Plantas com ação no sistema nervoso central que constam na relação nacional de plantas medicinais de interesse ao sus (RENISUS) / Plants acting on the central nervous system: review plantas com ação no sistema nervoso central que constam na relação nacional de plantas medicinais de interesse ao sus (RENISUS) / Plantas con acción sobre el sistema nervioso central incluidas en la lista nacional de plantas medicinales de interés para sus (RENISUS)

A depressão é uma doença grave que atinge a população em geral, estudos epidemiológicos estimam que a prevalência da depressão ao longo da vida no Brasil está em torno de 15,5%. Os fatores que desencadeiam o aparecimento da depressão incluem fatores sociais, psicológicos, biológicos e também fatores externos específicos como eventos estressantes, solidão, consumo de álcool e drogas, doenças crônicas e dar á luz (depressão pós-parto). O objetivo da presente pesquisa consistiu em realizar uma revisão bibliográfica sobre as principais plantas medicinais com ação antidepressiva. A ansiedade vem se tornando um dos principais problemas da atualidade, sendo intensificada pela pandemia causada pelo coronavírus, onde constatou-se que durante o pico da pandemia onde os casos confirmados de COVID-19 no Brasil ascenderam de 45.757 para 330.890, e as mortes, de 2.906 para 21.048, o sentimento de tristeza/depressão atingiu 40% dos adultos brasileiros. Os sintomas de depressão podem ser amenizados quando a disponibilidade sináptica de monoaminas são aumentadas, e esse aumento pode ocorrer através da diminuição da metabolização desses neurotransmissores. Neste sentido, busca-se através da farmacoterapia a utilização de antidepressivos que disponibilizem as monoaminas na fenda sináptica. A escolha do fármaco é feita com base nos sintomas da depressão e na boa resposta a uma determinada classe de antidepressivos. Em fevereiro de 2009 o Ministério da saúde lançou a Relação Nacional de Plantas Medicinais de Interesse ao SUS (RENISUS), contendo 71 espécies vegetais que são distribuídas de forma in natura nas unidades básicas de saúde (UBS). Destas, somente três espécies apresentam efeito antidepressivo e ansiolítico comprovados na literatura sendo Matricharia chamomilla, Erytrinum mulungu e a Passiflora incarnata que também fazem parte da RENISUS. Além destas, outras espécies como a Melissa officinalis, Lippia alba, Valeriana officinalis e Piper methysticum são utilizadas pela população para tratar ansiedade, insônia e depressão, sugerindo desta forma que estas espécies sejam incluídas na RENISUS.

Depression is a serious disease that affects the general population, epidemiological studies estimate that the prevalence of depression throughout life in Brazil is around 15.5%. The factors that trigger the onset of depression include social, psychological, biological and also specific external factors such as stressful events, loneliness, alcohol and drug consumption, chronic diseases and giving birth (postpartum depression). The objective of the present research was to carry out a literature review on the main medicinal plants with antidepressant action. Anxiety has become one of the main problems of today, being intensified by the pandemic caused by the coronavirus, where it was found that during the peak of the pandemic where confirmed cases of COVID-19 in Brazil rose from 45,757 to 330,890, and deaths, from 2,906 to 21,048, the feeling of sadness/depression reached 40% of Brazilian adults. Symptoms of depression can be alleviated when synaptic availability of monoamines is increased, and this increase can occur through decreased metabolization of these neurotransmitters. In this sense, the use of antidepressants that make monoamines available in the synaptic cleft is sought through pharmacotherapy. The choice of drug is based on symptoms of depression and good response to a particular class of antidepressants. In February 2009, the Ministry of Health launched the National List of Medicinal Plants of Interest to the SUS (RENISUS), containing 71 plant species that are distributed in natura form in basic health units (UBS). Of these, only three species have antidepressant and anxiolytic effects proven in the literature, being Matricharia chamomilla, Erytrinum mulungu and Passiflora incarnata, which are also part of RENISUS. In addition to these, other species such as Melissa officinalis, Lippia alba, Valeriana officinalis and Piper methysticum are used by the population to treat anxiety, insomnia and depression, thus suggesting that these species are included in RENISUS.

