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Stroke is considered one of the leading causes of death worldwide. The treatment is limited; however, the Brazilian flora has a great source of natural products with therapeutic potentials. Studies with the medicinal plant Polygala sabulosa W. Bennett provided evidence for its use as an anti-inflammatory and neuroprotective drug. In the case of ischemic stroke due to lack of oxygen, both acute and chronic inflammatory processes are activated. Thus, we hypothesized that P. sabulosa (HEPs) has the potential to treat the motor and cognitive deficits generated by ischemic stroke. Male mice were subjected to global ischemia for 60 min, followed by reperfusion and orally treated with HEPs (100 mg/kg in saline + 3% tween 20) twice a day (12 h apart) for 48 h starting 3 h after surgery. Motor skills were assessed using grip force and open field tasks. Hippocampi were then collected for mRNA quantification of the cytokines IL-1-β and TNF-α levels. After 48 h of acute treatment, spatial reference memory was evaluated in a Morris water maze test for another group of animals. We show that HEPs treatment significantly prevented motor weakness induced by ischemia. Brain infarct area was reduced by 22.25% with downregulation of the levels of IL-1β and TNF-α mRNA. Learning performance and memory ability on Morris water maze task were similar to the sham group. Our data demonstrates the neuroprotective properties of HEPs through its anti-inflammatory activities, which prevent motor and cognitive impairments, suggesting that HEPs may be an effective therapy for ischemic stroke.

O presente trabalho discute e sugere estudos de desenvolvimento de protocolos para atendimento em saúde mental frente à situação de emergência e crise proporcionada pela COVID-19. Há evidências de repercussões na saúde mental e restrições no modo de enfrentamento da pandemia, tendo em vista a situação de isolamento e confinamento prolongadas pela quarentena, sejam entre os suspeitos de contágio, os enfermos pela COVID-19, os familiares ou as equipes de saúde envolvidas na linha de frente do tratamento. Entretanto, há escassez de literatura técnico-científica de protocolos de atendimento para pessoas com necessidade de afastamento social e do trabalho em função da pandemia.

Complex regional pain syndrome type-I (CRPS-I) is a chronic painful condition resulting from trauma. Bradykinin (BK) is an important inflammatory mediator required in acute and chronic pain response. The objective of this study was to evaluate the association between BK receptors (B1 and B2) and chronic post-ischaemia pain (CPIP) development in mice, a widely accepted CRPS-I model. We assessed mechanical and cold allodynia, and paw oedema in male and female Swiss mice exposed to the CPIP model. Upon induction, the animals were treated with BKR antagonists (HOE-140 and DALBK); BKR agonists (Tyr-BK and DABK); antisense oligonucleotides targeting B1 and B2 and captopril by different routes in the model (7, 14 and 21 days post-induction). Here, we demonstrated that treatment with BKR antagonists, by intraperitoneal (i.p.), intraplantar (i.pl.), and intrathecal (i.t.) routes, mitigated CPIP-induced mechanical allodynia and oedematogenic response, but not cold allodynia. On the other hand, i.pl. administration of BKR agonists exacerbated pain response. Moreover, a single treatment with captopril significantly reversed the anti-allodynic effect of BKR antagonists. In turn, the inhibition of BKRs gene expression in the spinal cord inhibited the nociceptive behaviour in the 14th post-induction. The results of the present study suggest the participation of BKRs in the development and maintenance of chronic pain associated with the CPIP model, possibly linking them to CRPS-I pathogenesis.

Citral ((2E)-3,7-dimethylocta-2,6-dienal), a bioactive component of lemongrass, inhibits oxidant activity, nuclear factor kappa B (NF-κB) activation, and cyclooxygenase-2 (COX-2) expression, even a...

Acute ethanol (EtOH) consumption exerts a biphasic effect on behavior and increases serotonin levels in the brain. However, the molecular mechanisms underlying alcohol-mediated behavioral responses still remain to be fully elucidated. Here, we investigate pharmacologically the involvement of the serotonergic pathway on acute EtOH-induced behavioral changes in zebrafish. We exposed zebrafish to 0.25, 0.5, 1.0% (v/v) EtOH for 1 h and analyzed the effects on aggression, anxiety-like behaviors, and locomotion. EtOH concentrations that changed behavioral responses were selected to the subsequent experiments. As a pharmacological approach, we used pCPA (inhibitor of tryptophan hydroxylase), WAY100135 (5-HT1A antagonist), buspirone (5-HT1A agonist), CGS12066A and CGS12066B (5-HT1B antagonist and agonist, respectively), ketanserin (5-HT2A antagonist) and (±)-DOI hydrochloride (5-HT2A agonist). All serotonergic receptors tested modulated aggression, with a key role of 5-HT2A in aggressive behavior following 0.25% EtOH exposure. Because CGS12066B mimicked 0.5% EtOH anxiolysis, which was antagonized by CGS12066A, we hypothesized that anxiolytic-like responses are possibly mediated by 5-HT1B receptors. Conversely, the depressant effects of EtOH are probably not related with direct changes on serotonergic pathway. Overall, our novel findings demonstrate a role of the serotonergic system in modulating the behavioral effects of EtOH in zebrafish. These data also reinforce the growing utility of zebrafish models in alcohol research and help elucidate the neurobiological mechanisms underlying alcohol abuse and associated complex behavioral phenotypes.

Since the 1970s, when ATP was identified as a co-transmitter in sympathetic and parasympathetic nerves, it and its active metabolite adenosine have been considered relevant signaling molecules in biological and pathological processes in the central nervous system (CNS). Meanwhile, inosine, a naturally occurring purine nucleoside formed by adenosine breakdown, was considered an inert adenosine metabolite and remained a neglected actor on the purinergic signaling scene in the CNS. However, this scenario began to change in the 1980s. In the last four decades, an extensive group of shreds of evidence has supported the importance of mediated effects by inosine in the CNS. Also, inosine was identified as a natural trigger of adenosine receptors. This evidence has shed light on the therapeutic potential of inosine on disease processes involved in neurological and psychiatric disorders. Here, we highlight the clinical and preclinical studies investigating the involvement of inosine in chronic pain, schizophrenia, epilepsy, depression, anxiety, and in neural regeneration and neurodegenerative diseases, such as Parkinson and Alzheimer. Thus, we hope that this review will strengthen the knowledge and stimulate more studies about the effects promoted by inosine in neurological and psychiatric disorders.

Epilepsy is one of the most common chronic neurological diseases. It is characterized by recurrent epileptic seizures, where one-third of patients are refractory to existing treatments. Evidence revealed the association between neuroinflammation and increased susceptibility to seizures since there is a pronounced increase in the expression of key inflammatory mediators, such as prostaglandin E2 (PGE2), during seizures. The purpose of this study was to investigate whether PGE2 increases susceptibility to pentylenetetrazol-induced (PTZ) seizures. Subsequently, we evaluated if the flavonoid isolated from the plant Piper aleyreanum (galangin) presented any anticonvulsive effects. Our results demonstrated that the group treated with PGE2 increased susceptibility to PTZ and caused myoclonic and generalized seizures, which increased seizure duration and electroencephalographic wave amplitudes. Furthermore, treatment with PGE2 and PTZ increased IBA-1 (microglial marker), GFAP (astrocytic marker), 4-HNE (lipid peroxidation marker), VCAM-1 (vascular cell adhesion molecule 1), and p-PKAIIα (phosphorylated cAMP-dependent protein kinase) immunocontent. Indeed, galangin prevented behavioral and electroencephalographic seizures, reactive species production, decreased microglial and astrocytic immunocontent, as well as decreased VCAM-1 immunocontent and p-PKA/PKA ratio induced by PGE2/PTZ. Therefore, this study suggests galangin may have an antagonizing role on PGE2-induced effects, reducing cerebral inflammation and protecting from excitatory effects evidenced by administrating PGE2 and PTZ. However, further studies are needed to investigate the clinical implications of the findings and their underlying mechanisms.

