Food-Derived Peptides: Beneficial CNS Effects and Cross-BBB Transmission Strategies.

Food-derived peptides, as dietary supplements, have significant effects on promoting brain health and relieving central nervous system (CNS) diseases. However, the blood-brain barrier (BBB) greatly limits their in-brain bioavailability. Thus, overcoming the BBB to target the CNS is a major challenge for bioactive peptides in the prevention and treatment of CNS diseases. This review discusses improvement in the neuroprotective function of food-derived active peptides in CNS diseases, as well as the source of BBB penetrating peptides (BBB-shuttles) and the mechanism of transmembrane transport. Notably, this review also discusses various peptide modification methods to overcome the low permeability and stability of the BBB. Lipification, glycosylation, introduction of disulfide bonds, and cyclization are effective strategies for improving the penetration efficiency of peptides through the BBB. This review provides a new prospective for improving their neuroprotective function and developing treatments to delay or even prevent CNS diseases.

Central inhibition prevents the in vivo acute toxicity of harmine in mice.

BACKGROUND: Harmine is a ß-carboline alkaloid that displays antidepressant, antitumor and other pharmacological effects. However, the strong toxic effects limit its clinical application, and should be first considered. PURPOSE: To evaluate the in vivo toxicity of harmine and explore intervention strategies against its toxicity. METHODS: The in vivo toxicity of harmine was assessed from the symptoms, biochemical indices, and cardiovascular effects in mice. The intervention experiments were performed by using anesthetics, central drugs, and peripheral anticholinergics. RESULTS: The acute toxicity of harmine is significantly dose-dependent and the median lethal dose is 26.9 mg/kg in vivo. The typical symptoms include convulsion, tremor, jumping, restlessness, ataxia, opisthotonos, and death; it also changes cardiovascular function. The anesthetics improved the survival rate and abolished the symptoms after harmine poisoning. Two central inhibitors, benzhexol and phenytoin sodium, uniformly improved the survival rates of mice poisoned with harmine. The peripheral anticholinergics didn't show any effects. CONCLUSION: Harmine exposure leads to central neurological symptoms, cardiovascular effects and even death through direct inhibition of the central AChE activity, where the death primarily comes from central neurological symptoms and is cooperated by the secondary cardiovascular collapse. Central inhibition prevents the acute toxicity of harmine, and especially rapid gaseous anesthetics such as isoflurane, might have potential application in the treatment of harmine poisoning.

Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46-/- mice.

Mitochondrial disorders are the result of nuclear and mitochondrial DNA mutations that affect multiple organs, with the central and peripheral nervous system often affected. Currently, there is no cure for mitochondrial disorders. Currently, gene therapy offers a novel approach for treating monogenetic disorders, including nuclear genes associated with mitochondrial disorders. We utilized a mouse model carrying a knockout of the mitochondrial fusion-fission-related gene solute carrier family 25 member 46 (Slc25a46) and treated them with neurotrophic AAV-PHP.B vector carrying the mouse Slc25a46 coding sequence. Thereafter, we used immunofluorescence staining and western blot to test the transduction efficiency of this vector. Toluidine blue staining and electronic microscopy were utilized to assess the morphology of optic and sciatic nerves following treatment, and the morphology and respiratory chain activity of mitochondria within these tissues were determined as well. The adeno-associated virus (AAV) vector effectively transduced in the cerebrum, cerebellum, heart, liver and sciatic nerves. AAV-Slc25a46 treatment was able to rescue the premature death in the mutant mice (Slc25a46-/-). The treatment-improved electronic conductivity of the peripheral nerves increased mobility and restored mitochondrial complex activities. Most notably, mitochondrial morphology inside the tissues of both the central and peripheral nervous systems was normalized, and the neurodegeneration, chronic neuroinflammation and loss of Purkinje cell dendrites observed within the mutant mice were alleviated. Overall, our study shows that AAV-PHP.B's neurotrophic properties are plausible for treating conditions where the central nervous system is affected, such as many mitochondrial diseases, and that AAV-Slc25a46 could be a novel approach for treating SLC25A46-related mitochondrial disorders.

Neuroprotective effects of anthocyanins and its major component cyanidin-3-O-glucoside (C3G) in the central nervous system: An outlined review.