Los estudios epidemiológicos estiman que la prevalencia de la depresión a lo largo de la vida en Brasil es de alrededor del 15,5%. Los factores que desencadenan la aparición de la depresión son sociales, psicológicos, biológicos y también factores externos específicos, como los acontecimientos estresantes, la soledad, el consumo de alcohol y drogas, las enfermedades crónicas y el parto (depresión posparto). El objetivo de esta investigación fue realizar una revisión bibliográfica sobre las principales plantas medicinales con acción antidepresiva. La ansiedad se ha convertido en uno de los principales problemas de la actualidad, intensificándose por la pandemia causada por el coronavirus, donde se encontró que durante el pico de la pandemia donde los casos confirmados de COVID-19 en Brasil aumentaron de 45.757 a 330.890, y las muertes, de 2.906 a 21.048, el sentimiento de tristeza/depresión alcanzó el 40% de los adultos brasileños. Los síntomas de la depresión pueden aliviarse cuando se aumenta la disponibilidad sináptica de las monoaminas, y este aumento puede producirse mediante una disminución de la metabolización de estos neurotransmisores. En este sentido, se busca a través de la farmacoterapia el uso de antidepresivos que hagan disponibles las monoaminas en la hendidura sináptica. La elección del fármaco se hace en función de los síntomas de la depresión y de la buena respuesta a una clase concreta de antidepresivos. En febrero de 2009, el Ministerio de Salud lanzó la Lista Nacional de Plantas Medicinales de Interés para el SUS (RENISUS), que contiene 71 especies de plantas que se distribuyen in natura en unidades básicas de salud (UBS). De ellas, sólo tres especies tienen efectos antidepresivos y ansiolíticos probados en la literatura: Matricharia chamomilla, Erytrinum mulungu y Passiflora incarnata, que también forman parte del RENISUS. Además de éstas, otras especies como Melissa officinalis, Lippia alba, Valeriana officinalis y Piper methysticum son utilizadas por la población para tratar la ansiedad, el insomnio y la depresión, lo que sugiere que estas especies se incluyan en el RENISUS.

Bacopa monnieri: historical aspects to promising pharmacological actions for the treatment on central nervous system diseases / Bacopa monnieri: aspectos históricos de las acciones farmacológicas prometedoras para el tratamiento de enfermedades del sistema nervioso central

Bacopa monnieri(L.) Wettst. (Plantaginaceae), also known as Brahmi, has been used to improve cognitive processes and intellectual functions that are related to the preservation of memory. The objective of this research is to review the ethnobotanical applications, phytochemical composition, toxicity and activity of B. monnieri in the central nervous system. It reviewed articles on B. monnieri using Google Scholar, SciELO, Science Direct, Lilacs, Medline, and PubMed. Saponins are the main compounds in extracts of B. monnieri. Pharmacological studies showed that B. monnieri improves learning and memory and presents biological effects against Alzheimer's disease, Parkinson's disease, epilepsy, and schizophrenia. No preclinical acute toxicity was reported. However, gastrointestinal side effects were reported in some healthy elderly individuals. Most studies with B. monnieri have been preclinical evaluations of cellular mechanisms in the central nervous system and further translational clinical research needs to be performed to evaluate the safety and efficacy of the plant.

Bacopa monnieri (L.) Wettst. (Plantaginaceae), también conocida como Brahmi, se ha utilizado para mejorar los procesos cognitivos y las funciones intelectuales que están relacionadas con la preservación de la memoria. El objetivo de esta investigación es revisar las aplicaciones etnobotánicas, composición fitoquímica, toxicidad y actividad de B. monnieri en el sistema nervioso central. Se revisaron artículos sobre B. monnieri utilizando Google Scholar, SciELO, Science Direct, Lilacs, Medline y PubMed. Las saponinas son los principales compuestos de los extractos de B. monnieri. Los estudios farmacológicos mostraron que B. monnieri mejora el aprendizaje y la memoria y presenta efectos biológicos contra la enfermedad de Alzheimer, la enfermedad de Parkinson, la epilepsia y la esquizofrenia. No se informó toxicidad aguda preclínica. Sin embargo, se informaron efectos secundarios gastrointestinales en algunos ancianos sanos. La mayoría de los estudios con B. monnieri han sido evaluaciones preclínicas de los mecanismos celulares en el sistema nervioso central y es necesario realizar más investigaciones clínicas traslacionales para evaluar la seguridad y eficacia de la planta.

