Guettarda viburnoides Cham. & Schltdl.: Neuroprotective Activities in Mice, Molecular Docking and Microchemical and Morphoanatomical Characteristics of Leaves and Stems.

BACKGROUND: Guettarda viburnoides Cham. & Schltdl., "veludinho do campo", is used in the Brazilian Amazon for its effects on the central nervous system (CNS) as a "brain tonic"; however, scientific evidence is needed to elucidate its ethnobotanical uses. OBJECTIVE: This study evaluated the neurobehavioural effects of an ethanolic extract of G. viburnoides (EEGV). Molecular docking, microchemical and morphoanatomical features of the species were investigated. METHODS: EEGV was investigated by UHPLC‒MS/MS and dereplication and molecular network were investigated using platforms available for natural product chemistry. For the in vivo assay, EEGV was administered to mice orally (3, 30 or 100 mg/kg). The effect of EEGV on spatial memory was measured using the Morris water maze test in mice with scopolamine-induced amnesia. The depression- and anxiety-like effects were assessed by forced swimming, tail suspension, marble burying and elevated plus maze tests. The AChE inhibition was evaluated in the brains of treated mice and molecular docking simulations were carried out with the main constituents. The leaves and stems of G. viburnoides were analysed via optical microscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy. RESULTS: Secoxyloganin, grandifloroside, hyperin/or isoquercitrin, uncaric acid and ursolic acid were identified by UHPLC‒MS/MS. Molecular networking by three flavonoids, three triterpenes, two coumarins, two iridoids, and one phenolic acid. EEGV reversed these scopolamineinduced effects. In the forced swim and tail suspension test, EEGV (30 and 100 mg/kg) significantly reduced the immobility time. EEGV significantly reduced the number of buried marbles, while in the elevated plus maze test, no changes were observed compared to the Sco group. AChE activity was altered in the hippocampus. Studies of the molecular coupling of iridoid glycosides (grandifloroside and secoxyloganin) and flavonoid hyperin with AChE revealed significant interactions, corroborating the activity indicated by the inhibition assay. CONCLUSIONS: These results might be in accordance with medicinal use for neuroprotetor effects and important microchemical and micromorphological data that support the identification and quality control of G. viburnoides.

A Comprehensive Description of the Anatomy and Histochemistry of Psychotria capillacea (Müll. Arg.) Standl. and an Investigation into Its Anti-Inflammatory Effects in Mice and Role in Scopolamine-Induced Memory Impairment.

Species of the genus Psychotria are used in popular medicine for pain, inflammatory symptoms, and mental disorders. Psychotria capillacea (Müll. Arg.) Standl. (Rubiaceae) is commonly known as coffee and some scientific studies have demonstrated its therapeutic potential. The goal of this study was to investigate the anti-inflammatory and neuroprotective effects, and acetylcholinesterase (AChE) inhibitory activity of a methanolic extract obtained from leaves of P. capillacea (MEPC), as well as the micromorphology and histochemistry of the leaves and stems of this plant. In addition, the MEPC was analyzed by UHPLC-MS/MS and the alkaloidal fraction (AF) obtained from the MEPC was tested in a mouse model of inflammation. MEPC contained three indole alkaloids, one sesquiterpene (megastigmane-type) and two terpene lactones. MEPC (3, 30 and 100 mg/kg) and AF (3 and 30 mg/kg) were evaluated in inflammation models and significantly inhibited edema at 2 h and 4 h, mechanical hyperalgesia after 4 h and the response to cold 3 h and 4 h after carrageenan injection. Scopolamine significantly increased the escape latency, and reduced the swimming time and number of crossings in the target quadrant and distance, while MEPC (3, 30 and 100 mg/kg), due to its neuroprotective actions, reversed these effects. AChE activity was significantly decreased in the cerebral cortex (52 ± 3%) and hippocampus (60 ± 3%), after MEPC administration. Moreover, micromorphological and histochemical information was presented, to aid in species identification and quality control of P. capillacea. The results of this study demonstrated that P. capillacea is an anti-inflammatory and antihyperalgesic agent that can treat acute disease and enhance memory functions in mouse models.

