for central nervous system (CNS) homeostasis or function. Indeed, recent studies report CNS biosynthesis of endogenous 25(OH)D, the CNS expression of the CYP group of enzymes which catalyse conversion to 1,25(OH)2D3 and thereafter, deactivation. Moreover, in the periphery, there is significant ethnic/genetic heterogeneity in vit-D conversion to 1,25(OH)2D3 and there is a paucity of studies which have actually investigated vit-D kinetics across the cerebrovasculature. Compared with peripheral organs, the CNS also has differential expression of receptors that trigger cellular response to 1,25(OH)2D3 metabolites. To holistically consider the putative association of peripheral (blood) abundance of 25(OH)D on cognitive function, herein, we have reviewed population and genetic studies, pre-clinical and clinical intervention studies and moreover have considered potential confounders of vit-D analysis.

It has been nearly 70 years since the discovery that strict adherence to a diet low in phenylalanine prevents severe neurological sequelae in patients with phenylalanine hydroxylase deficiency (phenylketonuria; PKU). Today, dietary treatment with restricted phenylalanine intake supplemented with non-phenylalanine amino acids to support growth and maintain a healthy body composition remains the mainstay of therapy. However, a better understanding is needed of the factors that influence N balance in the context of amino acid supplementation. The aim of the present paper is to summarise considerations for improving N balance in patients with PKU, with a focus on gaining greater understanding of amino acid absorption, disposition and utilisation. In addition, the impact of phenylalanine-free amino acids on 24 h blood phenylalanine/tyrosine circadian rhythm is evaluated. We compare the effects of administering intact protein v. free amino acid on protein metabolism and discuss the possibility of improving outcomes by administering amino acid mixtures so that their absorption profile mimics that of intact protein. Protein substitutes with the ability to delay absorption of phenylalanine and tyrosine, mimicking physiological absorption kinetics, are expected to improve the rate of assimilation into protein and minimise fluctuations in quantitative plasma amino acid levels. They may also help maintain normal glycaemia and satiety sensation. This is likely to play an important role in improving the management of patients with PKU.

The present review examines the pig as a model for physiological studies in human subjects related to nutrient sensing, appetite regulation, gut barrier function, intestinal microbiota and nutritional neuroscience. The nutrient-sensing mechanisms regarding acids (sour), carbohydrates (sweet), glutamic acid (umami) and fatty acids are conserved between humans and pigs. In contrast, pigs show limited perception of high-intensity sweeteners and NaCl and sense a wider array of amino acids than humans. Differences on bitter taste may reflect the adaptation to ecosystems. In relation to appetite regulation, plasma concentrations of cholecystokinin and glucagon-like peptide-1 are similar in pigs and humans, while peptide YY in pigs is ten to twenty times higher and ghrelin two to five times lower than in humans. Pigs are an excellent model for human studies for vagal nerve function related to the hormonal regulation of food intake. Similarly, the study of gut barrier functions reveals conserved defence mechanisms between the two species particularly in functional permeability. However, human data are scant for some of the defence systems and nutritional programming. The pig model has been valuable for studying the changes in human microbiota following nutritional interventions. In particular, the use of human flora-associated pigs is a useful model for infants, but the long-term stability of the implanted human microbiota in pigs remains to be investigated. The similarity of the pig and human brain anatomy and development is paradigmatic. Brain explorations and therapies described in pig, when compared with available human data, highlight their value in nutritional neuroscience, particularly regarding functional neuroimaging techniques.

Curcumin derived from turmeric is well documented for its anti-carcinogenic, antioxidant and anti-inflammatory properties. Recent studies show that curcumin also possesses neuroprotective and cognitive-enhancing properties that may help delay or prevent neurodegenerative diseases, including Alzheimer’s disease (AD). Currently, clinical diagnosis of AD is onerous, and it is primarily based on the exclusion of other causes of dementia. In addition, phase III clinical trials of potential treatments have mostly failed, leaving disease-modifying interventions elusive. AD can be characterised neuropathologically by the deposition of extracellular β amyloid (Aβ) plaques and intracellular accumulation of tau-containing neurofibrillary tangles. Disruptions in Aβ metabolism/clearance contribute to AD pathogenesis. In vitro studies have shown that Aβ metabolism is altered by curcumin, and animal studies report that curcumin may influence brain function and the development of dementia, because of its antioxidant and anti-inflammatory properties, as well as its ability to influence Aβ metabolism. However, clinical studies of curcumin have revealed limited effects to date, most likely because of curcumin’s relatively low solubility and bioavailability, and because of selection of cohorts with diagnosed AD, in whom there is already major neuropathology. However, the fresh approach of targeting early AD pathology (by treating healthy, pre-clinical and mild cognitive impairment-stage cohorts) combined with new curcumin formulations that increase bioavailability is renewing optimism concerning curcumin-based therapy. The aim of this paper is to review the current evidence supporting an association between curcumin and modulation of AD pathology, including in vitro and in vivo studies. We also review the use of curcumin in emerging retinal imaging technology, as a fluorochrome for AD diagnostics.