Anthocyanins, a class of water soluble flavonoids extracted from plants like berries and soybean seed, have been shown to display obvious anti-oxidative, anti-inflammatory, and anti-apoptotic activities. They are recommended as a supplementation for prevention and/or treatment of disorders ranging from cardiovascular disease, metabolic syndrome, and cancer. In the central nervous system (CNS), anthocyanins and its major component cyanidin-3-O-glucoside (C3G) have been reported to produce preventive and/or therapeutic activities in a wide range of disorders, such as cerebral ischemia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and glioblastoma. Both anthocyanins and C3G can also affect some important processes in aging, including neuronal apoptosis and death as well as learning and memory impairment. Further, the anthocyanins and C3G have been shown to prevent neuro-toxicities induced by different toxic factors, such as lipopolysaccharide, hydrogen peroxide, ethanol, kainic acid, acrolein, glutamate, and scopolamine. Mechanistic studies have shown that inhibition of oxidative stress and neuroinflammation are two critical mechanisms by which anthocyanins and C3G produce protective effects in CNS disorder prevention and/or treatment. Other mechanisms, including suppression of c-Jun N-terminal kinase (JNK) activation, amelioration of cellular degeneration, activation of the brain-derived neurotrophic factor (BDNF) signaling, and restoration of Ca2+ and Zn2+ homeostasis, may also mediate the neuroprotective effects of anthocyanins and C3G. In this review, we summarize the pharmacological effects of anthocyanins and C3G in CNS disorders as well as their possible mechanisms, aiming to get a clear insight into the role of anthocyanins in the CNS.

A Higher Mediterranean Diet Score, Including Unprocessed Red Meat, Is Associated with Reduced Risk of Central Nervous System Demyelination in a Case-Control Study of Australian Adults.

BACKGROUND: The evidence associating diet and risk of multiple sclerosis (MS) is inconclusive. OBJECTIVES: The aim of this study was to investigate associations between a Mediterranean diet and risk of a first clinical diagnosis of central nervous system demyelination (FCD), a common precursor to MS. METHODS: We used data from the 2003-2006 Ausimmune Study, an Australian multicenter, case-control study examining environmental risk factors for FCD, with participants matched on age, sex, and study region (282 cases, 558 controls; 18-59 y old; 78% female). The alternate Mediterranean diet score (aMED) was calculated based on data from a food-frequency questionnaire. We created a modified version of the aMED (aMED-Red) where ∼1 daily serving (65 g) of unprocessed red meat received 1 point. All other components remained the same as aMED. Conditional logistic regression (254 cases, 451 controls) was used to test associations between aMED and aMED-Red scores and categories and risk of FCD, adjusting for history of infectious mononucleosis, serum 25-hydroxyvitamin D concentrations, smoking, education, total energy intake, and dietary underreporting. RESULTS: There was no statistically significant association between aMED and risk of FCD [per 1-SD increase in aMED score: adjusted odds ratio (aOR): 0.89; 95% CI: 0.75, 1.06; P = 0.181]. There was evidence of a nonlinear relation between aMED-Red and risk of FCD when a quadratic term was used (P = 0.016). Compared with the lowest category of aMED-Red, higher categories were significantly associated with reduced risk of FCD, corresponding to a 37% (aOR: 0.63; 95% CI: 0.41, 0.98; P = 0.039), 52% (aOR: 0.48; 95% CI: 0.28, 0.83; P = 0.009), and 42% (aOR: 0.58; 95% CI: 0.35, 0.96; P = 0.034) reduced risk of FCD in categories 2, 3, and 4, respectively. CONCLUSIONS: A Mediterranean diet, including unprocessed red meat, was associated with reduced risk of FCD in this Australian adult population. The addition of unprocessed red meat to a Mediterranean diet may be beneficial for those at high risk of MS.

Tea Polyphenols in Promotion of Human Health.

Tea is the most widely used beverage worldwide. Japanese and Chinese people have been drinking tea for centuries and in Asia, it is the most consumed beverage besides water. It is a rich source of pharmacologically active molecules which have been implicated to provide diverse health benefits. The three major forms of tea are green, black and oolong tea based on the degree of fermentation. The composition of tea differs with the species, season, leaves, climate, and horticultural practices. Polyphenols are the major active compounds present in teas. The catechins are the major polyphenolic compounds in green tea, which include epigallocatechin-3-gallate (EGCG), epigallocatechin, epicatechin-3-gallate and epicatechin, gallocatechins and gallocatechin gallate. EGCG is the predominant and most studied catechin in green tea. There are numerous evidences from cell culture and animal studies that tea polyphenols have beneficial effects against several pathological diseases including cancer, diabetes and cardiovascular diseases. The polyphenolic compounds present in black tea include theaflavins and thearubigins. In this review article, we will summarize recent studies documenting the role of tea polyphenols in the prevention of cancer, diabetes, cardiovascular and neurological diseases.