Traumatic brain injury (TBI) is a public health problem characterized by a combination of immediate mechanical dysfunction of the brain tissue, and secondary damage. Based on the hypothesis that selected targets, such as Na+ K+-ATPase are involved in the secondary damage after TBI and modulation of this enzyme activity by triterpene 3β, 6β, 16β-trihidroxilup-20 (29)-ene (TTHL) supports the ethnomedical applications of this plant, we decided to investigate whether previous TTHL treatment interrupts the progression of pathophysiology induced by TBI. Statistical analyses revealed that percussion fluid injury (FPI) increased Na+,K+-ATPase activity in all isoform (α1 and α2/3) 15 min after neuronal injury. The FPI protocol inhibited Na+,K+-ATPase activity total and α1 isoform, increased [3H]MK-801 binding but did not alter Dichloro-dihydro-fluorescein diacetate (DCFH-DA) oxidation, carbonylated proteins and free –SH groups 60 min after injury. The increase of immunoreactivity of protein PKC and state of phosphorylation of at Ser16 of Na+,K+-ATPase 60 min after FPI suggest the involvement of PKC on Na+,K+-ATPase activity oscillations characterized by inhibition of total and α1 isoform. Our experimental data also revealed that natural product rich in compounds such as triterpenes (TTHL; 30 mg/kg) attenuates [3H]MK-801 binding increase, phosphorylation of the PKC and the Na+,K+-ATPase alpha 1 subunit (Ser16) induced by FPI. The previous TTHL treatment had not effect on motor disability but protected against spatial memory deficit, BDNF, TrKB expression decrease, protein carbonylation and hippocampal cell death 7 days after FPI. These data suggest that TTHL-induced reduction on initial damage limits the long-term secondary degeneration and supports neural repair or behavioral compensation after neuronal injury.

OBJECTIVES Previous studies demonstrated significant improvement in mean pain scores and quality of life (QOL) scales in patients with chronic pain who underwent spinal cord stimulation (SCS). However, the number of individuals who experience relevant improvements in QOL, termed the meaningful clinical improvement (MCI), is not known. The present study investigated changes in pain measurements based on MCI after SCS. MATERIALS AND METHODS Thirty-four patients with chronic intractable pain completed scales of pain (visual analogue scale [VAS]), QOL (SF-36), and psychological dimensions during a 22-month follow-up period (mean). Patient-centered MCI of the VAS and SF-36 domain scores were determined based on the MacNab criteria of surgical global effectiveness. Independent presurgical predictors for MCI in the VAS and SF-36 domains were analyzed using multiple binary logistic regression. RESULTS There was significant improvement of pain and QOL after the SCS (p < 0.00001). Twenty-three patients (67.6%) reached an MCI of pain, and 16 (47.7%)-23 (67.7%) reported an MCI of QOL. Predictors of MCI included ≥80% paresthesia coverage of the painful area, lower levels of anxiety and catastrophizing symptoms, shorter pain duration, female gender and no use of opioids before surgery. MCI of pain and QOL was observed in 50%-70% of patients with chronic pain after SCS. CONCLUSIONS The identification of determinants for MCI is a challenge to improve the accuracy of prognostic models in SCS for patients with chronic pain. Our results, if confirmed in other populations with a larger sample size, have implications for patients with chronic pain who are candidates for SCS treatment.

While chronic high-fat feeding has long been associated with the rising incidence of obesity/type 2 diabetes, recent evidence has established that it is also associated with deficits in hippocampus-dependent memory. In this regard, environmental enrichment (EE) is an animal housing technique composed of increased space, physical activity, and social interactions, which in turn increases sensory, cognitive, motor, and social stimulation. EE leads to improved cerebral health as defined by increased neurogenesis, enhanced learning and memory and resistance to external cerebral insults. In the present study, the impacts of environmental enrichment (EE) on Swiss mice fed a high-fat, cholesterol-enriched diet (HFECD; 20% fat and 1.5% cholesterol) were investigated. Here, we demonstrated that EE, when initiated 4 weeks after the beginning of HFECD in mice, prevents HFECD-induced spatial memory and object recognition impairment, which were tested in T-maze and object recognition tests. Although EE did not affect HFECD-induced weight gain or hypercholesterolaemia, it improved glucose tolerance. On the other hand, EE was unable to mitigate a decrease in brain-derived neurotrophic factor (BDNF) and IL-6 hippocampal levels induced by the HFECD. Overall, while our results reinforce the positive and neuroprotective effects of EE on cognition they do not support a role for EE in preventing the neurochemical changes induced by the HFECD. Based on clinical observations that nondiabetic individuals with mild forms of impaired glucose tolerance have a higher risk of cognitive impairments, one can speculate about the connection between the effects of EE on glucose intolerance and its effects on cognition.

In sepsis, greater understanding of the inflammatory mechanism involved would provide insights into the condition and into its extension to the muscular apparatus in critically ill patients. Therefore, this study evaluates the inflammatory profile of pneumosepsis induced by Klebsiella pneumoniae (K.p.) in lungs and skeletal muscles during the first 72 h. Male BALB/c mice were divided into 4 groups, submitted to intratracheal inoculation of K.p. at a concentration of 2 × 108 (PS) or PBS, and assessed after 24 (PS24), 48 (PS48) and 72 (PS72) hours. The Maximum Physical Capacity Test (MPCT) was performed before and after induction. Pulmonary inflammation was assessed by total cell number, nitric oxide levels (NOx), IL-1β and TNF-α levels in bronchoalveolar lavage fluid (BALF); inflammation and muscle trophism were evaluated by the levels of TNF-α, IL-6, TGF-β and BDNF by ELISA and NF-κB by western blotting in muscle tissue. Cells and colony forming units (CFU) were also analyzed in blood samples. The PS groups showed an increase in total cells in the BALF (p

Pain, a severely debilitating symptom of many human disorders, is a growing, unmet biomedical problem. Although the use of zebrafish (Danio rerio) to investigate both behavioral and physiological nociception-related responses is expanding rapidly, the characterization of behavioral phenotypes that reflect injury location is limited, making the results of such studies difficult to interpret. Here, we characterize putative nociception-related behavioral phenotypes in adult zebrafish following an intraperitoneal (i.p.) administration of acetic acid, a well-established protocol for visceral pain in rodents. Acetic acid (2.5 and 5.0%) induced an abdominal constriction-like response, which was assessed by measuring a body curvature index. Moreover, all doses tested (0.5-5.0%) reduced distance traveled and vertical activity in the novel tank test. Freezing duration increased following 5.0% acetic acid, whereas fish injected with 1.0, 2.5, and 5.0% spent more time in top area of the tank. Both morphine (an opioid analgesic) and diclofenac (a nonsteroidal anti-inflammatory drug, NSAID) prevented the 5.0% acetic acid-induced changes in body curvature index, whereas naloxone blocked these effects of morphine. Overall, zebrafish exposed to a single acetic acid i.p. injection display abnormal body curvature and specific changes in behavioral parameters sensitive to anti-nociceptive pharmacological modulation. We suggest that the abdominal constriction-like response represents a novel specific nociceptive-related phenotype in zebrafish. In general, our findings support the growing utility of zebrafish in translational pain research and antinociceptive drug discovery.

The flavonoid myricitrin showed an antidepressant-like effect in the tail suspension test and increased hippocampal neurogenesis, as well as demonstrating anti-inflammatory effects. Interestingly, inflammation has been linked to depression, and anti-inflammatory drugs showed promising results as antidepressant-like drugs. Thus, the present study evaluated the effects of myricitrin in the chronic mild stress (CMS) model, a translational and valid animal model of depression, using the mini-experiment design to improve the reproducibility of the findings. The sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST) were the readouts of depressive-like phenotypes induced by CMS. Relative adrenal weight was employed as an index of the hypothalamus-pituitary-adrenal (HPA) axis activation. Interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha levels were measured in the hippocampus. Myricitrin (10 mg/kg, intraperitoneally, for 14 days) reversed depressive-like behaviors induced by CMS (increased immobility in the FST, the TST and anhedonia), as well as decreased adrenal hypertrophy and hippocampal levels of IL-6 in stressed mice. Similar results were observed by imipramine (20 mg/kg, intraperitoneally, for 14 days), a serotonin and norepinephrine reuptake inhibitor (positive control). A significant correlation was observed between immobility time in the TST, and hippocampal IL-6 levels. Hippocampal TNF-α levels were not affected by CMS or drug treatment. In conclusion, myricitrin exhibited an antidepressant-like profile in CMS, and this effect may be associated with its anti-inflammatory activity.

The present study investigated the effects of pulsed and continuous ultrasound (USP and USC) in edema and hyperalgesia after chronic inflammatory process induced by Complete Freund's Adjuvant-CFA and analyzing the relationship of the application frequency of ultrasound, in pro- and anti-inflammatory cytokine production.Forty-five animals were divided into 9 groups; all animals from groups 2 to 9 were subjected to a persistent inflammation model induced by CFA in mice. We report the effects and the underlying action mechanisms of USP and USC in the animals which were irradiated two, three or five times a week on the left hind paw. The analyses performed in this study were: evaluation of hind paw edema through the plethysmometer, evaluation of thermal hyperalgesia through withdrawal test using a water container at 44.5°C (± 0.5°C), and the plantar region of the left paw which was removed for analysis of cytokines.Our results showed that USP and USC consistently reduced paw edema, and pulsed ultrasound showed a higher significant effect than the continuous mode. Moreover, groups with irradiation frequency of five times a week presented an inhibition of the edema, and groups with frequency of three or two times a week reduced mainly hyperalgesia, in comparison with the control group. The beneficial effects of the US then seem to be associated with upregulation of anti- and pro-inflammatory mediators, such as IL-10 and IL-6, respectively.This study provided evidence that ultrasound constitutes an important non-pharmacological intervention for the management of inflammatory and pain states.

