Perivascular Innervation in the Nasal Mucosa and Clinical Findings in Patients with Allergic Rhinitis and Idiopathic Rhinitis

Abstract Introduction The nonspecific hyperreactivity of rhinitis has been attributed to neurotrophins activating sensory nerves and inflammatory cells. The relationship between these markers and the intensity of the symptoms is not well established and few studies have evaluated individuals with idiopathic rhinitis. Objective The present study aims to evaluate whether perivascular innervation and nerve growth factor (NGF) are related to the intensity of the clinical conditions in allergic rhinitis (AR) and idiopathic rhinitis (IR). Methods A total of 15 patients with AR and 15 patients with IR with the indication for inferior turbinectomy (associated or not with septoplasty) were selected. The patients received a score according to their signs and symptoms. After the surgery, we quantified eosinophils, mast cells, NGF, and nerve fibers in the nasal turbinate. Results The score of the signs and symptoms was higher in the AR group. Nerve growth factor was found in the cytoplasm of inflammatory cells in the submucosa in greater quantity in the AR group. The nerve fibers were distributed throughout the tissue, mainly in the subepithelial, glandular, and vascular regions, and there was no difference between the groups. Greater perivascular innervation was associated with a higher signs and symptoms score. Conclusions We concluded that these findings suggest that the NGF produced by submucosal inflammatory cells stimulates increased perivascular innervation in rhinitis, thus directly reflecting in more intense clinical conditions, especially in AR.

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial

Abstract Objectives Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD). Methods Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards. Results There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms. Conclusion There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion. This clinical trial is registered on the Japan Primary Registries Network: UMIN000032355.

Biomarcadores na bexiga hiperativa: artigo de revisão / Biomarkers in overactive bladder: review article

A bexiga hiperativa caracteriza-se pela urgência miccional, geralmente acompa- nhada de noctúria e aumento da frequência urinária. Trata-se de afecção preva- lente, com enorme comprometimento da qualidade de vida, em todos os seus as- pectos. Diversos biomarcadores vêm sendo estudados para melhor caracterização dos diferentes fenótipos da afecção, entre eles as neurotrofinas urinárias, o ATP, a genômica e a microbiota urinária. Acredita-se que tal caracterização poderá ter implicações para prevenção, fisiopatologia e individualização do tratamento.(AU)

The overactive bladder is characterized by urinary urgency, usually accompanied by nocturia and increased urinary frequency. It is a prevalent condition, with enormous impairment of quality of life, in all its aspects. Several biomarkers have been studied to better characterize the different phenotypes of the condition, including urinary neurotrophins, ATP, genomics and urinary microbiota. It is believed that such charac- terization may have implications for prevention, pathophysiology and individualiza- tion of treatment.(AU)

Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings

Bipolar disorder (BD) is a chronic mental illness characterized by changes in mood that alternate between mania and hypomania or between depression and mixed states, often associated with functional impairment. Although effective pharmacological and non-pharmacological treatments are available, several patients with BD remain symptomatic. The advance in the understanding of the neurobiology underlying BD could help in the identification of new therapeutic targets as well as biomarkers for early detection, prognosis, and response to treatment in BD. In this review, we discuss genetic, epigenetic, molecular, physiological and neuroimaging findings associated with the neurobiology of BD. Despite the advances in the pathophysiological knowledge of BD, the diagnosis and management of the disease are still essentially clinical. Given the complexity of the brain and the close relationship between environmental exposure and brain function, initiatives that incorporate genetic, epigenetic, molecular, physiological, clinical, environmental data, and brain imaging are necessary to produce information that can be translated into prevention and better outcomes for patients with BD.

Effect of Mycobacterium leprae on neurotrophins expression in human Schwann cells and mouse sciatic nerves

BACKGROUND Although Mycobacterium leprae (ML) is well characterised as the causative agent of leprosy, the pathophysiological mechanisms underlying peripheral nerve damage still need further understanding. In vitro and in vivo studies have yielded insights into molecular mechanisms of ML interaction with Schwann cells (SC), indicating the regulation of genes and proteins crucial to neural plasticity. OBJECTIVES We aimed to investigate the effect of ML on neurotrophins expression in human SC (hSC) and mice sciatic nerves to better understand their role in leprosy neuropathy, and aiming to contribute to future therapeutic approaches. METHODS We evaluated mRNA and protein expression of BDNF, NGF, NT-3, NT-4 in hSC from amputation nerve fragments, as well as in athymic nude mice, infected by ML for eight months. FINDINGS and MAIN CONCLUSIONS Our in vitro results showed a trend to decline in NGF and BDNF mRNA in ML-treated hSC, compared to controls. The immunodetection of BDNF and NT-4 was significantly downregulated in ML-treated hSC. Conversely, ML-infected mice demonstrated upregulation of NT-3, compared to non-infected animals. Our findings indicate that ML may be involved in neurotrophins regulation, suggesting that a pathogen-related imbalance of these growth factors may have a role in the neural impairment of leprosy.