A systematic review on the neuroprotective perspectives of beta-caryophyllene.

Beta (ß)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect. This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords "beta (ß)-caryophyllene" and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action. A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer's disease. Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.

Intravenous C16 and angiopoietin-1 improve the efficacy of placenta-derived mesenchymal stem cell therapy for EAE.

The placenta has emerged as an attractive source of mesenchymal stem cells (MSCs) because of the absence of ethical issues, non-invasive access, and abundant yield. However, inflammatory cell invasion into grafts negatively impacts the survival and efficacy of transplanted cells. Previous studies have shown that synthetic C16 peptide can competitively block the transmigration of leukocytes into the central nerve system, while angiopoietin-1 (Ang-1) can inhibit inflammation-induced blood vessel leakage and inflammatory cell infiltration in rats with experimental allergic encephalomyelitis (EAE). In this study, we investigated the effects of intravenous administration of C16 and Ang-1 on the efficacy of placenta-derived MSC (PMSC) transplantation in a rat model of EAE. We found that, compared with PMSCs alone, treatment with PMSCs along with intravenously administered C16 and Ang-1 was more effective at ameliorating demyelination/neuronal loss and neurological dysfunction, reducing inflammatory cell infiltration, perivascular edema, and reactive astrogliosis (p < 0.05). Mechanistic studies revealed that intravenous C16 and Ang-1 increased PMSC engraftment in the central nervous system and promoted expression of the neurotropic proteins brain-derived neurotrophic factor, growth-associated protein 43, and p75 neurotrophin receptor as well as the neuronal-glial lineage markers neurofilament protein 200 and myelin basic protein in the engrafted PMSCs.

The Neuroprotective Effects of Phenolic Acids: Molecular Mechanism of Action.

The neuroprotective role of phenolic acids from food has previously been reported by many authors. In this review, the role of phenolic acids in ameliorating depression, ischemia/reperfusion injury, neuroinflammation, apoptosis, glutamate-induced toxicity, epilepsy, imbalance after traumatic brain injury, hyperinsulinemia-induced memory impairment, hearing and vision disturbances, Parkinson's disease, Huntington's disease, anti-amyotrophic lateral sclerosis, Chagas disease and other less distributed diseases is discussed. This review covers the in vitro, ex vivo and in vivo studies concerning the prevention and treatment of neurological disorders (on the biochemical and gene expression levels) by phenolic acids.

Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair.

A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies. The only known negative regulators of cyclic nucleotides are a family of enzymes called phosphodiesterases (PDEs) that hydrolyze cyclic nucleotides into adenosine monophosphate (AMP) or guanylate monophosphate (GMP). Herein, we discuss the structure and physiological function as well as the roles PDEs play in pathological processes of the diseased or injured CNS. Further we review the approaches that have been employed therapeutically in experimental paradigms to block PDE expression or activity and in turn elevate cyclic nucleotide levels to mediate neuroprotection or neurorepair as well as discuss both the translational pathway and current limitations in moving new PDE-targeted therapies to the clinic.

[Irbesartan reduces inflammatory response of central nervous system in a rat model of fluid percussion brain injury].

Objective To investigate the neuroprotective effect of the angiotensin II receptor 1 (AT1) antagonist irbesartan on rat models with lateral fluid percussion brain injury (FPBI). Methods FPBI models were prepared using a modified fluid percussion injury method. Before and after modeling, irbesartan was given to the rats. The regional cerebral blood flow (rCBF) was monitored by laser Doppler flowmetry. Neurologic status was evaluated before and 1, 3, 5, 7 days after FPBI surgery. Brains were removed for immunohistochemical evaluation of active microglias and macrophages. Results Compared to sham group, the rCBF and neurologic score of FPBI rats decreased significantly, while microglia and macrophage activation were confirmed. Treatment with irbesartan before FPBI surgery increased rCBF and improved neurological functions. In the peri-infarct cortex, irbesartan treatment attenuated the invasion of activated microglias and macrophages on day 7 after FPBI surgery. Conclusion Irbesartan can play a neuroprotective role through inhibiting microglia and macrophage activation in FPBI rats.

Polymer-induced central nervous system complications following vascular procedures: spectrum of iatrogenic injuries and review of outcomes.