Traumatic brain injury (TBI) represents one of the most common social problems worldwide. This neurologic pathology often affects several body systemic organs, including the cardiovascular autonomic system. Changes in cardiac autonomic nervous system (ANS) regulation through the heart rate variability (HRV) analysis have been observed in all degrees of TBI in patients. On the other hand, little research has been addressed in TBI models using rats as a potential target for better explore therapeutic approaches in this pathology. In this sense, we investigate the relationship before and after an induced moderate fluid percussion injury (FPI) model in rats on the HRV features. The findings found in our work showed clearly a decreasing the sympathetic (LF), parasympathetic (HF), and overall HRV (p < 0.01 for mean NN) activities post-TBI when compared to baseline animals. In concomitant to this, the heart rate increased, such as showed by decreasing the mean NN. Therefore, this study indicates that the impacted severity moderate TBI in rats impairs some cardiac autonomic function parameters. However, further research is needed to better understand this pathophysiology.

Reliable electrocardiogram (ECG) recording systems in rats become tools remarkably crucial for the drug safety evaluation in experimental physiological methods. However, the currently existing techniques for ECG measurement in rats still impair a better translational that occurs in the autonomic nervous system (ANS) models. For this reason, we developed a new tool for the ECG measurement in rats on the awake state, no surgical procedure, restraint, as well as anesthesia administration and compared to the isoflurane anesthesia administration. The heart rate variability (HRV) method was used to evaluate the ANS status. The findings demonstrated clearly that the isoflurane anesthesia influence the activities sympathetic and parasympathetic of ANS. Therefore, our newly introduced tool showed to be adequate to study cardiac electrical activity in rats.

The ability of the nervous system to detect a wide range of noxious stimuli is crucial to avoid life-threatening injury and to trigger protective behavioral and physiological responses. Pain represents a complex phenomenon, including nociception associated with cognitive and emotional processing. Animal experimental models have been developed to understand the mechanisms involved in pain response, as well as to discover novel pharmacological and non-pharmacological anti-pain therapies. Due to the genetic tractability, similar physiology, low cost, and rich behavioral repertoire, the zebrafish (Danio rerio) is a powerful aquatic model for modeling pain responses. Here, we summarize the molecular machinery of zebrafish responses to painful stimuli, as well as emphasize how zebrafish-based pain models have been successfully used to understand specific molecular, physiological, and behavioral changes following different algogens and/or noxious stimuli (e.g., acetic acid, formalin, histamine, Complete Freund's Adjuvant, cinnamaldehyde, allyl isothiocyanate, and fin clipping). We also discuss recent advances in zebrafish-based studies and outline the potential advantages and limitations of the existing models to examine the mechanisms underlying pain responses from evolutionary and translational perspectives. Finally, we outline how zebrafish models can represent emergent tools to explore pain behaviors and pain-related mood disorders, as well as to facilitate analgesic therapy screening in translational pain research.

Lesions of peripheral nerves lead to pain, hyperalgesia, and psychological comorbidities. However, the relationship between mood disorders and neuropathic pain is unclear, as well as the underlying mechanisms related to these disorders. Therefore, we investigated if nerve injury induces depression, anxiety, and cognitive impairment and if there were changes in cytokines, growth factors, and glial cell activation in cortical sites involved in processing pain and mood in animals with nerve injury. Nerve injury was induced by partial sciatic nerve ligation (PSNL) in male Swiss mice and compared to sham-operated animals. Nociceptive behavioral tests to mechanical and thermal (heat and cold) stimuli confirmed the development of hyperalgesia. We further examined mood disorders and memory behaviors. We show nerve injury induces a decrease in mechanical withdrawal thresholds and thermal latency to heat and cold. We also show that nerve injury causes depressive-like and anxiety-like behaviors as well as impairment in short-term memory in mice. There were increases in proinflammatory cytokines as well as Brain-Derived Neurotrophic Factor (BDNF) in the injured nerve. In the spinal cord, there were increases in both pro and anti-inflammatory cytokines, as well as of BDNF and Nerve Growth Factor (NGF). Further, in our data was a decrease in the density of microglia and astrocytes in the hippocampus and increased microglial density in the prefrontal cortex, areas associated with neuropathic pain conditions., Graphical abstract Image 1, Highlights • Partial sciatic nerve ligation induces hypersensitivity in mice. • Nerve injury induces depressant-like and anxiolytic-like behavior and memory loss. • The nerve and spinal cord showed an increase in cytokines and neurotrophins. • Nerve injury decreases density of microglia and astrocytes in the hippocampus. • Also, injury increases microglial density in the prefrontal cortex., Supraspinal astrocytes and microglia are involved in the pathogenesis of PSNL-induced painful neuropathy and mood disorders, as well as the increase of inflammatory factors in the spinal cord and nerve. This measure could potentially help clinicians to develop better treatment for chronic pain problems.

The role of peripheral adenosine receptors in pain is a controversial issue and seems to be quite different from the roles of spinal and central adenosine receptors. The present study is aimed at clarifying the role of these receptors in peripheral nociception. To clarify this, studies were done on Swiss mice with adenosine receptor agonists and antagonists. Nociceptive behavior was induced by subcutaneous injection of glutamate (10 μmol) into the ventral surface of the hind paw of mice. Statistical analyses were performed by one-way ANOVA followed by the Student-Newman-Keuls post hoc test. Results showed that intraplantar (i.pl.) administration of N6-cyclohexyl-adenosine (CHA), an adenosine A1 receptor agonist, at 1 or 10 μg/paw significantly reduced glutamate-induced nociception (p0.05 vs. vehicle for all tests). We also found that prior administration of DPCPX (3 μg/paw) significantly blocked the anti-nociceptive effect of CHA (1 μg/paw) (p0.05). In summary, these results demonstrate for the first time that i.pl administration of inosine induces an anti-nociceptive effect, similar to that elicited by CHA and possibly mediated by peripheral adenosine A1 receptor activation. Moreover, our results suggest that peripheral adenosine A2A receptor activation presents a pro-nociceptive effect, exacerbating glutamate-induced nociception independent of inosine-induced anti-nociceptive effects.

Depression has a multifactorial etiology that arises from environmental, psychological, genetic, and biological factors. Environmental stress and genetic factors acting through immunological and endocrine responses generate structural and functional changes in the brain, inducing neurogenesis and neurotransmission dysfunction. Terpineol, monoterpenoid alcohol, has shown immunomodulatory and neuroprotective effects, but there is no report about its antidepressant potential. Herein, we used a single lipopolysaccharide (LPS) injection to induce a depressive-like effect in the tail suspension test (TST) and the splash test (ST) for a preventive and therapeutic experimental schedule. Furthermore, we investigated the antidepressant-like mechanism of action of terpineol while using molecular and pharmacological approaches. Terpineol showed a coherent predicted binding mode mainly against CB1 and CB2 receptors and also against the D2 receptor during docking modeling analyses. The acute administration of terpineol produced the antidepressant-like effect, since it significantly reduced the immobility time in TST (100&ndash, 200 mg/kg, p.o.) as compared to the control group. Moreover, terpineol showed an antidepressant-like effect in the preventive treatment that was blocked by a nonselective dopaminergic receptor antagonist (haloperidol), a selective dopamine D2 receptor antagonist (sulpiride), a selective CB1 cannabinoid receptor antagonist/inverse agonist (AM281), and a potent and selective CB2 cannabinoid receptor inverse agonist (AM630), but it was not blocked by a nonselective adenosine receptor antagonist (caffeine) or a &beta, adrenoceptor antagonist (propranolol). In summary, molecular docking suggests that CB1 and CB2 receptors are the most promising targets of terpineol action. Our data showed terpineol antidepressant-like modulation by CB1 and CB2 cannabinoid receptors and D2-dopaminergic receptors to further corroborate our molecular evidence.