Expression of neurotrophins receptor p75NTR in human breast cancer resistant cell line and its correlation with multidrug resistance / 实用医学杂志

Objective To investigate the expression of neurotrophins receptor 75NTR in human breast cancer resistant cell line and its correlation with multidrug resistance. Methods Western blot was used to detect the expression level of p75NTR protein in various breast cancer cell lines and multidrug resistant cell lines. The over-expression vector and siRNA vector of p75NTR were constructed by gene recombination method. Western blot was used to detect the expression levels of p75NTR protein in transfected p75NTR and p75NTR - siRNA breast cancer resistant cell line MDA-MB-231/ADR;the sensitivity of MDA-MB-231 and MDA-MB-231/ADR to different chemotherapeutic anticancer drug (PTX ,ADM ,GEM ,DDP ,OXA) and the multi-drug resistance effects in over-expression and knock-down p75NTR MDA-MB-231/ADR were detected by CCK-8 assay. Results Western blot result showed that the expressions of p75NTR protein in the multidrug-resistant breast cancer cell lines MDA-MB-231/ADR and MCF-7/5-FU were higher than that of other breast cancer cell lines. Over-expression of p75NTRcan up-regulate the expression of p75NTR protein in MDA-MB-231/ADR;the CCK-8 assay indicated that over-expression of p75NTR can effectively enhance the resistance of MDA-MB-231/ADR cells to ADM,GEM and OXA. Conclusion The expression of p75NTR in breast cancer resistant cell line is higher than that of its parental cell line;over-expression of p75NTR can reduce the sensitivity to chemotherapeutic drugs and promote its multidrug resistance.

Peripheral brain-derived neurotrophic factor is related to cardiovascular risk factors in active and inactive elderly men

Regular exercise plays an important preventive and therapeutic role in heart and vascular diseases, and beneficially affects brain function. In blood, the effects of exercise appear to be very complex and could include protection of vascular endothelial cells via neurotrophic factors and decreased oxidative stress. The purpose of this study was to identify the age-related changes in peripheral brain-derived neurotrophic factor (BDNF) and its relationship to oxidative damage and conventional cardiovascular disease (CVD) biomarkers, such as atherogenic index, C-reactive protein (hsCRP) and oxidized LDL (oxLDL), in active and inactive men. Seventeen elderly males (61-80 years) and 17 young males (20-24 years) participated in this study. According to the 6-min Åstrand-Rhyming bike test, the subjects were classified into active and inactive groups. The young and elderly active men had a significantly better lipoprotein profile and antioxidant status, as well as reduced oxidative damage and inflammatory state. The active young and elderly men had significantly higher plasma BDNF levels compared to their inactive peers. BDNF was correlated with VO2max (r=0.765, P<0.001). In addition, we observed a significant inverse correlation of BDNF with atherogenic index (TC/HDL), hsCRP and oxLDL. The findings demonstrate that a high level of cardiorespiratory fitness reflected in VO2max was associated with a higher level of circulating BDNF, which in turn was related to common CVD risk factors and oxidative damage markers in young and elderly men.

Bipolar Disorder: Role of Inflammation and the Development of Disease Biomarkers

Bipolar disorder is a severe and enduring psychiatric condition which in many cases starts during early adulthood and follows a relapsing and remitting course throughout life. In many patients the disease follows a progressive path with brief periods of inter-episode recovery, sub-threshold symptoms, treatment resistance and increasing functional impairment in the biopsychosocial domains. Knowledge about the neurobiology of bipolar disorder is increasing steadily and evidence from several lines of research implicates immuno-inflammatory mechanisms in the brain and periphery in the etiopathogenesis of this illness and its comorbidities. The main findings are an increase in the levels of proinflammatory cytokines during acute episodes with a decrease in neurotrophic support. Related to these factors are glial cell dysfunction, neuro-endocrine abnormalities and neurotransmitter aberrations which together cause plastic changes in the mood regulating areas of the brain and neuroprogression of the bipolar diathesis. Research in the above mentioned areas is providing an opportunity to discover novel biomarkers for the disease and the field is reaching a point where major breakthroughs can be expected in the not too distant future. It is hoped that with new discoveries fresh avenues will be found to better treat an otherwise recalcitrant disease.