De-risking in Tier I CNS safety assessments is the primary function of study design and technical training of laboratory staff observers.

Derisking is not a pharmaceutical industry strategy to reduce time, effort, or costs in drug development. Derisking strategies originated within the National Institutes of Health as a predicate to good science. There is a growing sentiment within drug development programs to diminish the importance of behavioral measures in toxicological studies and in the Tiered Safety assessment plans of the U.S. Regulatory Agencies and the International Commission on Harmonization. The validity and reliability of the Functional Observational Batter (FOB) is critically dependent on consistency and technical quality in each risk assessment plan. US Federal and International drug approval organizations have universally adopted the concept of principles of test construction rather than delineating specific behavioral assay endpoints for inclusion of the FOB in nonclinical safety protocols. The validity and reliability of behavioral observations in standardized neurotoxicity screening is critically dependent on the FOB developed by the Study Director with the Sponsor throughout all stages of testing.. The individual risk factors selected for observation to be included in the early Tier 1 safety program should be determined by the mechanism and mode of action of the test article. The results of Tier I testing are the basis for Tier II testing designs. Critical to the compliance with Good Laboratory Practices is the documentation of training of the operational staff scheduled to conduct all aspects of the established protocol.

Combination of Ephedra sinica stems and Terminalia chebula fruits produces new ephedrine derivatives in vivo that diminish the permeability to BBB while retaining airway dilation and hepatoprotective effects.

ETHNOPHARMACOLOGICAL RELEVANCE: The stems of Ephedra sinica and the fruits of Terminalia chebula are combined using in traditional Mongolian medicine formula "Gurigumu-7" for liver diseases. E. sinica stems contains ephedrine with broncho-dilatory activity. However, ephedrine can pass through the blood-brain barrier (BBB) and excite the central nervous system (CNS) to cause insomnia and restlessness. AIM OF THE STUDY: The present study was to investigate the structures and bioactivities of new compounds formed in vivo after co-administration of E. sinica stems and T. chebula fruits. MATERIALS AND METHODS: Pharmacokinetic investigation was carried out in rats. A parallel artificial membrane permeability measurement system was used to determine BBB permeability. Ex vivo experiments using tracheal rings of guinea pig was performed to examine the tracheal relaxation effect. In vivo hepatoprotective tests were carried out in Tg (fabp10a: dsRed) liver transgenic zebrafish. The fluorescent probe, 2,7-dichlorodihydrofluorescein diacetate, was used to measure reactive oxygen species, and UHPLC-MS was used to determine glutathione concentrations after derivatization with N-ethylmaleimide. RESULTS: New ephedrine derivatives (1 and 2) formed in vivo and reached their maximum serum concentrations at 0.5 h after administration of the two herbal drugs. Compounds 1 and 2 showed lower BBB permeability than ephedrine, suggesting that they have less adverse effects on the CNS. Compounds 1 and 2 relaxed the tracheal rings and had strong hepatoprotective effect on transgenic zebrafish with liver specific expression of RFP. Compounds 1 and 2 significantly reduced the level of reactive oxygen species while increasing that of glutathione in thioacetamide-treated zebrafish, which might be the hepatoprotective mechanism. CONCLUSION: These results provided evidences that the chemical constituents in various herbal drugs in a medicinal formula can interact to generate new compounds with fewer side effects and increased or additive bioactivity.

Application and advantages of zebrafish model in the study of neurovascular unit.

The concept of "Neurovascular Unit" (NVU) was put forward, so that the research goal of Central Nervous System (CNS) diseases gradually transitioned from a single neuron to the structural and functional integrity of the NVU. Zebrafish has the advantages of high homology with human genes, strong reproductive capacity and visualization of neural circuits, so it has become an emerging model organism for NVU research and has been applied to a variety of CNS diseases. Based on CNKI (https://www.cnki.net/) and PubMed (https://pubmed.ncbi.nlm.nih.gov/about/) databases, the author of this article sorted out the relevant literature, analyzed the construction of a zebrafish model of various CNS diseases，and the use of diagrams showed the application of zebrafish in the NVU, revealed its relationship, which would provide new methods and references for the treatment and research of CNS diseases.