Arachis hypogaea L. (peanut) leaf is traditionally used for the treatment of insomnia in Asia. However, studies describing the safety and toxicity profile for this plant preparation are limited. Thus, the goal of this study was to investigate the toxicity of peanut leaf hydroalcoholic extract (PLHE) repeated treatment. The extract was administered orally (100, 300 or 1000 mg/kg) in male and female Wistar rats for 28 days (OECD guideline 407). PLHE treatment did not cause mortality or weight variation in the animals. Also, there was no alteration on locomotor activity (open field test), motor coordination (rotarod test), or anxiety behaviour (elevated plus-maze test). Male rats had a reduction in relative liver weight (100 mg/kg) and an increase in total kidney weight (1000 mg/kg), but there was no change in biochemical and haematological parameters after PLHE treatment. Free extracellular double-stranded DNA (dsDNA) levels was also evaluated, but PLHE treatment did not increase this parameter in rat organs. Also, the dose of 1000 mg/kg of PLHE significantly increased the total thiols in the liver of females compared with the control animals. Thus, PLHE did not induce toxicity after repeated exposure for 28 days in rats.

Dysfunction of basal ganglia neurons is a characteristic of glutaric acidemia type I (GA-I), an autosomal recessive inherited neurometabolic disease characterized by deficiency of glutaryl-CoA dehydrogenase (GCDH) and accumulation of glutaric acid (GA). The affected patients present clinical manifestations such as motor dysfunction and memory impairment followed by extensive striatal neurodegeneration. Knowing that there is relevant striatal dysfunction in GA-I, the purpose of the present study was to verify the performance of young rats chronically injected with GA in working and procedural memory test, and whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Rat pups were injected with GA (5 μmol g body weight−1, subcutaneously; twice per day; from the 5th to the 28th day of life) and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). We found that GA injection caused delay procedural learning; increase of cytokine concentration, oxidative markers, and caspase levels; decrease of antioxidant defenses; and alteration of acetylcholinesterase (AChE) activity. Interestingly, we found an increase in glial cell immunoreactivity and decrease in the immunoreactivity of nuclear factor-erythroid 2-related factor 2 (Nrf2), nicotinic acetylcholine receptor subunit alpha 7 (α7nAChR), and neuronal nuclei (NeuN) in the striatum. Indeed, NAC administration improved the cognitive performance, ROS production, neuroinflammation, and caspase activation induced by GA. NAC did not prevent neuronal death, however protected against alterations induced by GA on Iba-1 and GFAP immunoreactivities and AChE activity. Then, this study suggests possible therapeutic strategies that could help in GA-I treatment and the importance of the striatum in the learning tasks.

Hyperammonemia is a common finding in patients with methylmalonic acidemia. However, its contribution to methylmalonate (MMA)-induced neurotoxicity is poorly understood. The aim of this study was evaluate whether an acute metabolic damage to brain during the neonatal period may disrupt cerebral development, leading to neurodevelopmental disorders, as memory deficit. Mice received a single intracerebroventricular dose of MMA and/or NH4Cl, administered 12 hs after birth. The maze tests showed that MMA and NH4Cl injected animals (21 and 40 days old) exhibited deficit in the working memory test, but not in the reference memory test. Furthermore, MMA and NH4Cl increased the levels of 2′,7′-dichlorofluorescein-diacetate (DCF), TNF-α, IL-1β in the cortex, hippocampus and striatum of mice. MMA and NH4Cl also increased glial proliferation in all structures. Since the treatment of MMA and ammonia increased cytokines levels, we suggested that it might be a consequence of the glial activation induced by the acid and ammonia, leading to delay in the developing brain and contributing to behavioral alterations. However, this hypothesis is speculative in nature and more studies are needed to clarify this possibility.

Background: Low back pain (LBP) has more than doubled in the last 20 years, probably influenced by biopsychosocial factors. Noninvasive treatments have been applied in individuals with chronic nonspecific LBP as spinal manipulation and pain education. However, the neurophysiological effects of these treatments are not clear. The aim of this research is to verify the pain control, functional and neurophysiological effects of spinal manipulation, and pain education in individuals with chronic nonspecific LBP. Methods: This research is an assessor and subject blinded, 2-arm, randomized sham-controlled trial and will be conducted at Governador Celso Ramos Hospital, Florianópolis, Brazil. One hundred and twenty-eight individuals with chronic nonspecific LBP will be recruited for this study. Individuals will be randomly allocated into one of the two groups: (1) spinal manipulation plus pain education or (2) sham treatment plus pain education. Each group will be received two sessions per week over six weeks of treatment. The measures will be applied at baseline, six weeks, and three months after randomization. The primary outcome will be a pain intensity at six weeks postrandomization. Secondary outcomes will be pressure pain threshold, disability, fear and avoidance beliefs, kinesiophobia, risk of poor prognosis, quality of life, and inflammatory biomarkers. Discussion: Evidence has shown that psychosocial factors are more involved in chronic pain than we thought a few years ago. Then, studies investigating both functional and neurophysiological effects of these interventions to evaluate the effectiveness of treatment and what else is happening at the cellular level in nervous system are needed. Keywords: Low back pain, Musculoskeletal manipulations, Neurophysiology, Education, Randomized controlled trial

Ethnopharmacological relevance Eugenia brasiliensis Lam. (Myrtaceae) is a Brazilian tree distributed throughout Atlantic rain forest, since Bahia until Santa Catarina state, and is popularly known as “grumixaba, grumixameira, cumbixaba, ibaporoiti, and cereja-brasileira”. The bark and leaves of Eugenia brasiliensis are used in folk medicine as adstringent, diuretic, energizing, anti-rheumatic and anti-inflammatory. This study aimed at investigating the chemical composition, antinociceptive and anti-inflammatory effect of the hydroalcoholic extract of Eugenia brasiliensis (HEEb). Material and methods Chemical composition of the HEEb was determined by High Performance Liquid Chromatography/ESI-Mass Spectrometry (HPLC-ESI-MS/MS). The antinociceptive and anti-inflammatory effects of HEEb (30–300 mg/kg) was verified in mice after oral administration by intra-gastric gavage (i.g.) 60 min prior to experimentation. It was investigated whether HEEb decreases visceral pain and leukocyte migration induced by an intraperitoneal (i.p.) injection of acetic acid (0.6%). We also evaluated whether HEEb decreases nociceptive behavior induced by formalin (including paw edema and temperature), prostaglandin E2 (PGE2), histamine, and compound 48/80. Finally, we evaluated the effect of HEEb in the chronic inflammatory (mechanical and thermal hypersensitivity) pain induced by complete Freund's adjuvant (CFA), as well as quantifying the concentration of the pro-inflammatory cytokines TNF-α and IL-6 in the paw by ELISA method. Results Seven polyphenols were identified in HEEb by HPLC-ESI-MS/MS analysis. HEEb treatment alleviated nocifensive behavior and leukocyte migration caused by acetic acid. Moreover, HEEb also reduced the inflammatory pain and paw temperature induced by formalin, as well as it decreased nociceptive behavior induced by histamine and compound 48/80. Finally, acute and repeated treatment of animals with HEEb (100 mg/kg, i.g.) markedly reduced the mechanical and thermal (heat) hypersensitivity, besides decrease paw edema and temperature induced by CFA, and this effect was evident until the day 7. Moreover, repeated treatment with HEEb (100 mg/kg, i.g.) significantly reduced the levels of IL-6 and TNF-α in the paw when compared to the CFA group. Conclusions This is the first report showing that HEEb presents antinociceptive and anti-inflammatory effects in the visceral and somatic inflammatory pain in mice, possibly involving the inhibition of histamine receptors and pro-inflammatory cytokines activated pathways. Our results are of interest because they support the use of Eugenia brasiliensis as a potential source of phytomedicine for inflammatory diseases and pain.

Purpose Zoledronic acid (ZOL) and denosumab (Dmab) are commonly used to treat bone pathologies. Because these drugs suppress bone metabolism, this study sought to compare their effect on bone repair after tooth extraction. Materials and Methods Four-week-old male Wistar rats were randomly assigned to 1 of 3 groups: ZOL 0.125 mg/kg, Dmab 0.25 mg/kg, or saline solution 10 mL/kg (control). After 1 week of treatment, the first left molar was extracted; the rats were euthanized at 28 days. The jaws were removed and photographed for macroscopic analysis of wound healing and then subjected to tomographic and histologic analyses. Immunohistochemistry was carried out against the receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG). Results No difference in wound healing, presence of inflammatory infiltrate and bone sequestration, or osteocyte expression of RANKL and OPG was found among groups. Tomographic analysis showed that the ZOL group had less alveolar resorption and more complete alveolar repair compared with the other groups. There was a statistically significant difference in the OPG marker in the control ( P = .008) and ZOL ( P = .05) groups when comparing the extracted and non-extracted sides. Conclusion Systemic use of ZOL can improve alveolar bone healing; however, the potential risk for the development of osteonecrosis should be considered. Higher expression of OPG seems to be associated with the control of osteoclastogenesis during bone repair.