Decreased brain-derived neurotrophic factor plasma levels in psoriasis patients

Brain-derived neurotrophic factor (BDNF) is associated with neuroplasticity and synaptic strength, and is decreased in conditions associated with chronic stress. Nevertheless, BDNF has not yet been investigated in psoriasis, a chronic inflammatory systemic disease that is exacerbated by stress. Therefore, our aim was to determine BDNF plasma levels in psoriasis patients and healthy controls. Adult patients (n=94) presenting with psoriasis for at least 1 year were enrolled, and age- and gender-matched with healthy controls (n=307) from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Participants had neither a previous history of coronary artery disease nor current episode of major depression. BDNF plasma levels were determined using the Promega ELISA kit. A general linear model was used to compare BDNF levels in psoriasis patients and controls, with age, gender, systolic blood pressure, serum fasting glucose, blood lipid levels, triglycerides, smoking status, and body mass index examined. After adjusting for clinical and demographic variables, significantly decreased BNDF plasma levels were observed in psoriasis patients (P=0.01) (estimated marginal means of 3922 pg/mL; 95%CI=2660-5135) compared with controls (5788 pg/mL; 95%CI=5185-6442). Similar BDNF levels were found in both mild and severe cases of psoriasis. Our finding, that BDNF is decreased in psoriasis, supports the concept of a brain-skin connection in psoriasis. Further studies should determine if BDNF is increased after specific psoriasis treatments, and associated with different disease stages.

Influence of swimming training on the expression of nerve growth factor and neurotrophins-3 in rats with cerebral infarction / 中华物理医学与康复杂志

Objective To observe the influence of swimming training on the expression of nerve growth factor (NGF) and neurotrophins-3 (NT-3) in rats with cerebral infarction,and to explore the underlying neuroprotection mechanism of exercise training on cerebral infarction.Methods Forty-five healthy male Sprague-Dawley rats were randomly divided into a sham-operation group,a control group and a training group,with 15 rats in each group.Each group was further divided into a 3-day,7-day and 14-day subgroups,which amounts to 9 groups.To establish animal model of cerebral ischemia-reperfusion in rats,the intraluminal thread method was applied to cause left middle cerebral artery occlusion (MCAO) for 2 h before reperfusion.The rats of the training group were given swimming training for 10 min,once daily,while those of the sham-operation and control groups were not given any training.Neurological deficits were assessed using Bederson scores.The expression of NGF mRNA and NT-3 mRNA in the ischemiareperfusion pallium was examined using reverse transcription-polymerase chain reaction (RT-PCR).Results The rats of the sham-operation group showed no neurological deficits.At the same time points,the average Bederson scores of the training group were significantly lower than the control group,but significantly higher than the sham group.Moreover,the 14 d training group had the lowest Bederson score (1.20 ±0.45),compared to the value 3 and 7 days after modeling.The expression of NGF mRNA and NT-3 mRNA of ischemic cerebral cortex in the training group was significantly improved when compared to the sham-operation group or the control group.On day 14,the expression of the NGF mRNA (0.66 ± 0.07),and the NT-3 mRNA (0.79 ± 0.06),were significantly higher than those on day 3 and 7.Conclusions Swimming training could increase the expressions of NGF mRNA and NT-3 mRNA in the ischemic cerebral cortex.It might be one of the key mechanisms that exercise training could promote the recovery of damaged neurological function in rats with cerebral infarction.

Expression of Neurotrophic Factors and Their Receptors in Rat Posterior Taste Bud Cells

Taste is an important sense in survival and growth of animals. The growth and maintenance of taste buds, the receptor organs of taste sense, are under the regulation of various neurotrophic factors. But the distribution aspect of neurotrophic factors and their receptors in distinct taste cell types are not clearly known. The present research was designed to characterize mRNA expression pattern of neurotrophic factors and their receptors in distinct type of taste cells. In male 45-60 day-old Sprague-Dawley rats, epithelial tissues with and without circumvallate and folliate papillaes were dissected and homogenized, and mRNA expressions for neurotrophic factors and their receptors were determined by RT-PCR. The mRNA expressions of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), receptor tyrosine kinase B (TrkB), exclusion of nerve growth factor (NGF), neurotrophin-4/5 (NT4/5), receptor tyrosine kinase A (TrkA), receptor tyrosine kinase C (TrkC), and p75NGFR were observed in some population of taste cell. In support of this result and to characterize which types of taste cells express NT3, BDNF, or TrkB, we examined mRNA expressions of NT3, BDNF, or TrkB in the PLCbeta2 (a marker of Type II cell)- and/or SNAP25 (a marker of Type III cell)-positive taste cells by a single taste cell RT-PCR and found that the ratio of positively stained cell numbers were 17.4, 6.5, 84.1, 70.3, and 1.4% for PLCbeta2, SNAP25, NT3, BDNF, and TrkB, respectively. In addition, all of PLCbeta2- and SNAP25-positive taste cells expressed NT3 mRNA, except for one taste bud cell. The ratios of NT3 mRNA expressions were 100% and 91.7% in the SNAP25- and PLCbeta2-positive taste cells, respectively. However, two TrkB-positive taste cells co-expressed neither PLCbeta2 nor SNAP 25. The results suggest that the most of type II or type III cells express BDNF and NT3 mRNA, but the expression is shown to be less in type I taste cells.