Creatine Supplementation: An Update.

ABSTRACT: Creatine is a popular and widely used ergogenic dietary supplement among athletes, for which studies have consistently shown increased lean muscle mass and exercise capacity when used with short-duration, high-intensity exercise. In addition to strength gains, research has shown that creatine supplementation may provide additional benefits including enhanced postexercise recovery, injury prevention, rehabilitation, as well as a number of potential neurologic benefits that may be relevant to sports. Studies show that short- and long-term supplementation is safe and well tolerated in healthy individuals and in a number of patient populations.

Is intravenous fish oil associated with the neurodevelopment of extremely low birth weight preterm infants on parenteral nutrition?

BACKGROUND & AIMS: Preterm infants are at increased risk of long-term neurodevelopmental disabilities (NDD). Long chain n-3 fatty acids play a key role during the development of the central nervous system and some studies in preterm infants showed benefits of docosahexaenoic acid and arachidonic acid supplementation for visual and cognitive development. In recent years fish oil has been added to the fat blend of intravenous (IV) lipid emulsions (LE) but to date scanty data are available on neurodevelopmental outcome of preterm infants that received fish oil containing LE. We studied the effect of fish oil containing IV LE vs standard IV LE on neurodevelopment in a large cohort of preterm infants who received routine parenteral nutrition (PN) from birth. METHODS: We retrospectively reviewed the neurodevelopmental outcome of 477 preterm infants (birth weight (BW): 400-1249 g and gestational age (GA) at birth: 24+0 - 35+6 weeks (W)) admitted to our NICU between Oct-2008 and June-2017, who received routine PN with different LE, with and without fish oil (IV-FO vs CNTR). We compared neurodevelopment at 2 years corrected age by the Bayley III development scale and the incidence of NDD. RESULTS: Demographics, birth data and the incidence of the main clinical short-term outcomes of prematurity were similar in the two groups (IV-FO: n = 178, GA 197 ± 14 days, BW 931 ± 182 g; CNTR: n = 192, GA 198 ± 15 days, BW 944 ± 194 g). No differences were found in maternal demographics nor in parental education between the two groups. Cognitive score was not significantly different between IV-FO and CNTR (92 ± 15 vs 93 ± 13, p = 0.5). No differences were found in motor and language scores, and in the incidence of NDD in the two groups. CONCLUSIONS: Contrary to our hypothesis, the use of fish oil containing LE in a large cohort of preterm infants on routine PN did not result in better neurodevelopment. Large randomized controlled trials powered for neurodevelopment are needed to clarify the impact of the widely used fish oil containing LE on neurodevelopment of preterm infants.

Central and peripheral pain intervention by Ophiorrhizarugosa leaves: Potential underlying mechanisms and insight into the role of pain modulators.