Ethnopharmacological relevance Cedar is part of the phylum of conifers, and it's essential oil has been used for therapeutic purposes since ancient times. In our previous study, we have demonstrated that the inhalation of the Cedrus atlantica essential oil (CaEO) induces an antihyperalgesic effect in a model of postoperative pain. But the mechanism that underlies this effect is not yet fully known. Aim of the study This study investigates the involvement of the endocannabinoid system in the antihyperalgesic effect produced by the inhalation of CaEO in a post operative pain model. Materials and Methods Male Swiss mice (25–35±2 g) were subjected to plantar incision. To assess the involvement of the endocannabinoid system, two different approaches were made: (1) by administering antagonists to the CB 1 and CB 2 receptors in different sites (intraperitoneal [i.p.], intraplantar [i.pl.] and intrathecal [i.t.]) and (2) by assessing the synergic effect of the inhalation of sub-effective doses of CaEO, Fatty acid hydrolase (FAAH) and Monoacylglycerol lipase (MAGL), and endocannabinoid degradation inhibitors (URB937 and JZL184, respectively). Results The antihyperalgesic effect of CaEO inhalation was prevented by pretreatment with AM281 or AM630 given by i.p. and i.t., but not i.pl. Additionally, in mice pretreated with FAAH or the MAGL inhibitors, the antihyperalgesic effect of CaEO inhalation was significantly longer, which demonstrates the involvement of the endocannabinoid system in the antihyperalgesic effect of CaEO inhalation in a preclinical model of postoperative pain. Conclusions The present study shows that CaEO inhalation exerts an antihyperalgesic effect, possibly by the activation of the endocannabinoid system in a preclinical model of postoperative pain. It could be a new alternative to treat pain in a clinical environment.

Although training programs with regular eccentric (ECC) exercise are more commonly used for improving muscular strength and mobility, ECC exercise effects upon functional recovery of the sciatic nerve has not yet been determined. After sciatic nerve crush, different mice groups were subjected to run on the treadmill for 30 min at a speed of 6, 10, or 14 m/min with - 16° slope, 5 days per week, over 8 weeks. During the training time, neuropathic pain-like behavior (mechanical and cold hyperalgesia) was assessed and functional recovery was determined with the grip strength test and the Sciatic Functional and Static indexes (SFI and SSI). After 9 weeks, triceps surae muscle weight and morphological alterations were assessed. Tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-4 (IL-4), interleukin-1Ra (IL-1Ra), insulin-like growth factor-1 (IGF-1) levels, and markers pro- and anti-inflammatory and regeneration, respectively, were quantified in the muscle and sciatic nerve on day 14 post-crushing. Exercised groups presented less neuropathic pain-like behavior and better functional recovery than non-exercised groups. Biochemically, ECC exercise reduced TNF-α increase in the muscle. ECC exercise increased sciatic nerve IGF-1 levels in sciatic nerve crush-subjected animals. These findings provide new evidence indicating that treatment with ECC might be a potential approach for neuropathy induced by peripheral nerve injury.

Background Electrical stimulation is often used to treat weakness in people with spinal cord injury (SCI); however its efficacy for increasing strength and trophism is weak, and the mechanisms underlying the therapeutic benefits are unknown. Objective The purpose of this study was to analyze the effects of neuromuscular electrical stimulation (NMES) on muscle function, trophism, and the Akt pathway signaling involved in muscular plasticity after incomplete SCI in rats. Design This was an experimental study. Methods Twenty-one adult female Wistar rats were divided into sham, SCI, and SCI plus NMES groups. In injured animals, SCI hemisection was induced by a surgical procedure at the C5-C7 level. The 5-week NMES protocol consisted of biceps brachii muscle stimulation 5 times per week, initiated 48 h after injury. Forepaw function and strength, biceps muscle trophism, and the expression of phosphorylated Akt, p70S6K, and GSK-3ß cellular anabolic pathway markers in stimulated muscle tissue were assessed. Results There was an increase in bicep muscle strength in the NMES group compared with the untreated SCI group, from postoperative day 21 until the end of the evaluation period. Also, there was an increase in muscle trophism in the NMES group compared with the SCI group. Forelimb function gradually recovered in both the SCI group and the NMES group, with no differences between them. Regarding muscle protein expression, the NMES group had higher values for phospho-Akt, phospho-p70S6K, and phospho-GSK-3ß than did the SCI group. Limitations The experimental findings were limited to an animal model of incomplete SCI and may not be fully generalizable to humans. Conclusions Early cyclical NMES therapy was shown to increase muscle strength and induce hypertrophy after incomplete SCI in a rat model, probably by increasing phospho-Akt, phospho-p70S6K, and phospho-GSK-3ß signaling protein synthesis.

Atorvastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor with cholesterol-lowering, anti-inflammatory, and antioxidant properties. Increasing evidence show atorvastatin acts as a protective agent against insults in the central nervous system (CNS). The regular use of statins has been associated with a reduced risk of Parkinson's disease (PD) development. Here, we evaluated early events involved in the neurotoxicity induced by intranasal (i.n.) infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rats and the potential of atorvastatin to prevent these early toxic events. Male Wistar rats were pretreated orally with atorvastatin (10 mg/kg/day) or vehicle once a day during seven consecutive days. Twenty-four hours after atorvastatin administration, animals received a single bilateral i.n. infusion of MPTP (1 mg/nostril), and 6 h later, the striatum and the hippocampus were collected to evaluate early oxidative stress parameters and inflammatory cytokines. Atorvastatin prevented MPTP-induced increase in reactive species (RS) generation and in glutathione levels in the striatum. Atorvastatin also prevented the reduction in mitochondrial respiratory chain complex I and II activities evoked by MPTP in the striatum. Atorvastatin per se reduced the levels of the cytokines TNF-α and IL-1β, and surprisingly, it reduced IL-10 and nerve growth factor levels in the striatum. However, the anti-inflammatory IL-10 levels increased in the striatum following atorvastatin plus MPTP treatment. These effects were not observed in the hippocampus. Our findings reinforce and extend the notion of the neuroprotective effects of atorvastatin in a PD model and indicate the modulation of oxidative and inflammatory responses as the mechanisms associated with therapeutic action of atorvastatin in PD.

Peripheral nerve injury (PNI) activates the immune system, resulting in increased proinflammatory cytokines at the site of injury and in the spinal cord dorsal horn. Exercise modulates the immune system promoting an anti-inflammatory phenotype of macrophages in uninjured muscle, and increases in anti-inflammatory cytokines can promote healing and analgesia. We proposed that PNI will decrease, and treadmill exercise will increase, release of anti-inflammatory cytokines at the site of injury and in the spinal cord. We show that 2 weeks of treadmill exercise improves neuropathic pain behaviors in mice: mechanical hyperalgesia, escape and avoidance behavior, and spontaneous locomotor activity. Peripheral nerve injury reduced anti-inflammatory cytokines (interleukin-4 [IL-4], IL-1ra, and IL-5) at the site of nerve injury and in the spinal dorsal horn, whereas exercise restored IL-4, IL-1ra, and IL-5 concentrations to preinjury levels. IL4 mice and mice treated with IL-4 antibody did not develop analgesia to treadmill exercise. Using immunohistochemical staining of the sciatic nerve, treadmill exercise increased the percentage of M2 macrophages (secretes anti-inflammatory cytokines) and decreased M1 macrophages (secretes proinflammatory cytokines) when compared with sedentary mice. The increased M2 and decreased M1 macrophages in exercised mice did not occur in IL-4 mice. In the spinal cord, PNI increased glial cell activation, brain-derived neurotrophic factor and β-nerve growth factor levels, and decreased IL-4 and IL-1ra levels, whereas treadmill exercise suppressed glial cells activation (Glial Fibrillary Acidic Protein and Iba1 immunoreactivity), reduced brain-derived neurotrophic factor and β-nerve growth factor, and increased IL-4, IL-1ra, and IL-5 concentrations. Our results suggest that IL-4 mediates the analgesia produced by low-intensity exercise by modulating peripheral and central neuroimmune responses in mice with neuropathic pain.