Analysis of the expression of neurotrophins during regeneration of peripheral nerves in rats with vein graft / Análise da expressão de neurotrofinas durante a regeneração de nervo periférico de rato por enxerto venoso

Vein grafts have been employed to bridge the gap in transected peripheral nerves to produce better functional recovery. However several disadvantages such as secondary graft constriction were observed and a new alternative to this technique was developed by simply reversing the vein inside out. Both inside out and standard vein grafts were successfully used in recovering the sensory segmental defect in humans. Neurotrophins are a family of eurotrophic factors known to play an important role in the regeneration of peripheral nerves. The neurotrophin family consists of Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3) and Neurotropinh-4 (NT-4). In the neurobiology field, several authors have been using PCR technique in order to gain more information regarding regenerated nerves. In this study, we employed this molecular biology technique to explore the role and level of the neurotrophins during the peripheral nerve regeneration with vein graft. The sciatic nerve of rats were sectioned and repaired with Inside out vein graft (IOVG) and standard vein graft techniques (SVG). In the control group the rats were sham operated wherein the sciatic nerve was kept intact. The animals were euthanized at 6 and 12 weeks and the grafts were harvested to observe the level the neurotrophins. EDL and Sol muscles were excised and measured to determine any weight difference between the groups. A small segment of the distal stumps from both the SVG and IOVG groups were also excised and were subjected to histological process to examine the amount of regenerated axon. In addition, another small segment of the distal stump was processed for RT-PCR to further examine the level of the neurotrophins in this area. At 6 weeks, no significant neuronal growth was observed in the distal stump of both graft types but a distinct growth was seen at 12 weeks. Walk track analysis showed poor motor function recovery ...

Análise da expressão de neurotrofinas durante a regeneração de nervo periférico de rato por enxerto venoso Enxertos de veias têm sido empregados para preencher lacunas em nervos periféricos transeccionados para melhor recuperação funcional. No entanto, vários inconvenientes, como a constrição do enxerto secundário foram observados. Uma nova alternativa para esta técnica foi desenvolvida. Simplesmente invertendo a veia de dentro para fora, chamado do Inside- out vein graft. As neurotrofinas são uma família de fatores neurotróficos conhecidos por desempenhar um papel significativo na regeneração de nervos periféricos. A família da neurotrofina é constituído por fator de crescimento nervoso (NGF), fator neurotrófico derivado do cérebro (BDNF), Neurotrofina-3 (NT-3) e Neurotrofina-4 (NT-4). No campo da neurobiologia, vários autores têm utilizado a técnica de PCR a fim de obter mais informações sobre os nervos regenerados. Neste estudo, foi utilizada a técnica de biologia molecular para explorar o papel e o nível das neurotrofinas durante a regeneração de nervos periféricos com enxerto de veia. O nervo isquiático de ratos foi seccionado e reparado com enxerto de veia invertida (IOVG) e técnicas de enxerto de veia padrão (SVG). No grupo controle, os ratos foram operados e o nervo isquiático foi mantido intacto. Os animais foram sacrificados após 6 e 12 semanas e os enxertos foram colhidos para observar o nível das neurotrofinas. Músculos EDL e Sóleo foram excisados e pesados para determinar a diferença de peso entre os grupos. Um pequeno segmento dos cotos distais de ambos os grupos SVG e IOVG também foram excisados e foram processados histologicamente para examinar a quantidade de axónios regenerados. Além disso, um outro pequeno segmento do coto distal foi processado para RT-PCR para analisar o nível das neurotrofinas nesta área.A tecnica do walk track analysis foi realizada para determinar o índice funcional do nervo isquiático nos grupos...

Analysis of the expression of neurotrophins during regeneration of peripheral nerves in rats with vein graft / Análise da expressão de neurotrofinas durante a regeneração de nervo periférico de rato por enxerto venoso