Polymer substances are commonly applied as surface coatings on endovascular catheters and vascular devices. Adverse effects related to their use have been reported, although the overall clinical significance and appropriate methods of detection of these complications have been unclear. In this analysis, we systematically reviewed clinical and diagnostic features in 32 patients (age, 36-87years; mean, 59years) in whom intracranial polymer reactions were documented following vascular interventions. Associated neuroradiologic and neuropathologic findings were variable and included cerebral vasculitis or vasculopathy (63%), abscess or granuloma formation (38%), ischemic infarcts (28%), parenchymal hematomas (28%), white matter change (25%), and/or chemical meningitis (22%). Location(s) of polymer reactions varied and included sites adjacent to and/or downstream from instrument insertion or implantation. Presenting clinical signs included focal neurologic deficits (41%), headache (22%), constitutional symptoms (19%), meningitis (16%), seizure and/or involuntary movements (9%), coma (6%), and syncope (3%). Adverse outcomes included stroke (31%), death (28%), delayed communicating hydrocephalus (9%), steroid dependency (9%), steroid complications (6%), and cerebral volume loss (3%). In some cases, these complications necessitated increased cost and length of medical care. In this review, we highlight the diverse features of polymer-induced reactions involving the central nervous system and summarize distinct diagnostic patterns that may enable earlier premortem detection of these lesions in the postprocedural clinical setting. Further work in this area is necessary to identify additional etiologic, preventative and therapeutic strategies. These data have potentially broad implications pertaining to the safety, efficacy, standards of use, storage, manufacturing, and regulation of new and emerging vascular devices and polymer nanotechnologies.

Strategies for the Prevention of Central Nervous System Complications in Patients with Langerhans Cell Histiocytosis: The Problem of Neurodegenerative Syndrome.

Diseases of the central nervous system (CNS) are common in patients with Langerhans cell histiocytosis (LCH). Besides active LCH lesions, neurodegenerative (ND) lesions of the cerebellum and/or basal ganglia may occur as late sequelae of LCH. While the etiology of this ND disease remains unclear, biomarkers in cerebrospinal fluid (CSF) may reflect the activity of CNS disease in these patients. However, no well-planned CSF studies have yet been performed in patients at high risk for ND-CNS-LCH. Potential parallels with other neuroinflammatory/neurodegenerative disease suggest the utility of examining these other disorders in establishing strategies for the prevention and/or treatment of ND-CNS-LCH.

Gender-related protection from or vulnerability to severe CNS diseases: gonado-structural and/or gonado-activational? A meta-analysis of relevant epidemiological studies.

BACKGROUND: A vast scientific literature has dealt with gender-specific risk for brain disorder. That field is evolving toward a consensus to the effect that the estrogen hormone family is outstandingly and uniquely neuroprotective. However, the epidemiology relevant to this general outlook remains piecemeal. METHOD: The present investigation strategically formats the relevant epidemiological findings around the world in order to quantitatively meta-analyze gender ratio of risk for a variety of relevant severe central nervous system (CNS) diseases at all three gonadal stages of the life cycle, pre pubertal, post adolescent/pre menopausal, and post menopausal. RESULTS: The data quantitatively establish that (1) no single epidemiological study should be cited as evidence of gender-specific neuroprotection against the most common severe CNS diseases because the gender-specific risk ratios are contradictory from one study to the other; (2) risk for severe CNS disease is indeed significantly gender-specific, but either gender can be protected: it depends on the disease, not at all on the age bracket. CONCLUSION: Our assay of gender-specific risk for severe brain disease around the world has not been able to support the idea according to which any one gender-prevalent gonadal steroid hormone dominates as a neuroprotective agent at natural concentrations.

Neuroprotective potential of silymarin against CNS disorders: insight into the pathways and molecular mechanisms of action.

Silymarin, a C25 containing flavonoid from the plant Silybum marianum, has been the gold standard drug to treat liver disorders associated with alcohol consumption, acute and chronic viral hepatitis, and toxin-induced hepatic failures since its discovery in 1960. Apart from the hepatoprotective nature, which is mainly due to its antioxidant and tissue regenerative properties, Silymarin has recently been reported to be a putative neuroprotective agent against many neurologic diseases including Alzheimer's and Parkinson's diseases, and cerebral ischemia. Although the underlying neuroprotective mechanism of Silymarin is believed to be due to its capacity to inhibit oxidative stress in the brain, it also confers additional advantages by influencing pathways such as ß-amyloid aggregation, inflammatory mechanisms, cellular apoptotic machinery, and estrogenic receptor mediation. In this review, we have elucidated the possible neuroprotective effects of Silymarin and the underlying molecular events, and suggested future courses of action for its acceptance as a CNS drug for the treatment of neurodegenerative diseases.

Central nervous system prophylaxis with intrathecal liposomal cytarabine in diffuse large B-cell lymphomas.