Although photobiomodulation therapy (PBM) has been applied clinically for the treatment of pain and inflammation, wound healing, sports and soft tissue injuries, as well as to repair injured spinal cords and peripheral nerves, it remains unclear which molecular substrates (receptor) are implicated in the cellular mechanisms of PBM. Here, we reported that PBM (660 nm, 30 mW, 0.06 cm2, 50 J/cm2, plantar irradiation) significantly inhibited carrageenan-induced paw oedema, but not noxious thermal response, through positive modulation to both CB1 and CB2 cannabinoid receptors. The use of CB1 antagonist AM281 or CB2 antagonist AM630 significantly reversed the anti-inflammatory effect of PBM. Analysis of signalling pathway downstream of cannabinoid receptors activation reveals that anti-inflammatory effects of PBM depend, in great extent, on its ability to activate ATP-dependent K+ channels and p38 mitogen-activated protein kinase. Moreover, PBM therapy significantly reduced the levels of pro-inflammatory cytokine IL-6 in both paw and spinal cord, and restored the reduction of the level of anti-inflammatory cytokine IL-10 in spinal cord after carrageenan injection. Unlike the potent cannabinoid receptor agonist (WIN 55212-2), PBM did not exert any CNS-mediated effects in the tetrad assay. Finally, PBM does not reduce inflammation and noxious thermal response induced by LPS and zymosan, a TLR4 and TLR2/dectin-1 ligand, respectively. Thus, cannabinoid receptors and, possibly, the endocannabinoid system, represent an important site of action of PBM that opens the possibility of complementary and nonpsychotropic therapeutic interventions in clinical practice.

Species of the Byrsonima genus are widely used in Brazil, especially for the treatment of gastrointestinal disorders. However, species from the Amazonian region are still poorly studied. Thus, we studied the antioxidant, antinociceptive, and anti-inflammatory activities of for Amazonian species, Byrsonima crispa, Byrsonima duckeana, Byrsonima garcibarrigae, and Byrsonima incarnata. Phenolic composition was determined by chemical and chromatographic methods. The aqueous extracts were evaluated in DPPH• , ABTS+• , and superoxide (O2•- ) tests, LPS-activated macrophage assay, and formalin test. All species contained a high phenolic and flavonoid content. We identified 15 phenolic compounds, including phenolic acids, hydroxycinnamic acids, flavonoids, and catechins. The extracts showed high antioxidant activity and were more active than quercetin at inhibiting nitric oxide release in the LPS-activated macrophage assay. B. duckeana and B. garcibarrigae showed higher in vivo antinociceptive and anti-inflammatory activities. B. garcibarrigae presented significant effect on the early phase of the formalin test, pointing to an antinociceptive mechanism distinct from traditional anti-inflammatory medicines. In conclusion, the pharmacological potential of these species is closely related to their flavonoid-rich chemical composition, which seems to act through antioxidant mechanisms. Copyright © 2017 John Wiley & Sons, Ltd.

Aerobic exercise (AE) reduces lung function decline and risk of exacerbations in asthmatic patients. However, the inflammatory lung response involved in exercise during the sensitization remains unclear. Therefore, we evaluated the effects of exercise for 2 weeks in an experimental model of sensitization and single ovalbumin-challenge. Mice were divided into 4 groups: mice non-sensitized and not submitted to exercise (Sedentary, n=10); mice non-sensitized and submitted to exercise (Exercise, n=10); mice sensitized and exposed to ovalbumin (OVA, n=10); and mice sensitized, submitted to exercise and exposed to OVA (OVA+Exercise, n=10). 24 h after the OVA/saline exposure, we counted inflammatory cells from bronchoalveolar fluid (BALF), lung levels of total IgE, IL-4, IL-5, IL-10 and IL-1ra, measurements of OVA-specific IgG1 and IgE, and VEGF and NOS-2 expression via western blotting. AE reduced cell counts from BALF in the OVA group (p

Acute pain post-surgery is one of the major problems of public health, and its treatment is still a challenge. In this study, it was investigated the analgesic effect of a standardized methanolic extract of Condalia buxifolia (MECb) (30 and 100 mg/kg, i.g.) in a plantar incision surgery (PIS) model in mice, and the possible mechanism that underlying its effect. The effect of MECb was evaluated on the hyperalgesia (mechanical, cold and heat stimuli), and in this same model, it was analyzed the effect of MECb (100 mg/kg, i.g.) on the concentration of cytokines (TNF-α, IL-1β, IL-10) and nerve growth factor (NGF) in the paw and spinal cord. Further we investigated the effects of MECb (100 mg/kg, i.g.) on the nocifensive behaviour (spontaneous pain and hyperalgesia) induced by AMPA and kainate. Moreover, the safety profile of prolonged treatment with MECb (100 and 300 mg/kg, i.g.) and involvement of C fibers sensitive to capsaicin in its effect (100 mg/kg, i.g.) was evaluated. MECb showed a marked reduction on mechanical and heat hyperalgesia, and reduced the concentrations of TNF-α, IL-1β, and NGF. The treatment with MECb prevented the nocifensive behaviour and central sensitization caused by AMPA and kainate. Moreover, the analgesic effect of MECb was not affected by the ablation of the central afferent C fibers, and it showed reduced toxicity, indicating good safety and efficacy. The current data showed, for the first time, the analgesic and anti-inflammatory effect of MECb in an animal model of postoperative pain. The results support and suggest the use of MECb as an alternative treatment and a possible source of analgesics substances to postoperative pain.

Ethnopharmacological relevance 3β,6β,16β-Trihydroxylup-20(29)-ene (TTHL) is a triterpene isolated from the flowers of Combretum leprosum, a plant used in folk medicine in the north of Brazil for the treatment of skin disorders. Aim of the study In the present study, TTHL was evaluated as a potential topical anti-inflammatory and anti-proliferative agent through in vivo and in vitro models. Material and methods Anti-inflammmatory and anti-proliferative effects of TTHL were assessed using Swiss mice in acute and chronic models of skin inflammation induced by 12- O -tetradecanoylphorbol-acetate (TPA) application. Anti-proliferative activity was proved through in vitro experiments with the HaCaT human keratinocyte cell line. Results Treatment with TTHL inhibited inflammatory parameters such as oedema formation and cellular infiltration in acute and chronic models. In the chronic model, TTHL also inhibited epidermal hyperproliferation, as evidenced by reduction of epidermis thickness and proliferating cell nuclear antigen expression. The anti-proliferative effect was confirmed by the capability of TTHL in reducing the proliferation and inducing cell apoptosis of HaCaT cells. Suggesting a mechanism of action, TTHL showed activation of corticosteroid receptors, but without the induction of corticosteroid-related cutaneous side effects. Conclusion Our results demonstrate consistent anti-inflammatory and anti-proliferative activity and assign TTHL as a valuable tool in the development of a new treatment for skin inflammatory and proliferative diseases, such as psoriasis.

Objective This study aims to investigate the efficacy of cognitive functional therapy (CFT) compared to core training exercise (CTE) on pain and specific disability of patients with failed back surgery syndrome (FBSS). Design This will be a randomized controlled clinical trial of two groups with blinded evaluators. Setting The study will be conducted at the Federal University of Santa Catarina (UFSC) and a private clinic in Florianopolis, SC, Brazil. Participants A total of 80 participants, of both sexes, with FBSS. Intervention Subjects will be randomized into two groups: one group receiving CFT or CTE. Individuals will be assisted once a week, for a maximum period of 12 weeks, with four being the minimum number of visits and 12 being the maximum number of visits. Measurements The primary outcomes will be pain and specific disability. Conclusions This is the first study investigating whether CFT is efficacious for patients with FBSS and chronic low back pain. The study's sample size was calculated to detect the effect of clinically relevant treatment with a low risk of bias. This clinical trial was designed to be able to reproduce an approach as a physiotherapist trained in CFT would do. That is, in a pragmatic way, increasing the significance of this study. CTE comprises a strategy widely used by physiotherapists to treat low back pain. Given that the scientific evidence of its efficacy for pain management is limited, the findings of this study will assist physiotherapists in their clinical decision-making.

Adipose tissue accumulation, resulting from the consumption of hypercaloric foods, can cause a dysfunction of the endocrine system. Such endocrine changes can influence the expression of various neurochemicals including brain-derived neurotrophic factor (BDNF) - associated with cognitive and emotional problems. Here, we investigated the effects of a hypercaloric diet on depression- and anxiety-like behaviors in young rats along with concomitant changes in BDNF expression levels in the hippocampus. Eight week-old Wistar rats (n = 20) were divided in: control diet (CD) group which received industrial food (n = 8) and hypercaloric diet (HD) group which received animal fat and soybean oil (n = 12). After 45 days on the diet, the animals were evaluated: body weight and blood biochemical analisys. Changes in mood disposition were evaluated using forced swim test and the elevated plus-maze, whereas hippocampal BDNF expression levels were quantified by ELISA. After 45 weeks, the CD group showed a significant increase in body weight relative to the HD group. However, the HD rats had a body fat percentage and exhibited increased level of the biochemical markers. Furthermore, the animals in the HD group presented increased immobility time in the forced swimming test, as well as reduced response to plus-maze test suggesting a depression- and anxiety-like emotional state. In addition, the HD group also showed lower BDNF expression levels in the hippocampus. This study demonstrates that a hypercaloric diet induced increase in adipose tissue concentration in young rats was associated with reduced hippocampal BDNF expression and resulted in an increase in depression- and anxiety-like behaviors. Graphical abstract.