Vein grafts have been employed to bridge the gap in transected peripheral nerves to produce better functional recovery. However several disadvantages such as secondary graft constriction were observed and a new alternative to this technique was developed by simply reversing the vein inside out. Both inside out and standard vein grafts were successfully used in recovering the sensory segmental defect in humans. Neurotrophins are a family of eurotrophic factors known to play an important role in the regeneration of peripheral nerves. The neurotrophin family consists of Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3) and Neurotropinh-4 (NT-4). In the neurobiology field, several authors have been using PCR technique in order to gain more information regarding regenerated nerves. In this study, we employed this molecular biology technique to explore the role and level of the neurotrophins during the peripheral nerve regeneration with vein graft. The sciatic nerve of rats were sectioned and repaired with Inside out vein graft (IOVG) and standard vein graft techniques (SVG). In the control group the rats were sham operated wherein the sciatic nerve was kept intact. The animals were euthanized at 6 and 12 weeks and the grafts were harvested to observe the level the neurotrophins. EDL and Sol muscles were excised and measured to determine any weight difference between the groups. A small segment of the distal stumps from both the SVG and IOVG groups were also excised and were subjected to histological process to examine the amount of regenerated axon. In addition, another small segment of the distal stump was processed for RT-PCR to further examine the level of the neurotrophins in this area. At 6 weeks, no significant neuronal growth was observed in the distal stump of both graft types but a distinct growth was seen at 12 weeks. Walk track analysis showed poor motor function recovery...

Análise da expressão de neurotrofinas durante a regeneração de nervo periférico de rato por enxerto venoso Enxertos de veias têm sido empregados para preencher lacunas em nervos periféricos transeccionados para melhor recuperação funcional. No entanto, vários inconvenientes, como a constrição do enxerto secundário foram observados. Uma nova alternativa para esta técnica foi desenvolvida. Simplesmente invertendo a veia de dentro para fora, chamado do Inside- out vein graft. As neurotrofinas são uma família de fatores neurotróficos conhecidos por desempenhar um papel significativo na regeneração de nervos periféricos. A família da neurotrofina é constituído por fator de crescimento nervoso (NGF), fator neurotrófico derivado do cérebro (BDNF), Neurotrofina-3 (NT-3) e Neurotrofina-4 (NT-4). No campo da neurobiologia, vários autores têm utilizado a técnica de PCR a fim de obter mais informações sobre os nervos regenerados. Neste estudo, foi utilizada a técnica de biologia molecular para explorar o papel e o nível das neurotrofinas durante a regeneração de nervos periféricos com enxerto de veia. O nervo isquiático de ratos foi seccionado e reparado com enxerto de veia invertida (IOVG) e técnicas de enxerto de veia padrão (SVG). No grupo controle, os ratos foram operados e o nervo isquiático foi mantido intacto. Os animais foram sacrificados após 6 e 12 semanas e os enxertos foram colhidos para observar o nível das neurotrofinas. Músculos EDL e Sóleo foram excisados e pesados para determinar a diferença de peso entre os grupos. Um pequeno segmento dos cotos distais de ambos os grupos SVG e IOVG também foram excisados e foram processados histologicamente para examinar a quantidade de axónios regenerados. Além disso, um outro pequeno segmento do coto distal foi processado para RT-PCR para analisar o nível das neurotrofinas nesta área.A tecnica do walk track analysis foi realizada para determinar o índice funcional do nervo isquiático nos grupos...

Serum levels of brain-derived neurotrophicfactor correlate with the number of T2 MRI lesions in multiple sclerosis

The objective of the present study was to determine if there is a relationship between serum levels of brain-derived neurotrophic factor (BDNF) and the number of T2/fluid-attenuated inversion recovery (T2/FLAIR) lesions in multiple sclerosis (MS). The use of magnetic resonance imaging (MRI) has revolutionized the study of MS. However, MRI has limitations and the use of other biomarkers such as BDNF may be useful for the clinical assessment and the study of the disease. Serum was obtained from 28 MS patients, 18-50 years old (median 38), 21 women, 0.5-10 years (median 5) of disease duration, EDSS 1-4 (median 1.5) and 28 healthy controls, 19-49 years old (median 33), 19 women. BDNF levels were measured by ELISA. T1, T2/FLAIR and gadolinium-enhanced lesions were measured by a trained radiologist. BDNF was reduced in MS patients (median [range] pg/mL; 1160 [352.6-2640]) compared to healthy controls (1640 [632.4-4268]; P = 0.03, Mann-Whitney test) and was negatively correlated (Spearman correlation test, r = -0.41; P = 0.02) with T2/FLAIR (11-81 lesions, median 42). We found that serum BDNF levels were inversely correlated with the number of T2/FLAIR lesions in patients with MS. BDNF may be a promising biomarker of MS.