Effects of Anodal Transcranial Direct Current Stimulation on the Primary Motor Cortex in Women With Fibromyalgia: A Randomized, Triple-Blind Clinical Trial.

OBJECTIVES: The aim of this study was to analyze the effects of ten sessions of active transcranial direct current stimulation transcranial direct current stimulation (tDCS) (2 mA) with 13:20:13 stimulation at M1 in women with fibromyalgia (FM). To the best of our knowledge, this is the first article that uses this protocol in patients with FM. The main hypothesis is that the protocol would be effective in decreasing pain and that the results would last for up to 90 days. MATERIALS AND METHODS: This study was a randomized clinical trial with 35 women with FM divided into two groups, active tDCS group and sham tDCS group. A conventional tDCS device was used to deliver 2 mA for 13 minutes, with a 20-minute break followed by a further 13 minutes of stimulation for ten sessions. The anodal stimulus was in the left primary motor cortex M1 region. The primary outcome was a change in the visual analog scale and the Survey of Pain Attitudes pain score at the end of treatment, after 30 days, and 90 days after the end of treatment. Secondary outcomes included changes in the Fibromyalgia Impact Questionnaire, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, World Health Organization's Quality of Life Questionnaire, and Fatigue Assessment Scale. The Research Ethics Committee of the Centro Universitário da Grande Dourados under registration number Certificado de Apresentação de Apreciação Ética approved this research: 36444920.5.0000.5159. The study was registered in The Brazilian Registry of Clinical Trials with the identifier RBR-8wc8rjq. RESULTS: The active tDCS group showed improvement in pain after ten sessions (p < 0.001), after 30 days (p < 0.01), and after 90 days (p < 0.001) compared with sham tDCS. In addition, improvement in quality of life (QoL) and fatigue was observed in the active tDCS group. CONCLUSION: The results of this study suggest that active tDCS with an intensity of 2 mA for ten sessions was effective in decreasing pain and fatigue and improving QoL in patients with FM.

Potential anti-arthritic and analgesic properties of essential oil and viridiflorol obtained from Allophylus edulis leaves in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Viridiflorol was identified and isolated from the essential oil of Allophylus edulis leaves (EOAE). A. edulis was used as "tereré", which is a drink made by the infusion of herbs in cold water, to treat pain (toothache and headache). All anti-nociceptive (analgesic) and anti-arthritic properties of EOAE and viridiflorol have not been completely scientifically clarified. AIM OF THE STUDY: The aim of the present study was to investigate the analgesic (anti-hyperalgesic and anti-nociceptive) and anti-arthritic properties of EOAE and viridiflorol using in vivo models. MATERIALS AND METHODS: The oral administration (p.o.) of EOAE (30, 100 and 300 mg/kg), viridiflorol (30, 100 and 200 mg/kg), morphine (1 mg/kg, subcutaneous route (s.c.)) and the intraplantar (local) administration (i.pl.) of viridiflorol (100 µg/paw) were tested using formalin model in Swiss mice. EOAE (100 mg/kg, p.o.), viridiflorol (200 mg/kg, p.o.), and dexamethasone (1 mg/kg, s.c.) were tested by zymosan-articular inflammation and in open-field models. Viridiflorol (0.3, 20 and 200 µg/paw) was also tested in carrageenan model, and viridiflorol (200 µg/paw) was also tested in tumor necrosis factor-α (TNF-α), and dopamine (DOPA) models. RESULTS: The oral administration of EOAE (100 and 300 mg/kg, p.o.), viridiflorol (200 mg/kg, p.o.), morphine (1 mg/kg, s.c.) (MOR) and local administration of viridiflorol (100 µg/paw) significantly inhibited edema and nociception in formalin model. Oral treatments with EOAE and viridiflorol (200 mg/kg) did not cause motor impairment in the open field test since they did not reduce locomotor activity. EOAE, viridiflorol and dexamethasone significantly reduced mechanical hyperalgesia, edema, total leukocytes, polymorphonuclear cells, nitric oxide and protein exudation in the zymosan-induced articular inflammation model. The local administration of viridiflorol (200 µg/paw, i.pl.) significantly inhibited mechanical hyperalgesia and edema induced by carrageenan, TNF-α and DOPA. CONCLUSIONS: This study confirms the potential anti-arthritic, anti-nocicepttive and anti-hyperalgesic properties of EOAE and viridiflorol. These properties could explain, at least in part, the folk use of A. edulis against including pain (toothache and headache). Viridiflorol could be partially responsible for the EOAE anti-hyperalgesic, anti-nociceptive and anti-arthritic properties and its mechanism of action could involve the inhibition of TNF-α and DOPA pathways.