Post-traumatic headache (PTH) is a condition that frequently affects individuals after traumatic brain injury (TBI). Inflammation is one of the major causes of this disability. However, little is known about the trigger for, and endurance of, this painful process. Thus, the involvement of fibers containing the transient receptor potential vanilloid 1 (TRPV1) channels on the PTH and inflammation after TBI through neonatal treatment with capsaicin are investigated. Fluid percussion injury (FPI) in adult male Wistar rats caused periorbital allodynia in one, three and seven days after injury, and the neonatal treatment reversed the painful sensation in seven days. The lack of TRPV1 channels reduced the activation of macrophages and glial cells induced by TBI in the trigeminal system, which were characterized by glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule-1 (IBA-1) immune content in the ipsilateral trigeminal ganglion, brainstem, and perilesional cortex. Immunofluorescence analyses of the ipsilateral Sp5C nucleus demonstrated a hypertrophic astrocytes profile after TBI which was reduced with treatment. Moreover, effects of succinate sumatriptan (SUMA - 1 mg/kg), TRPV1 selective antagonist capsazepine (CPZ - 2 mg/kg), and TRP non-selective antagonist ruthenium red (RR - 3 mg/kg) were evaluated. Although all mentioned drugs reduced the painful sensation, SUMA and CPZ demonstrated a stronger effect compared to the RR treatment, reinforcing the involvement of TRPV1 channels in periorbital allodynia after TBI. Hence, this report suggests that TRPV1-containing fibers and TRPV1 channels are able to induce inflammation of the trigeminal system and maintain the painful sensation after TBI.

As exercise intervention solely for pain reduction is relatively new, the available research still leaves an incomplete picture of responsible mechanisms and pathways. Nonetheless, evidence indicates that exercise-induced analgesia involves activation of the endocannabinoid (eCB) system. The present study investigated the role of the eCB system on the antihyperalgesic effect of high-intensity swimming exercise (HISE) in an animal model of peripheral persistent inflammation. Male Swiss mice were allocated to non-exercised and exercised groups and subjected to subcutaneous intraplantar injection (i.pl.) of a single dose of complete Freund's adjuvant (CFA) to induce inflammatory pain. Cumulative HISE was performed once a day, and mechanical hyperalgesia and edema were evaluated 0.5 hour after HISE for seven consecutive days. To investigate the role of the eCB system on the antihyperalgesic effect of HISE, non-exercised and exercised mice received intraperitoneal (ip), intrathecal (i.t.) or i.pl. injections of vehicle, AM281 (a CB1 cannabinoid receptor antagonist) or AM630 (a CB2 cannabinoid receptor antagonist) from the 3rd to 5th day after CFA injection. Mechanical hyperalgesia was evaluated 0.5 hour after HISE. In addition, the effect of the fatty acid amide hydrolase [FAAH] inhibitor or monoacylglycerol lipase [MAGL] inhibitor on the antihyperalgesic action of HISE was investigated. HISE reduced mechanical hyperalgesia with effects prevented by AM281 or AM630 pretreatment in all delivery routes tested. The inhibition of FAAH and MAGL prolonged the antihyperalgesic effect of HISE. These data demonstrate evidence for the role of the eCB system upon exercise-induced analgesia in a murine model of inflammatory pain.

Context Biochemical markers correlate positively with the development and severity of obesity, depression, and anxiety, and can be modulated by changes in intestinal microbiota composition. Objective A systematic review and meta-analysis was conducted to determine the effects of prebiotics or synbiotics on blood biomarkers of obesity, depression, and anxiety (including: ACTH [adrenocorticotropic hormone], cortisol, leptin, ghrelin, TSH [thyroid-stimulating hormone], PTH [parathyroid hormone], vitamin D, BDNF [brain-derived neurotrophic factor], and PCR [polymerase chain reaction]) in individuals with overweight or obesity. Data Sources MEDLINE, Web of Science, Scopus, and CENTRAL databases were searched, along with the reference lists of included articles. Authors were contacted for unpublished data. Study Selection RCT in individuals with overweight or obesity, supplemented with prebiotics or synbiotics, assessing any of the outcomes of interest. Data Extraction Data were extracted independently by three researchers. Results Thirteen studies were identified up to March 7, 2018. Regarding outcomes, 1 study assessed leptin, 4 studies assessed ghrelin, and 10 studies assessed CRP (C-reactive protein). Meta-analysis showed reduction in serum concentrations of ghrelin (−37.17 pg/mL; 95%CI = −69.62, −4.73; P = 0.025) and CRP (SMD [standardized mean difference] = −0.31; 95%CI = −0.58, −0.04; P = 0.027) after supplementation of inulin-type fructans. Conclusions Prebiotics may help regulate blood concentrations of ghrelin and CRP in overweight or obese individuals.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces motor and nonmotor dysfunctions resembling Parkinson’s disease (PD); however, studies investigating the effects of 1-methyl-4-phenylpyridinium (MPP+), an active oxidative product of MPTP, are scarce. This study investigated the behavioral and striatal neurochemical changes (related to oxidative damage, glial markers, and neurotrophic factors) 24 h after intracerebroventricular administration of MPP+ (1.8–18 μg/mouse) in C57BL6 mice. MPP+ administration at high dose (18 μg/mouse) altered motor parameters, since it increased the latency to leave the first quadrant and reduced crossing, rearing, and grooming responses in the open-field test and decreased rotarod latency time. MPP+ administration at low dose (1.8 μg/mouse) caused specific nonmotor dysfunctions as it produced a depressive-like effect in the forced swim test and tail suspension test, loss of motivational and self-care behavior in the splash test, anxiety-like effect in the elevated plus maze test, and short-term memory deficit in the step-down inhibitory avoidance task, without altering ambulation. MPP+ at doses of 1.8–18 μg/mouse increased tyrosine hydroxylase (TH) immunocontent and at 18 μg/mouse increased α-synuclein and decreased parkin immunocontent. The astrocytic calcium-binding protein S100B and glial fibrillary acidic protein (GFAP)/S100B ratio was decreased following MPP+ administration (18 μg/mouse). At this highest dose, MPP+ increased the ionized calcium-binding adapter molecule 1 (Iba-1) immunocontent, suggesting microglial activation. Also, MPP+ at a dose of 18 μg/mouse increased thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels and increased glutathione peroxidase (GPx) and hemeoxygenase-1 (HO-1) immunocontent, suggesting a significant role for oxidative stress in the MPP+-induced striatal damage. MPP+ (18 μg/mouse) also increased striatal fibroblast growth factor 2 (FGF-2) and brain-derived neurotrophic factor (BDNF) levels. Moreover, MPP+ decreased tropomyosin receptor kinase B (TrkB) immunocontent. Finally, MPP+ (1.8–18 μg/mouse) increased serum corticosterone levels and did not alter acetylcholinesterase (AChE) activity in the striatum but increased it in cerebral cortex and hippocampus. Collectively, these results indicate that MPP+ administration at low doses may be used as a model of emotional and memory/learning behavioral deficit related to PD and that MPP+ administration at high dose could be useful for analysis of striatal dysfunctions associated with motor deficits in PD.

Epilepsy is a chronic neurological disease characterized by spontaneous recurrent seizures (SRS). Current anticonvulsant drugs are ineffective in nearly one-third of patients and may cause significant adverse effects. Rosmarinic acid is a naturally occurring substance which displays several biological effects including antioxidant and neuroprotective activity. Since oxidative stress and excitotoxicity play a role in the pathophysiology of seizures, we aimed the present study to test the hypothesis that rosmarinic acid displays anticonvulsant and disease-modifying effects. Female C57BL/6 mice received rosmarinic acid (0, 3, 10, or 30mg/kg; p.o.) 60min before the injection of pentylenetetrazol (PTZ, 60mg/kg; i.p.) or pilocarpine (300mg/kg, i.p.). Myoclonic and generalized tonic-clonic seizure latencies and generalized seizure duration were analyzed by behavioral and electroencephalographic (EEG) methods. The effect of acute administration of rosmarinic acid on mice behavior in the open-field, object recognition, rotarod, and forced swim tests was also evaluated. In an independent set of experiments, we evaluated the effect of rosmarinic acid (3 or 30mg/kg, p.o. for 14days) on the development of SRS and behavioral comorbidities in the pilocarpine post-status epilepticus (SE) model of epilepsy. Rosmarinic acid dose-dependently (peak effect at 30mg/kg) increased the latency to myoclonic jerks and generalized seizures in the PTZ model and increased the latency to myoclonic jerks induced by pilocarpine. Rosmarinic acid (30mg/kg) increased the number of crossings, the time at the center of the open field, and the immobility time in the forced swim test. In the chronic epilepsy model, treatment with rosmarinic acid did not prevent the appearance of SRS or behavioral comorbidities. In summary, rosmarinic acid displayed acute anticonvulsant-like activity against seizures induced by PTZ or pilocarpine in mice, but further studies are needed to determine its epilepsy-modifying potential.