INTRODUCTION:  Central nervous system (CNS) involvement is a serious and potentially fatal complication in patients with lymphoma because it is associated with a particularly poor prognosis (median progression­free survival [PFS] of 4-6 months). Although CNS prophylaxis is considered necessary, there are no clear guidelines on identifying high­risk patients or selecting treatment regimen.  OBJECTIVES:  The aim of the study was to assess the safety and efficacy of CNS prophylaxis with intrathecal liposomal cytarabine. PATIENTS AND METHODS:  We analyzed the data of 79 patients (46 men and 33 women; median age, 48.5 years [20-79]) with diffuse large B­cell lymphoma (83.5% of the patients) and primary mediastinal large B­cell lymphoma (16.5%). Patients were treated in the departments of hematology in Kraków and Wroclaw, Poland, between the years 2009-2012. They were considered to be at a high risk of developing CNS involvement associated with a lymphoma. RESULTS:  Adverse reactions after intrathecal liposomal cytarabine were reported in 59 patients (74.7%); in 7 cases, the reactions were severe. The most common side effect was headache (67.1%). During antilymphoma therapy and prophylaxis, the functional status assessed by the Karnofsky score improved in 56 patients (70.9%) and remained unchanged in the remaining cases. A median follow­up time did not exceed 28 months (range, 1.4-52.1); during follow­up, neither median overall survival (OS) nor PFS were reached (projected OS and PFS at 48 months are 86.1% and 90.1%, respectively).  CONCLUSIONS:  Our results encourage the use of intrathecal liposomal cytarabine in CNS prophylaxis in patients with lymphoma.

Vitamin D and the central nervous system.

Vitamin D is formed in human epithelial cells via photochemical synthesis and is also acquired from dietary sources. The so-called classical effect of this vitamin involves the regulation of calcium homeostasis and bone metabolism. Apart from this, non-classical effects of vitamin D have recently gained renewed attention. One important yet little known of the numerous functions of vitamin D is the regulation of nervous system development and function. The neuroprotective effect of vitamin D is associated with its influence on neurotrophin production and release, neuromediator synthesis, intracellular calcium homeostasis, and prevention of oxidative damage to nervous tissue. Clinical studies suggest that vitamin D deficiency may lead to an increased risk of disease of the central nervous system (CNS), particularly schizophrenia and multiple sclerosis. Adequate intake of vitamin D during pregnancy and the neonatal period seems to be crucial in terms of prevention of these diseases.

Functional foods and nutraceuticals as therapeutic tools for the treatment of diet-related diseases.

In Western societies, the incidence of diet-related diseases is progressively increasing due to greater availability of hypercaloric food and a sedentary lifestyle. Obesity, diabetes, atherosclerosis, and neurodegeneration are major diet-related pathologies that share a common pathogenic denominator of low-grade inflammation. Functional foods and nutraceuticals may represent a novel therapeutic approach to prevent or attenuate diet-related disease in view of their ability to exert anti-inflammatory responses. In particular, activation of intestinal T regulatory cells and homeostatic regulation of the gut microbiota have the potential to reduce low-grade inflammation in diet-related diseases. In this review, clinical applications of polyphenol-rich functional foods and nutraceuticals in postprandial inflammation, obesity, and ageing will be discussed. We have placed special emphasis on polyphenols since they are broadly distributed in plants.

Transplantation of umbilical cord-derived mesenchymal stem cells as a novel strategy to protect the central nervous system: technical aspects, preclinical studies, and clinical perspectives.

The prevention of perinatal neurological disabilities remains a major challenge for public health, and no neuroprotective treatment to date has proven clinically useful in reducing the lesions leading to these disabilities. Efforts are, therefore, urgently needed to test other neuroprotective strategies including cell therapies. Although stem cells have raised great hopes as an inexhaustible source of therapeutic products that could be used for neuroprotection and neuroregeneration in disorders affecting the brain and spinal cord, certain sources of stem cells are associated with potential ethical issues. The human umbilical cord (hUC) is a rich source of stem and progenitor cells including mesenchymal stem cells (MSCs) derived either from the cord or from cord blood. hUC MSCs (hUC-MSCs) have several advantages as compared to other types and sources of stem cells. In this review, we will summarize the most recent findings regarding the technical aspects and the preclinical investigation of these promising cells in neuroprotection and neuroregeneration, and their potential use in the developing human brain. However, extensive studies are needed to optimize the administration protocol, safety parameters, and potential preinjection cell manipulations before designing a controlled trial in human neonates.