ETHNOPHARMACOLOGICAL RELEVANCE: Ophiorrhiza rugosa var. prostrata is a traditional medicinal plant used by the indigenous and local tribes (Chakma, Marma and Tanchangya) of Bangladesh for the management of chest pain, body ache, and earache. However, the knowledge of anti-nociceptive and anti-inflammatory potentials of this plant is scarce. AIM OF THE STUDY: Therefore, we scrutinized the anti-nociceptive and anti-inflammatory properties of O. rugosa leaves along with its possible mechanism(s) of action using chemical and heat-induced pain models. METHODS AND MATERIALS: O. rugosa was extracted using 100% ethanol (EEOR) followed by exploring phytochemicals and assessing acute toxicity. To determine anti-nociceptive potentials, chemical-induced (acetic acid and formalin) and heat-induced (hot plate and tail immersion) nociceptive models were followed. To investigate the possible involvement of opioid receptors during formalin, hot plate, and tail immersion tests, naltrexone was administered whereas methylene blue and glibenclamide were used to explore cGMP involvement and ATP-sensitive K+ channel pathways, respectively. Moreover, the anti-inflammatory potential was assessed using the carrageenan-induced paw edema test model. Motor behaviours of EEOR were assessed by the open-field test. Finally, bioactive constituents (identified by GC-MS) from O. rugosa were subjected to molecular docking and ADME/t analysis to evaluate its potency and safety. RESULTS: During chemical-induced and heat-induced pain models, EEOR exhibited significant and effective nociception suppression at all experimental doses (200 and 400 mg/kg). Also, the administration of naltrexone corroborated the association of opioid receptors with the anti-nociceptive activity by EEOR. Similarly, cGMP and ATP-sensitive K+ channel pathways were also found to be involved in the anti-nociceptive mechanism. Furthermore, significant and dose-dependent inhibition of inflammation induced by carrageenan was recorded for EEOR. Both doses of EEOR did not affect the animal's locomotor capacity in the open-field test. Besides, in silico test identified the key compounds (loliolide, harman, squalene, vitamin E, and gamma-sitosterol) that inhibited some particular receptors regarding pain and inflammation. CONCLUSION: This research exposes central and peripheral pain intervention as well as anti-inflammatory activity of O. rugosa. Also, the identified compounds from this plant support its activities by effectively inhibiting anti-nociceptive and anti-inflammatory receptors. Overall, these outcomes valorize the ethnomedicinal efficacy of O. rugosa in managing various painful conditions.

Postnatal Iron Supplementation with Ferrous Sulfate vs. Ferrous Bis-Glycinate Chelate: Effects on Iron Metabolism, Growth, and Central Nervous System Development in Sprague Dawley Rat Pups.

Iron-fortified formulas and iron drops (both usually ferrous sulfate, FS) prevent early life iron deficiency, but may delay growth and adversely affect neurodevelopment by providing excess iron. We used a rat pup model to investigate iron status, growth, and development outcomes following daily iron supplementation (10 mg iron/kg body weight, representative of iron-fortified formula levels) with FS or an alternative, bioavailable form of iron, ferrous bis-glycinate chelate (FC). On postnatal day (PD) 2, sex-matched rat litters (n = 3 litters, 10 pups each) were randomly assigned to receive FS, FC, or vehicle control until PD 14. On PD 15, we evaluated systemic iron regulation and CNS mineral interactions and we interrogated iron loading outcomes in the hippocampus, in search of mechanisms by which iron may influence neurodevelopment. Body iron stores were elevated substantially in iron-supplemented pups. All pups gained weight normally, but brain size on PD 15 was dependent on iron source. This may have been associated with reduced hippocampal oxidative stress but was not associated with CNS mineral interactions, iron regulation, or myelination, as these were unchanged with iron supplementation. Additional studies are warranted to investigate iron form effects on neurodevelopment so that iron recommendations can be optimized for all infants.

Neuroprotective Herbs for the Management of Alzheimer's Disease.

Background-Alzheimer's disease (AD) is a multifactorial, progressive, neurodegenerative disease that is characterized by memory loss, personality changes, and a decline in cognitive function. While the exact cause of AD is still unclear, recent studies point to lifestyle, diet, environmental, and genetic factors as contributors to disease progression. The pharmaceutical approaches developed to date do not alter disease progression. More than two hundred promising drug candidates have failed clinical trials in the past decade, suggesting that the disease and its causes may be highly complex. Medicinal plants and herbal remedies are now gaining more interest as complementary and alternative interventions and are a valuable source for developing drug candidates for AD. Indeed, several scientific studies have described the use of various medicinal plants and their principal phytochemicals for the treatment of AD. This article reviews a subset of herbs for their anti-inflammatory, antioxidant, and cognitive-enhancing effects. Methods-This article systematically reviews recent studies that have investigated the role of neuroprotective herbs and their bioactive compounds for dementia associated with Alzheimer's disease and pre-Alzheimer's disease. PubMed Central, Scopus, and Google Scholar databases of articles were collected, and abstracts were reviewed for relevance to the subject matter. Conclusions-Medicinal plants have great potential as part of an overall program in the prevention and treatment of cognitive decline associated with AD. It is hoped that these medicinal plants can be used in drug discovery programs for identifying safe and efficacious small molecules for AD.