Aplicación clínica de marcadores periféricos de respuesta a la terapia antidepresiva neurotrofinas y citocinas / Clinical applications of peripheral markers of response in antidepressant treatment: neurotrophins and cytokines

Introducción: Las teorías explicativas de la depresión han avanzado en las últimas décadas, desde la monoaminérgica hasta la alteración de la neurogénesis, pasando por la hipótesis neurohormonal, que incluye la disfunción de la respuesta inflamatoria. Actualmente existe un creciente interés por el desarrollo de biomarcadores que contribuyan diagnóstico y tratamiento adecuado. Objetivos: Describir el rol de las neurotrofinas especialmente del factor neurotrópico derivado del cerebro (BDNF) y de las citocinas en la fisiopatología del trastorno depresivo; además, revisar y analizar la evidencia respecto de su aplicación clínica como biomarcadores de la terapia antidepresiva. Método: Búsqueda de información relevante en diferentes bases de datos. Resultados y conclusiones: En los últimos años ha crecido la evidencia de la alteración en la neurogénesis mediada por la expresión del BDNF en el hipocampo, en la fisiopatología de la depresión y el respaldo en cuanto a su uso como biomarcador del diagnóstico y la efectividad del tratamiento antidepresivo. Existe menor información para otras neurotrofinas. También se observa un mayor interés respecto a la depresión como una “enfermedad inflamatoria”, relacionando también la “cascada” de citocinas con su patogénesis. Se ha reportado evidencia amplia acerca de la utilidad de algunas citosinas, especialmente de la IL-1 (interleucina 1), IL-6 (interleucina 6) y FNT (factor de necrosis tumoral) como biomarcadores de la respuesta farmacológica antidepresiva en humanos…

Introduction: Explanatory theories of depression have advanced in recent decades from the monoaminergic hypothesis to neurogenesis alterations to the neurohormonal hypothesis that includes the dysfunction of the inflammatory response. Currently there is a growing interest in the development of biomarkers that can contribute to diagnosis and proper treatment. Objectives: To describe the role of neurotrophins such as brain-derived neurotrophic factor (BDNF) and cytokines in the pathophysiology of depressive disorder in addition to reviewing and analyzing evidence about their clinical application as biomarkers of antidepressant therapy. Method: Relevant data research in several databases. Results and conclusions: In recent years evidence of alterations in neurogenesis mediated by the expression of BDNF in the hippocampus in the pathophysiology of depression has increased and there is ample evidence that BDNF is a marker of the diagnosis of depressive disorder and also of treatment effectiveness. There is little information about other neurotrophins. There has also been increased interest in relation to depression as an “inflammatory disease” and the link with cytokines in its pathogenesis.Evidence has been found for the usefulness of some cytokines especially IL-1 (interleukin 1), IL-6 (interleukin 6), and TNF (tumor necrosis factor) as biomarkers of antidepressant drug response in humans…

Marcadores periféricos e a fisiopatologia do transtorno bipolar / Peripheral markers and the pathophysiology of bipolar disorder

INTRODUÇÃO: O entendimento da fisiopatologia do transtorno bipolar vem tendo avanços consistentes nos últimos anos. Um enfoque na relação entre carga alostática e alterações sistêmicas vem tomando corpo, com o objetivo de se entender a frequente progressão da doença. Proeminentes entre os mediadores periféricos têm sido as moléculas que poderiam ser amplamente agrupadas em neurotrofinas, marcadores de estresse oxidativo e marcadores inflamatórios. OBJETIVO: Descrever achados recentes em relação à fisiopatologia sistêmica do transtorno bipolar, com enfoque especial em estudos brasileiros, tentando articular uma visão coerente do conhecimento atual do campo. MÉTODO: Revisão narrativa da literatura relacionada a neurotrofinas, estresse oxidativo e marcadores inflamatórios no transtorno bipolar. RESULTADOS: Diversas fontes de evidência, provenientes tanto de estudos pré-clínicos quanto clínicos, revelam consistentemente alterações sistêmicas no transtorno bipolar. Os achados são especialmente robustos em pacientes com múltiplos episódios. Nesses, alterações relacionadas a episódios de mania e depressão são notáveis em neurotrofinas e dano oxidativo a lipídeos. Um número menor de estudos mostra alterações no sistema imune, em particular estados pró-inflamatórios. CONCLUSÃO: Alterações sistêmicas que correlacionam o transtorno bipolar a comorbidade clínica, disfunção cognitiva, incapacidade e mortalidade precoce começam a ser traçadas. Estudos envolvendo desenhos longitudinais, amostras populacionais e ensaios clínicos envolvendo marcadores periféricos devem ser incorporados no futuro próximo e reforçar a validade de uma noção de envolvimento multissistêmico no transtorno bipolar.