Purpose The plants of the genus Polygala (Polygalaceae) have been used for a long time in folk medicine to treat pain and inflammation. The species Polygala molluginifolia is native to southern Brazil and is popularly known as “cânfora”. The presented study analyzes the antinociceptive effect of hydroalcoholic extract from Polygala molluginifolia (HEPm) and an isoflavone (ISO) isolated from the extract, in behavioral models of pain in mice, as well as the mechanism underlying this effect. Materials and methods The phytochemical analysis of HEPm was performed through a capillary electrophoresis analysis and colorimetric test. The antinociceptive effects of HEPm and ISO (10–1000 mg/kg, i.g.) were evaluated by applying the formalin test; mechanical and thermal hyperalgesia to postoperative pain in mice. The possible involvement of opioid receptors, TRPV1 and TRPA1 channels in the antinociceptive effect of HEPm and ISO were also evaluated. Finally, the nonspecific effects of HEPm and ISO were evaluated by measuring locomotor activity (Open-field Test) and corporal temperature. Results The 5,3′,4′-trihydroxy-6″,6″-dimethylpyrano[2″,3″:7,6] isoflavone (ISO) was identified in HEPm by capillary electrophoresis analysis and selected for the experimental tests. The oral administration of HEPm or of ISO significantly inhibited the neurogenic and inflammatory phases of formalin-induced pain, edema formation and local hyperemia, without causing any change to locomotor activity. Acute and repeated treatment of animals with HEPm reduced mechanical and thermal (heat and cold) hyperalgesia in the postoperative pain. In addition, administering HEPm or ISO markedly reduced nociceptive behavior induced by the peripheral and central injection of TRPV1 and TRPA1 channels activators. Finally, the antinociception provided by the administration of HEPm or ISO was reversed by the preadministration of naloxone. Conclusions Taken together, these results provide the first experimental evidence of the significant antinociceptive effect of HEPm and ISO in animal models of acute pain without causing sedation or locomotor dysfunction. This effect appears to be mediated, at least in part, by the activation of opioid receptors and/or by the inhibition of TRPV1 and TRPA1 channels. Moreover, this study adds new scientific evidence and highlights the therapeutic potential of the medicinal plant Polygala molluginifolia in the development of phytomedicines with analgesic properties.

Multiple sclerosis (MS) is a T cell autoimmune, inflammatory, and demyelinating disease of the central nervous system (CNS). Currently available therapies have partially effective actions and numerous side reactions. Inosine, an endogenous purine nucleoside, has immunomodulatory, neuroprotective, and analgesic properties. Herein, we evaluated the effect of inosine on the development and progression of experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Inosine (1 or 10 mg/kg, i.p.) was administrated twice a day for 40 days. Immunological and inflammatory responses were evaluated by behavioral, histological, immunohistochemical, ELISA, RT-PCR, and Western blotting analysis. The administration of inosine exerted neuroprotective effects against EAE by diminishing clinical signs, including thermal and mechanical hyperalgesia, as well as weight loss typical of the disease. These beneficial effects of inosine seem to be associated with the blockade of inflammatory cell entry into the CNS, especially lymphocytes, thus delaying the demyelinating process and astrocytes activation. In particular, up-regulation of IL-17 levels in the secondary lymphoid tissues, a result of EAE, was prevented by inosine treatment in EAE mice. Additionally, inosine consistently prevented A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. Altogether, these results allow us to propose that this endogenous purine might be a putative novel and helpful tool for the prevention of autoimmune and neurodegenerative diseases, such as MS. Thus, inosine could have considerable implications for future therapies of MS, and this study may represent the starting point for further investigation into the role of inosine and adenosinergic receptors in neuroinflammation processes. Graphical Abstract Preventive treatment with inosine inhibits the development and progression of EAE in C57Bl/6 mice. Furthermore, neuroinflammation and demyelinating processes were blocked by inosine treatment. Additionally, inosine consistently inhibited IL-17 levels in peripheral lymphoid tissue, as well as IL-4 levels and A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. EAE: experimental autoimmune encephalomyelitis; MS: multiple sclerosis; A2AR: adenosine A2A receptor; IL-17: interleukin-17; IL-4: interleukin-4.

Starfruit (Averrhoa carambola L.) is an edible tropical fruit, which is usually consumed as a fresh table fruit or as fruit juice. It also exhibits various pharmacological activities. In this study, polysaccharides were extracted with boiling water and purified by freeze-thawing and Fehling treatments. After purification steps, a homogenous fraction was obtained. It was analyzed by sugar composition, gel permeation chromatography, methylation, and two-dimensional nuclear magnetic resonance (2D NMR) spectroscopy analyses. It comprised arabinose (Ara), galactose (Gal), and galacturonic acid (GalA) in a molar ratio of 12.3:1.7:86.0. Methylation and NMR spectroscopy analyses showed that it contained a substituted galacturonan composed of (1→4)-linked α-D-Galp A units branched at O-2 by (1→5)-linked α-L-Araf and terminal α-L-Araf and α-D-Galp A units. The effect of PFSCW (10-300mg/kg, i.p.) on nocifensive behavior induced by intraplantar injection of formalin in mice was evaluated. The fraction demonstrated antinociceptive and anti-inflammatory properties, suggesting that it may be useful in therapeutic intervention for the management of inflammatory pain.

PURPOSE This study evaluated the tissue and inflammatory responses to the use of simvastatin and poly(lactic-co-glycolic acid) + hydroxyapatite + β-tricalcium phosphate (PLGA+HA+βTCP) scaffold for bone repair. MATERIALS AND METHODS Two defects of 5 mm in diameter were made in the calvaria of rats, which were shared into the following 6 groups: naive, sham, vehicle, PLGA+HA+βTCP scaffold, simvastatin (4 mg/mL), and simvastatin with the scaffold. Tissue samples were collected at 1, 7, 15, 30, and 60 days after surgery. Inflammation was evaluated by interleukin-1 beta and tumor necrosis factor alpha quantification and by a hemogram, whereas bone repair was evaluated using densitometry and scanning electron microscopy. Data were statistically analyzed using ANOVA followed by post hoc tests (P < 0.05). RESULTS There was an increased cytokine expression in the scaffold and simvastatin groups (P < 0.001 and P < 0.05, respectively) 1 day after surgery but no alterations on the hemogram were observed. It was found on bone tissue samples that 60 days after surgery all groups presented similar densitometry values and morphology characteristics, despite the occurrence of bone formation delay in the simvastatin group (P < 0.01). CONCLUSION The use of simvastatin and PLGA+HA+βTCP scaffold, associated or not, did not lead to improvement in bone repair.

Degeneration of striatal neurons and cortical atrophy are pathological characteristics of glutaric acidemia type I (GA-I), a disease characterized by accumulation of glutaric acid (GA). The mechanisms that lead to neuronal loss and cognitive impairment are still unclear. The purpose of this study was to verify if acute exposure to GA during the neonatal period is sufficient to trigger apoptotic processes and lead to learning delay in early and late period. Besides, whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Pups mice received a dose of GA (2.5 μmol/ g) or saline, 12 hs after birth, and were treated with NAC (250 mg/kg) or saline, up to 21th day of life. Although GA exhibited deficits in the procedural and working memories in 21 and 40-day-old mice, NAC protected against cognitive impairment. In striatum and cortex, NAC prevented glial cells activation (GFAP and Iba-1), decreased NGF, Bcl-2 and NeuN, the increase of lipid peroxidation and PARP induced by GA in both ages. NAC protected against increased p75NTR induced by GA, but not in cortex of 21-day-old mice. Thus, we showed that the integrity of striatal and cortical pathways has an important role for learning and suggested that sustained glial reactivity in neonatal period can be an initial trigger for delay of cognitive development. Furthermore, NAC protected against cognitive impairment induced by GA. This work shows that early identification of the alterations induced by GA is important to avoid future clinical complications and suggest that NAC could be an adjuvant treatment for this acidemia.