Analgesic and Anti-Inflammatory Properties of Ethanolic Extract of Piper vicosanum Leaves.

Nonclinical trials are important to validate the efficacy and safety of medicinal plants. Scientific toxicological studies with Piper vicosanum Yuncker have showed its safety; however, no studies have indicated the analgesic or antiarthritic potential of the ethanolic extract of P. vicosanum leaves (EEPV). The objective of the present work was to evaluate the antiarthritic and antinociceptive effects of EEPV in experimental mouse models. The oral administration of EEPV (100, 300, and 700 mg/kg) and dexamethasone (1 mg/kg) were performed in carrageenan-induced pleurisy, in formalin and acetic-acid-induced nociception, and in zymosan-induced articular inflammation models in Swiss mice. The EEPV (300 mg/kg) was tested in zymosan-articular inflammation, the complete Freund's adjuvant (CFA) inflammatory model, and in in situ intravitreal microscopy analysis of rolling and adhesion events of leukocytes in the mesenteric microcirculation in mice. EEPV significantly inhibited: (i) nociceptive response at phase 1 and 2, and also in the cold response in the formalin model; (ii) abdominal contortion induced by acetic acid; (iii) mechanical hyperalgesia after 4 and 6 h, knee edema after 6 h, and leukocyte migration in articular inflammation induced by zymosan. All doses of EEPV reduced the leukocyte migration to the inflamed pleural cavity and knee edema 4 h after the zymosan knee injection. The treatment with the EEPV significantly inhibited the CFA-induced edema, mechanical and cold hyperalgesia, and NAG and MPO. The EEPV also significantly inhibited carrageenan-induced leukocyte rolling and adhesion. The present study revealed, for the first time, the antiarthritic and antinociceptive effects of the EEPV.

Altered white matter integrity in the corpus callosum in adults with HIV: a systematic review of diffusion tensor imaging studies.

We systematically reviewed studies comparing differences in the integrity of the corpus callosum in adults with HIV compared to healthy controls, using Diffusion Tensor Imaging (DTI), using search engines Science Direct, Web of Science and PubMed. The search terms used were "HIV", "corpus callosum", and a variation of either "DTI" or "Diffusion Tensor Imaging" with or without the term "adults". We specifically examined the corpus callosum as it is the largest white matter tract in the brain, plays a primary role in cognition, and has been shown to be morphologically altered in people living with HIV. Lower fractional anisotropy (FA) was consistently found in the corpus callosum in people with HIV compared to controls. As most studies used only FA as a measure of diffusion, it would be informative for future research if other DTI metrics, such as mean diffusivity (MD), were also investigated as these metrics may be more sensitive markers of HIV-related neuropathology.

Effects of Music Therapy on Neuroplasticity, Welfare, and Performance of Piglets Exposed to Music Therapy in the Intra- and Extra-Uterine Phases.

The rearing environment of pigs can cause a high level of stress due to the lack of stimuli and the impossibility of carrying out natural behaviors. Music therapy is a way to enrich the environment and promote stress relief. Few studies in swine using environmental enrichers focus on functional benefits, such as stress resilience, improved biological functions, or mental status. The effect of environmental enrichment on neurobiological processes is particularly poorly understood in farm animals. Thus, our study sought to elucidate the influence of music in piglets exposed to music therapy in the intrauterine and extrauterine phase on neuroplasticity, evaluating the levels of brain-derived neurotrophic factor (BDNF). Behavioural responses were also evaluated using fear tests related to stress resilience. The productive performance of these piglets was analysed to relate the possible reduction in stress levels to greater productivity gains. Forty-eight sows were used at 90 days of gestation until the weaning of their piglets. In the gestation phase, the sows were divided into two treatments: control (without music therapy) and music (with music therapy). In the farrowing/lactation phase, the sows were separated into four treatments: control-control (no music in any phase); control-music (music only in farrowing/lactation); music-control (music only during pregnancy); and music-music (music in both reproductive phases). Music therapy did not cause a difference in the BDNF levels of piglets at birth. However, piglets born from sows of the music-music treatment did not show a reduction in BDNF between birth and weaning, unlike the other treatments. Exposure to music in the last 1/3 of pregnancy and farrowing/lactation improved the weight of piglets at birth and at weaning. Musical enrichment during pregnancy and lactation was able to cause changes in the piglets' neuroplasticity and improve their productive performances.