INTRODUCTION: The understanding of the pathophysiology of bipolar disorder has steadily advanced in the past few years. Thereby, a focus on allostatic load and systemic changes has appeared, with the aim to understand illness progression. Amongst the peripheral markers, molecules that can be widely classified into neurotrophins, oxidadive stress markers, and inflammation markers have been elevated. OBJECTIVE: To describe recent findings regarding the systemic pathophysiology of bipolar disorder, with a special focus on Brazilian studies and to create a coherent view of the current knowledge in the field. METHOD: Narrative review of the literature regarding neurotrophins, oxidative stress, and inflammatory markers in bipolar disorder. RESULTS: A diverse body of evidence, based on both pre-clinical and clinical studies, reveals consistent systemic changes in bipolar disorder. The findings are particularly robust in patients after multiple episodes. Thereby, remarkable changes related to manic and depressive episodes were found in neurotrophins and oxidative damage to lipids. Regarding to immune system alterations, in particular pro-inflammatory states, the literature is less consistent. DISCUSSION: Systemic changes that link bipolar disorder to clinical comorbidity, cognitive dysfunction, disability and early mortality are becoming evident. In the near future, longitudinal studies with population-based samples and clinical trials incorporating biomarkers are needed to shed light upon the notion of a multisystem involvement in bipolar disorder.

The Role of BDNF as a Mediator of Neuroplasticity in Bipolar Disorder

The cognitive impairment and neuroanatomical changes that takes place among patients with bipolar disorder (BD) patients has been well described. Recent data suggest that changes in neuroplasticity, cell resilience and connectivity are the main neuropathological findings in BD. Data from differential lines of research converges to the brain-derived neurotrophic factor (BDNF) as an important contributor to the neuroplasticity changes described among BD patients. BDNF serum levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. BDNF has also been shown to decrease as the disorder progresses. Moreover, factors that negatively influence the course of BD, such as life stress and trauma have been shown to be associated with a decrease in BDNF serum levels. These findings suggest that BDNF plays a central role in the progression of BD. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in portion with mood episodes and the potential use of serum BDNF as a biomarker in BD.

Neurotrofinas na epilepsia do lobo temporal / Neurotrophins in temporal lobe epilepsy

INTRODUÇÃO: A neurotrofinas NGF, BDNF, NT-3 e NT-4 são os principais representantes da família das neurotrofinas no sistema nervoso central de mamíferos. Estão presentes em estágios específicos do crescimento e sobrevivência neuronal como a divisão celular, diferenciação e axogênese e também nos processos naturais de morte celular neuronal. A atividade biológica das neurotrofinas é mediada pelos receptores de tropomiosina quinase Trk. NGF ativa principalmente os receptores TrkA, BDNF e NT-4 interagem com os receptores TrkB e NT-3 com TrkC. Todas as NTs também podem se ligar, com menor afinidade, ao receptor p75NTR. Nesta breve revisão serão levantadas as principais evidências sobre o papel e expressão das principais neurotrofinas no hipocampo, com ênfase nas alterações que ocorrem em modelos animais de epilepsia. RESULTADOS: As neurotrofinas parecem ter um papel chave na plasticidade sináptica relacionada à epilepsia, onde elas poderiam agir tanto como fatores promotores da epileptogênese quanto como substâncias anti-epiléptogênicas endógenas. Além disso a expressão dos genes que codificam os fatores neurotróficos e seus receptores pode ser alterada pela atividade de crises em diversos modelos de epilepsia. CONCLUSÃO: Vários estudos têm demonstrado a relação entre a expressão das neurotrofinas e as alterações na plasticidade dos circuitos neuronais que ocorrem após danos cerebrais, tais como a epilepsia. O conhecimento das alterações na expressão das neurotrofinas na plasticidade neuronal pode nos auxiliar a entender como estas moléculas participam dos mecanismos epileptogênicos e dessa forma, dar início ao estudo de novas terapias e ao desenvolvimento de novas drogas que auxiliem no tratamento da epilepsia.

INTRODUCTION: NGF, BDNF, NT-3 and NT-4 are the major neurotrophins in the mammal central nervous system. These proteins play key roles in development of the nervous system, but they are also responsible for important functions in the adult brain, such as trophic support of adult neurons, cell plasticity and death. The neurotrophins activate three different members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases. These three receptors exhibit distinct affinities for different neurotrophins, with NGF activating TrkA, BDNF and NT-4 activating TrkB, and NT-3 predominantly activating TrkC. All NTs can also interact with the receptor p75NTR, a member of the tumor necrosis factor receptor superfamily. RESULTS: NTs have a key role also in the neuronal plasticity related to epilepsy, and they are able to act as epileptogenic factors and anti-epileptogenic endogenous factors. Besides that, several studies have shown that status epilepticus and chronic seizures may alter gene and protein expression of these factors. CONCLUSION: Here, we briefly give a short review of current knowledge of the roles and expression of the major neurotrophins in the hippocampus, with emphasis to the changes that occur in animal models of epilepsy. The knowledge on how the mechanisms underlying the multiplicity of biological functions in which the neurotrophins take part may provide us key insights into the cellular mechanisms of neuronal function in health and disease.