Some dietary fats are a risk factor for Alzheimer's disease (AD) but the mechanisms for this association are presently unknown. In the present study we showed in wild-type mice that chronic ingestion of SFA results in blood–brain barrier (BBB) dysfunction and significant delivery into the brain of plasma proteins, including apo B lipoproteins that are endogenously enriched in amyloid-β (Aβ). Conversely, the plasma concentration of S100B was used as a marker of brain-to-blood leakage and was found to be increased two-fold because of SFA feeding. Consistent with a deterioration in BBB integrity in SFA-fed mice was a diminished cerebrovascular expression of occludin, an endothelial tight junction protein. In contrast to SFA-fed mice, chronic ingestion of MUFA or PUFA had no detrimental effect on BBB integrity. Utilising highly sensitive three-dimensional immunomicroscopy, we also showed that the cerebral distribution and co-localisation of Aβ with apo B lipoproteins in SFA-fed mice are similar to those found in amyloid precursor protein/presenilin-1 (APP/PS1) amyloid transgenic mice, an established murine model of AD. Moreover, there was a strong positive association of plasma-derived apo B lipoproteins with cerebral Aβ deposits. Collectively, the findings of the present study provide a plausible explanation of how dietary fats may influence AD risk. Ingestion of SFA could enhance peripheral delivery to the brain of circulating lipoprotein–Aβ and exacerbate the amyloidogenic cascade.

Little is known about the aetiology of brain tumours. One putative factor suggested from animal models is a protective effect of dietary Zn. We tested the hypothesis that increased compared with low dietary Zn intake is protective against brain tumour development. We conducted a population-based case–control study in the UK, of adults aged 18–69 years, between 2001 and 2004 aiming to identify possible risk factors. Dietary information was collected from 637 cases diagnosed with a glioma or meningioma, and 876 controls. Data were obtained from a self-completed FFQ. Multivariate logistic regression analysis was conducted, adjusting for socio-demographic factors, season of questionnaire return, multivitamin supplementation and energy intake. Although a weak protective effect was observed for the third quartile of intake (normal compared with low intake) in the meningioma group, this was limited to the specific brain tumour subtype and quartile, and was not significant after also adjusting for intake of other elements. Overall there was no significant effect of Zn intake. No association or dose–response relationship was observed between increased compared with low Zn intake and risk of glioma or meningioma.

An uncontrolled rise in intracranial pressure is probably the most common cause of death in traumatic brain-injured patients. The intracranial pressure rise is often due to cerebral oedema. Diffusion-weighted imaging has been extensively used to study cerebral oedema formation after trauma in experimental studies. Nevertheless, this technology is difficult to perform at the acute phase, especially in unstable head trauma patients. For these reasons, a safe examination allowing us to better understand the pathophysiology of cerebral oedema formation in such patients would be of great interest. Radiological attenuation is linearly correlated with estimated specific gravity in human tissue. This property gives the opportunity to measure in vivo the volume, weight and specific gravity of any tissue by computed tomography. We recently developed a software package (BrainView) for Windows workstations, providing semi-automatic tools for brain analysis from DICOM images obtained from cerebral computed tomography. In this review, we will discuss the results of the in vivo analysis of brain weight, volume and specific gravity and consider the use of this software as a new technology to improve our knowledge of cerebral oedema formation after trauma and to evaluate the severity of traumatic brain-injured patients.

The blood–brain barrier (BBB) is a specialized tissue interface that provides an important homeostatic and immunosurveillance role in the CNS. Unlike most microvascular tissues, which readily promote paracellular passage of solutes and macromolecules, the BBB is more analogous to polarized mucosal epithelia that restrict such permeability in order to prevent disease onset. Recent transgenic ablation studies have demonstrated that the BBB and mucosal tissues also share a requirement for astroglial-regulated barrier integrity. This review highlights the emerging concept that astroglia regulate barrier function at markedly different tissue interfaces. It also explores possible lessons that might be learnt by adopting epithelial model paradigms of the BBB. For example, novel glial-derived S-nitrosylation signals that regulate intestinal permeability in the digestive tract might provide new mechanistic insights into the function of the BBB. A better understanding of such universal mechanisms for barrier regulation will facilitate novel therapeutic strategies that target permeability disorders at CNS and mucosal tissue interfaces.

The role of T-cells in development of experimental cerebral malaria was analysed in C57B1/6J and C57B1/10 mice infected with Plasmodium berghei K173 or Plasmodium berghei ANKA by treatment with anti-CD4 or anti-CD8 mAbs. Mice were protected against cerebral malaria (CM) when anti-CD4 or anti-CD8 mAbs were injected before or during infection. Even in mice in end-stage disease, i.e. with a body temperature below 35·5 °C, treatment with anti-CD4 or anti-CD8 antibodies or the combination protected against CM, whereas chloroquine treatment was completely ineffective in inhibiting further development of the cerebral syndrome.