Water extract of Er-xian decoction selectively exerts estrogenic activities and interacts with SERMs in estrogen-sensitive tissues.

ETHNOPHARMACOLOGICAL RELEVANCE: The increasing use of "kidney"-nourishing Traditional Chinese Medicine (TCM) like Er-xian decoction (EXD) for management of menopausal symptoms and osteoporosis has aroused concerns about their safety, and whether they interact with prescription drugs as both of them act via estrogen receptors (ERs) and regulate serum estradiol. AIM OF THE STUDY: The present study aimed to evaluate whether EXD selectively exerted estrogenic activities and interacted with Selective Estrogen Receptor Modulators (SERMs). MATERIALS AND METHODS: In vivo, mature ovariectomized (OVX) rats were administrated with EXD or combined treatment of EXD and SERMs for 12 weeks. The tissue-selective effect of EXD and its interaction of SERMs were studied in four estrogen sensitive tissues, bone, brain, breast and uterus. In vitro, the interaction of extracts of EXD-treated serum and SERMs in four ER-positive cell lines. RESULTS: In OVX rats, EXD selectively alleviated estrogen deficiency-induced changes in the bone and brain without inducing any estrogenic effects in the breast or uterus. Two-way ANOVA indicated the presence of interactions between EXD and SERMs in OVX rats but EXD did not significantly alter the tissue responses to SERMs in the bone, breast or brain. Indeed, the combined use of EXD and SERMs appeared to suppress the estrogenic effect of raloxifene and tamoxifen in the uterus. Extract of EXD-treated serum directly stimulated cell proliferation or differentiation in human osteosarcoma MG-63, neuroblastoma SHSY5Y, breast cancer MCF-7, and endometrial Ishikawa cells. Two-way ANOVA revealed that EXD-treated serum interacted with SERMs at various concentrations and altered the effects of tamoxifen in MG-63 and MCF-7 cells. CONCLUSIONS: EXD exerted estrogenic effects in a tissue-selective manner and interacted with SERMs. Combined treatment of EXD and SERMs did not hamper the beneficial effects of SERMs on the bone or brain but appeared to moderate the estrogenic effect of SERMs in the uterus.

Salidroside: A review of its recent advances in synthetic pathways and pharmacological properties.

Salidroside has been identified as one of the most potent compounds isolated from various Rhodiola plants, which have been used for a long time as adaptogens in traditional Chinese medicine. However, due to the severe growing environment of herbal medicine and large-scale excavation, the content of natural salidroside is extremely small. Most of the previous studies focused on herbal medicine, and there were few reviews on the synthesis of its main active ingredient salidroside. This paper presents different synthetic routes of salidroside to resolve the contradiction between supply and demand and lays the foundation for new drug research and development. Furthermore, emerging evidence indicates that salidroside, a promising environmentally-adapted drug with low toxicity and few side effects, possesses a wide spectrum of pharmacological properties, including activities on the cardiovascular system and central nervous system, anti-hypoxia, anti-fatigue and anti-aging activities, anticancer activity, anti-inflammatory activity, antioxidant activity, antivirus and immune stimulation activities, antidiabetic activity, anti-osteoporotic activity, and so on. Although the former researches have summarized the pharmacological effects of salidroside, focusing on the central nervous system, diabetes, and cancer, the overall pharmacological aspects of it have not been analyzed. This review highlights biological characteristics and mechanisms of action from 2009 to now as well as toxicological and pharmacokinetic data of the analyzed compound reported so far, with a view to providing a reference for further development and utilization of salidroside.

Effects of essential oils on central nervous system: Focus on mental health.

Essential oils have been used as remedies since ancient times for the treatment of numerous illnesses on account of their wide range of biological activities. Recent preclinical and clinical studies have shown varying pharmacological responses in the nervous system leading to anxiolytic, antidepressant, sedative, and anticonvulsant effects. Experimentation in animal models has evidenced the involvement of multiple neurotransmitter systems in the mode of action of essential oils, resulting in measurable physiological effects in the brain. Additionally, clinical trials have demonstrated the influence of essential oils in physiological parameters such as blood pressure, heart rate, respiratory rate, brain waves composition, and cortisol serum levels with concomitant psychological effects. Although there is growing evidence of measurable effects of essential oils in animal brains, more clinical research is required to validate their influence in the human central nervous system. This will enable the development of essential oil-based drugs for the treatment of mental illnesses such as depression, anxiety and dementia.