El futuro de la depresión: una enfermedad sistémica neuroendócrina, inflamatoria y neurodegenerativa compleja / The future of depression: a complex neuroendocrine, inflammatory and neurodegenerative systemic illness

Los modelos neurobiológicos de la depresión han evolucionado más allá de la teoría monoaminérgica, que fue construida luego del advenimiento de las drogas antidepresivas en la década de 1950. Actualmente se considera que la depresión implica una amplia gama de neurotransmisores, incluyendo a la dopamina y el glutamato, y a prácticamente la totalidad del sistema nervioso central. La evidencia emergente está redefiniendo la depresión como una enfermedad crónica y sistémica que puede deteriorar la función neuroendocrina, los ritmos biológicos y las respuestas inmunes, y como una enfermedad que, de no ser tratada, puede conducir a la demencia. Diferentes abordajes de investigación, desde la biología molecular hasta los estudios clínicos, han ofrecido tanto nuevos conocimientos acerca de los mecanismos fisiológicos implicados como también indicios para desarrollar terapias antidepresivas efectivas en respuesta a los mismos. Además de los métodos ya bien establecidos, como los inhibidores de la recaptación de monoaminas y la terapia cognitivo-conductual, estos pueden incluir drogas anti-inflamatorias no esteroides, prescripción de ejercicio físico, tratamientos somáticos y toda una nueva generación de drogas antidepresivas dotadas de modos de acción originales. A medida que el manejo de la depresión se torna cada vez más multifacético, los médicos serán capaces de optimizar los resultados clínicos para sus pacientes integrando sinérgicamente las múltiples opciones terapéuticas disponibles.

Neurobiological models of depression have evolved far beyond the monoamine theory that was construed following the advent of antidepressant drugs in the 1950s. Depression is now seen to implicate a wide range of neurotransmitters, including dopamine and glutamate, and virtually the entire central nervous system. Emerging evidence is redefining depression as a chronic and systemic illness that may impair neuroendocrine function, biological rhythms and immune responses, and one which may lead to dementia if left untreated. Different research approaches, from molecular biology to clinical studies, have offered new insights into the physiological mechanisms involved as well as indications of how effective antidepressant therapies may develop in response to these. In addition to well-established methods, like monoamine reuptake inhibitors and cognitive behavioral therapy, these may include non-steroid anti-inflammatory drugs, prescription of physical exercise, somatic treatments and a whole new generation of antidepressant drugs endowed with original modes of action. As the management of depression becomes increasingly multifaceted, clinicians will be able to optimize clinical outcomes for their patients by synergistically integrating the multiple therapeutic options available.

Efeitos do exercício físico sobre o estado redox cerebral / Effects of physical exercise over the redox brain state

A atividade física é conhecida por promover saúde e bem-estar. O exercício também é responsável por aumentar a produção de Espécies Reativas de Oxigênio (ERO) pelo acréscimo do consumo de oxigênio mitocondrial nos tecidos. O desequilíbrio entre a produção de EROs e as defesas oxidantes dos tecidos pode provocar danos oxidativos a proteínas, lipídios e DNA. O dano oxidativo cerebral é um mecanismo etiopatológico comum da apoptose e da neurodegeneração. O fator de crescimento cérebro-derivado desempenha um importante papel neste contexto. Nesta revisão, apresentamos os resultados de diferentes modelos de exercício físico no metabolismo oxidativo e neurotrófico do Sistema Nervoso Central (SNC). Também revisamos estudos que utilizaram suplementação antioxidante para prevenir danos oxidativos exercício-induzido ao SNC. Os modelos de exercício físico mais comuns foram as rodas de correr, a natação e a esteira com configurações de treinamento muito diferentes como a duração e a intensidade. Os resultados do treinamento físico no tecido cerebral são muito controversos, mas geralmente demonstram ganhos na plasticidade sináptica e na função cognitiva com exercícios de intensidade moderada e baixa.

Physical activity is known for promoting health and well-being. Exercise is also responsible for increasing the production of Oxygen Reactive Species (ORS) by increasing mitochondrial oxygen consumption causing tissue oxidative stress. The imbalance between ORS production and tissue antioxidant defenses can cause oxidative damage to proteins, lipids and DNA. Brain oxidative damage is a common etiopathology mechanism of apoptosis and neurodegeneration. The brain-derived neurotrophic factor plays an important role in this context. In this review, we showed the results of different models and configurations of physical exercise in oxidative and neurotrophic metabolism of the Central Nervous System (CNS). We also reviewed studies that utilized antioxidant supplementation to prevent exercise-induced oxidative damage to CNS. The commonest physical exercise models were running wheels, swimming and treadmill with very different configurations of physical training such as duration and intensity. The results of physical training on brain tissues are very controversial, but generally show improvement in synaptic plasticity and cognition function with low and moderate intensity exercises.