Early childhood abuse: adult impulsivity and risky behavior / Abuso na infância: impulsividade no adulto e comportamentos de risco

We review the role of childhood abuse (CA) in the practice of impulsive, risk-taking behaviors during adulthood. CA deregulates the adult response to stress, which in turn disrupts the prefrontal-striatal systems that provide executive control over reward-related behavior. The result is impulsivity and risk-taking, including self-medication with drugs and alcohol and the practice of unsafe sex. These behaviors decrease quality of life and impair the attainment of long-term goals. Risky sexual behavior, in particular, increases the chance of HIV infection and perpetuates the epidemic.

Revisamos o papel do abuso na infância na prática de comportamentos impulsivos e de risco durante a vida adulta. O abuso na infância desregula a resposta do adulto ao estresse, o que, por sua vez, impede os circuitos frontoestriatais de fornecerem o adequado controle executivo sobre comportamentos associados à recompensa. O resultado é a impulsividade e escolhas de risco, incluindo automedicação com drogas e álcool e a prática de sexo inseguro, reduzindo a qualidade de vida e prejudicando o alcance de metas de longo prazo. O comportamento sexual de risco, em particular, aumenta a chance de infecção pelo Vírus de Imunodeficiência Humana e perpetua a sua epidemia.

Incidence and Persistence of Depression Among Women Living with and Without HIV in South Africa: A Longitudinal Study.

Depression and trauma are common among women living with HIV. This is the first study to track the longitudinal course of depression and examine the relationship between depression and trauma over time among women in South Africa. HIV-infected and uninfected women (N = 148) were assessed at baseline and one year later. Results of a path analysis show the multi-directional and entwined influence of early life stress, other life-threatening traumas across the lifespan, depression and PTSD over the course of HIV. We also observed higher rates of depressive symptomatology and more persistent cases among infected women compared to uninfected women, as well as a more consistent and enduring relationship between childhood trauma and depression among women living with HIV. The present study is unique in documenting the course of untreated depression and PTSD in women with and without HIV infection with a high prevalence of early childhood trauma.

The state of consciousness in patients in the vegetative and minimally conscious states / O estado de consciência em pacientes em estado vegetativo e em estado de consciência minima

Brain-injured patients may, with the assistance of life support, continue to perform basic bodily functions, but yet be deficient in wakefulness, awareness, decision making or other overt manifestations of consciousness. Here, we review two neurological states observed in brain injured patients with different degrees of brain impairment, the vegetative state (VS)and the minimally conscious state (MCS), and we discuss how these states are diagnosed through assessing patient behavioral responses during clinical examination. We consider howfunctional neuroimaging has revealed preserved cognitive capacities in patients that were supposed to be in the VS and has introduced a new diagnosis, cognitive motor dissociation.We review the GW Theory proposal that consciousness arises from functional connectivity (FC) of widely separated brain regions. We discuss how such high FC underlies the DefaultMode Network (DMN), a group of neural circuits that are active when an individual is not involved with external tasks and engages in introspective thinking. Finally, we discuss thefinding that the level of FC of the DMN is diminished in brain injured patients and the proposal that the level of residual DMN FC in brain injured patients is an index of their consciousness