Go-sha-jinki-Gan Alleviates Inflammation in Neurological Disorders via p38-TNF Signaling in the Central Nervous System.

Go-sha-jinki-Gan (GJG) is a traditional Japanese herbal medicine. In clinical practice, GJG is effective against neuropathic pain and hypersensitivity induced by chemotherapy or diabetes. In our previous study using a chronic constriction injury mouse model, we showed that GJG inhibited microglia activation by suppressing the expression of tumor necrosis factor-α (TNF-α) and p38 mitogen-activated protein kinase (p38 MAPK) in the peripheral nervous system. To investigate whether GJG can suppress inflammation in the central nervous system (CNS) in the context of neurological disorders, we examined the effect of GJG on the activation of resident glial cells and on p38-TNF signaling in two mouse models of neurological disorders: the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. GJG administration relieved the severity of clinical EAE symptoms and MPTP-induced inflammation by decreasing the number of microglia and the production of TNF-α in the spinal cord of EAE mice and the substantia nigra of MPTP-treated mice. Accordingly, GJG suppressed the phosphorylation of p38 in glial cells of these two mouse models. We conclude that GJG attenuates inflammation of the CNS by suppressing glial cell activation, followed by a decrease in the production of TNF-α via p38-TNF signaling.

Studying CNS effects of Traditional Chinese Medicine using zebrafish models.

ETHNOPHARMACOLOGICAL RELEVANCE: Although Traditional Chinese Medicine (TCM) has a millennia-long history of treating human brain disorders, its complex multi-target mechanisms of action remain poorly understood. Animal models are currently widely used to probe the effects of various TCMs on brain and behavior. The zebrafish (Danio rerio) has recently emerged as a novel vertebrate model organism for neuroscience research, and is increasingly applied for CNS drug screening and development. AIM OF THE STUDY: As zebrafish models are only beginning to be applied to studying TCM, we aim to provide a comprehensive review of the TCM effects on brain and behavior in this fish model species. MATERIALS AND METHODS: A comprehensive search of published literature was conducted using biomedical databases (Web of Science, Pubmed, Sciencedirect, Google Scholar and China National Knowledge Internet, CNKI), with key search words zebrafish, brain, Traditional Chinese Medicine, herbs, CNS, behavior. RESULTS: We recognize the developing utility of zebrafish for studying TCM, as well as outline the existing model limitations, problems and challenges, as well as future directions of research in this field. CONCLUSIONS: We demonstrate the growing value of zebrafish models for studying TCM, aiming to improve our understanding of TCM' therapeutic mechanisms and potential in treating brain disorders.

Organic Selenium Reaches the Central Nervous System and Downmodulates Local Inflammation: A Complementary Therapy for Multiple Sclerosis?

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). The persistent inflammation is being mainly attributed to local oxidative stress and inflammasome activation implicated in the ensuing demyelination and axonal damage. Since new control measures remain necessary, we evaluated the preventive and therapeutic potential of a beta-selenium-lactic acid derivative (LAD-ßSe), which is a source of organic selenium under development, to control experimental autoimmune encephalomyelitis (EAE) that is an animal model for MS. Two EAE murine models: C57BL/6 and SJL/J immunized with myelin oligodendrocyte glycoprotein and proteolipid protein, respectively, and a model of neurodegeneration induced by LPS in male C57BL/6 mice were used. The preventive potential of LAD-ßSe was initially tested in C57BL/6 mice, the chronic MS model, by three different protocols that were started 14 days before or 1 or 7 days after EAE induction and were extended until the acute disease phase. These three procedures were denominated preventive therapy -14 days, 1 day, and 7 days, respectively. LAD-ßSe administration significantly controlled clinical EAE development without triggering overt hepatic and renal dysfunction. In addition of a tolerogenic profile in dendritic cells from the mesenteric lymph nodes, LAD-ßSe also downregulated cell amount, activation status of macrophages and microglia, NLRP3 (NOD-like receptors) inflammasome activation and other pro-inflammatory parameters in the CNS. The high Se levels found in the CNS suggested that the product crossed the blood-brain barrier having a possible local effect. The hypothesis that LAD-ßSe was acting locally was then confirmed by using the LPS-induced neurodegeneration model that also displayed Se accumulation and downmodulation of pro-inflammatory parameters in the CNS. Remarkably, therapy with LAD-ßSe soon after the first remitting episode in SJL/J mice, also significantly downmodulated local inflammation and clinical disease severity. This study indicates that LAD-ßSe, and possibly other derivatives containing Se, are able to reach the CNS and have the potential to be used as preventive and therapeutic measures in distinct clinical forms of MS.

Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience.

BACKGROUND: In GM1 gangliosidosis the lack of function of ß-galactosidase results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. To date, there are no effective therapeutic options in preventing progressive neurological deterioration. Substrate reduction therapy with Miglustat, a N-alkylated sugar that inhibits the enzyme glucosylceramide synthase, has been proposed for the treatment of several lysosomal storage disorders such as Gaucher type 1 and Niemann Pick Type C diseases. However, data on Miglustat therapy in patients with GM1 gangliosidosis are still scarce. METHODS: We report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20-125) affected by GM1 gangliosidosis type 2 treated in three different Italian pediatric hospitals specialized in metabolic diseases. CONCLUSION: This treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.

Two Faces of Vitamin C-Antioxidative and Pro-Oxidative Agent.

Vitamin C has been known for decades. It is common in everyday use as an element of the diet, supplementation, and a preservative. For years, research has been conducted to precisely determine the mechanism of action of ascorbate in the cell. Available results indicate its multi-directional cellular effects. Vitamin C, which belongs to antioxidants scavenging free radicals, also has a 'second face'-as a pro-oxidative factor. However, whether is the latter nature a defect harmful to the cell, or whether a virtue that is a source of benefit? In this review, we discuss the effects of vitamin C treatment in cancer prevention and the role of ascorbate in maintaining redox balance in the central nervous system (CNS). Finally, we discuss the effect of vitamin C supplementation on biomarkers of oxidative DNA damage and review the evidence that vitamin C has radioprotective properties.

Beyond Oncological Hyperthermia: Physically Drivable Magnetic Nanobubbles as Novel Multipurpose Theranostic Carriers in the Central Nervous System.

Magnetic Oxygen-Loaded Nanobubbles (MOLNBs), manufactured by adding Superparamagnetic Iron Oxide Nanoparticles (SPIONs) on the surface of polymeric nanobubbles, are investigated as theranostic carriers for delivering oxygen and chemotherapy to brain tumors. Physicochemical and cyto-toxicological properties and in vitro internalization by human brain microvascular endothelial cells as well as the motion of MOLNBs in a static magnetic field were investigated. MOLNBs are safe oxygen-loaded vectors able to overcome the brain membranes and drivable through the Central Nervous System (CNS) to deliver their cargoes to specific sites of interest. In addition, MOLNBs are monitorable either via Magnetic Resonance Imaging (MRI) or Ultrasound (US) sonography. MOLNBs can find application in targeting brain tumors since they can enhance conventional radiotherapy and deliver chemotherapy being driven by ad hoc tailored magnetic fields under MRI and/or US monitoring.

Discovery and structure-activity relationships study of positive allosteric modulators of the M3 muscarinic acetylcholine receptor.

The M3 muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure--activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M3 mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M3 mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Compound 9 also showed excellent subtype selectivity over other subtypes of mAChRs including M1, M2, and M4 mAChRs, and moderate selectivity over the M5 mAChR, indicating that compound 9 is an M3-preferring M3/M5 dual PAM. Moreover, compound 9 displayed acceptable pharmacokinetics profiles after oral dosing to rats. These results suggest that compound 9 may be a promising chemical probe for the M3 mAChR for further investigation of its pharmacological function both in vitro and in vivo.