Pacientes com lesão cerebral, quando assistidos, podem continuar a desempenhar funções fisiológicas básicas, mesmo estando com a vigília, a atenção, a capacidade de decisão e outras funções de consciência prejudicadas. Revisamos aqui dois níveis de distúrbio de consciência o estado vegetativo (VS) e o nível de consciência mínima (MCS), e discutimos como são diagnosticados através das respostas comportamentais durante o exame clínico. Abordamos como a neuroimagem funcional revelou capacidades cognitivas preservadas em pacientes supostamente em estado vegetativo, introduzindo um novo diagnóstico: a dissociação cognitivo-motora. Revisamos a proposta da Global Workspace (GW) teoria de que a consciência surge a partir de um alto grau de conectividade funcional (FC) entre áreas cerebrais distantes. Discutimos como esta alta conectividade é a base do Default Mode Network (DMN), uma rede neural ativada quando o indivíduo não está envolvido com tarefas externas e se volta para atividade mental introspectiva. Finalmente, discutimos os achados de redução do nível de FC no DMN em pacientes com lesão cerebral e a proposta de que o mesmo poderia ser um índice do nível de consciência nesses pacientes.

Limonene reduces hyperalgesia induced by gp120 and cytokines by modulation of IL-1 ß and protein expression in spinal cord of mice.

AIMS: We have investigated the antihyperalgesic effects of limonene in mice that received intrathecal injection of gp120. MAIN METHODS: Male Swiss mice received gp120, IL-1ß or TNF-α intrathecally or sterile saline as a control. A mechanical sensitivity test was performed at 2 and 3h after the injection. Spinal cord and blood samples were isolated for protein quantification. KEY FINDINGS: Intrathecal administration of gp120 increased mechanical sensitivity measured with an electronic Von Frey apparatus, at 2 and 3h after the injections. Limonene administered orally prior to gp120 administration significantly decreased this mechanical sensitivity at 3h after the gp120 injection. In addition, intrathecal injection of gp120 increased IL-1ß and IL-10 in serum, and limonene prevented the ability of gp120 to increase these cytokines. Limonene also inhibited TNF-α and IL-1ß-induced mechanical hyperalgesia. Western blot assay demonstrated limonene was capable of increasing SOD expression in the cytoplasm of cells from spinal cord at 4h after intrathecal IL-1ß injection. SIGNIFICANCE: These results demonstrate that gp120 causes mechanical hyperalgesia and a peripheral increase in IL-1ß and IL-10, and that prior administration of limonene inhibits these changes. Also limonene modulates the activation of SOD expression in the spinal cord after spinal IL-1ß application. The ability of limonene to inhibit the mechanical hyperalgesia induced by gp120, TNF-α and IL-1ß emphasizes the anti-inflammatory action of limonene, specifically its ability to inhibit cytokine production and its consequences.

A neurodevelopmental model for the origin of depression amongst people living with HIV: convergence ofsSocial and neuroimmunological mechanisms / Modelo neurodesenvolvimenti sta da origem da depressão entre as pessoas que vivem com o HIV: convergência de mecanismos sociais e neuroimunológicos

Depression is a major challenge facing people living with HIV (PLHIV), with prevalence rates ranging from 25-36%. Depression impacts negati vely upon adherence and response to combined anti retroviral therapy (CART) and thetransmission of HIV infection through increased sexually risky behavior. This article proposes a neurodevelopmental model of depression, which tries to integrate the interplay between psychosocial adversity and HIV related- sti gma, on one hand, and HIV associated neuroinfl ammation, on the other hand, in the eti ology of depressionamongst PLHIV. We conclude that PLHIV should be provided an individualized treatment program that develops strategies including personal empowerment for coping with, and overcoming, psychosocial adversity. Further, neurobiologicalstudies should be vigorously pursued tounderstand the neuroplasti c changes leading to depression in PLHIV and to identi fy biomarkers of depression to be employed for clinical diagnosis, treatment follow-up and investigational purposes

A depressão é um grande desafio para as pessoas que vivem com o HIV (PVHIV) com taxas de prevalência entre 25-36%. A depressão tem um impacto negativo sobre a aderência e a resposta à terapia antirretroviral (CART) e a transmissão da infecção pelo HIV, devido ao aumento do comportamento sexual de risco. Este artigo propõe um modelo neurodesenvolvimentista da depressão, que tenta integrar a interação entre adversidade psicossocial e estigma relacionado ao HIV, por um lado, e a neuroinflamação associada ao HIV, por outro, na etiologia da depressão entre as PVHIV. Nós concluímos que as PVHIV deveriam receber um programa de tratamento individualizado que desenvolvesse estratégias de empoderamento para o enfrentamento e a superação da adversidade psicossocial. Ademais, estudos neurobiológicos deveriamser vigorosamente incentivados, visando compreender as mudanças neuroplásticas que levam à depressão nas PVHIV e identificar biomarcadores de depressão, aplicáveis para fins de diagnóstico e de acompanhamento clínicos, assim como para fins de pesquisa

Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from Schinus terebinthifolius fruits in a neuropathic pain model.

OBJECTIVES: Previous studies have shown that essential oil containing (R)-(+)-limonene and α-phellandrene, extracted from fruits of Schinus terebinthifolius Raddi, exhibit anti-inflammatory activity. This work aimed to verify the antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from S. terebinthifolius fruits in spared nerve injury (SNI) model of neuropathic pain in rats. METHODS: In the present work, essential oil from fruits of S. terebinthifolius, as well as the pure (R)-(+)-limonene and α-phellandrene compounds, were assayed for their effects on SNI-induced mechanical and cold hyperalgesia, and depressive-like behavior (immobility in forced swim test) in rats. The locomotor activity was evaluated in open-field test. RESULTS: Oral administration for up to 15 days of essential oil of S. terebinthifolius (100 mg/kg), (R)-(+)-limonene (10 mg/kg), α-phellandrene (10 mg/kg), and also subcutaneous 10 mg/kg dose of ketamine (positive control) significantly inhibited SNI-induced mechanical hyperalgesia and increased immobility in the forced swim test. On the 15th day of oral treatment, α-phellandrene, but neither the essential oil from S. terebinthifolius nor (R)-(+)-limonene, prevented the SNI-induced increase in sensitivity to a cold stimulus. The oral treatment with essential oil (100 mg/kg) or with compounds (10 mg/kg) did not interfere on locomotor activity. DISCUSSION: Together, the results of the present work show that essential oil of S. terebinthifolius and compounds present in this oil, including (R)-(+)-limonene and α-phellandrene, exhibit antihyperalgesic effects against mechanical hyperalgesia, and are antidepressive, while only α-phellandrene inhibited cold hyperalgesia in SNI rats.

Animal models for depression associated with HIV-1 infection.

Antiretroviral therapy has greatly extended the lifespan of people living with human immunodeficiency virus (PLHIV). As a result, the long-term effects of HIV infection, in particular those originating in the central nervous system (CNS), such as HIV associated depression, have gained importance. Animal models for HIV infection have proved very useful for understanding the disease and developing treatment strategies. However, HIV associated depression remains poorly understood and so far there is neither a fully satisfactory animal model, nor a pathophysiologically guided treatment for this condition. Here we review the neuroimmunological, neuroendocrine, neurotoxic and neurodegenerative basis for HIV depression and discuss strategies for employing HIV animal models, in particular humanized mice which are susceptible to HIV infection, for the study of HIV depression.

Brain and the music: a window to the comprehension of the interactive brain functioning

Here we review the most important psychological aspects of music, its neural substrates, its universality and likely biological origins and, finally, how the study of neurocognition and emotions of music can provide one of the most important windows to the comprehension of the higher brain functioning and human mind. We begin with the main aspects of the theory of modularity, its behavioral and neuropsychological evidences. Then, we discuss basic psychology and neuropsychology of music and show how music and language are cognitively and neurofunctionally related. Subsequently we briefly present the evidences against the view of a high degree of specification and encapsulation of the putative language module, and how the ethnomusicological, pscychological and neurocognitive studies on music help to shed light on the issues of modularity and evolution, and appear to give further support for a cross-modal, interactive view of neurocognitive processes. Finally, we will argue that the notion of large modules do not adequately describe the organization of complex brain functions such as language, math or music, and propose a less radical view of modularity, in which the modular systems are specified not at the level of culturally determined cognitive domains but more at the level of perceptual and sensorimotor representations.