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INTRODUCTION: Endometriosis is a chronic inflammatory disease that affects âˆ¼10 % of women. A significant fraction of patients experience limited or no efficacy with current therapies. Tissue adjacent to endometriosis lesions often exhibits increased neurite and vascular density, suggesting that disease pathology involves neurotrophic activity and angiogenesis. OBJECTIVES: We aim to evaluate the potential for key tyrosine-kinase-receptor-coupled neurotrophic molecules to contribute to endometriosis-associated pain in mice. METHODS: Peritoneal fluid was collected from endometriosis patients undergoing surgery and the levels of NGF and VEGFR1 regulators (VEGFA, VEGFB, PLGF, and sVEGFR1) were quantified by ELISA. VEGFR1 regulator concentrations were used to calculate VEGFR1 occupancy. We used genetic depletion, neutralizing antibodies, and pharmacological approaches to specifically block neurotrophic ligands (NGF or BDNF) or receptors (VEGFR1, TRKs) in a murine model of endometriosis-associated pain. Endometriosis-associated pain was measured using von Frey filaments, quantification of spontaneous abdominal pain-related behavior, and thermal discomfort. Disease parameters were evaluated by lesion size and prevalence. To evaluate potential toxicity, we measured the effect of entrectinib dose and schedule on body weight, liver and kidney function, and bone structure (via micro-CT). RESULTS: We found that entrectinib (pan-Trk inhibitor) or anti-NGF treatments reduced evoked pain, spontaneous pain, and thermal discomfort. In contrast, even though calculated receptor occupancy revealed that VEGFR1 agonist levels are sufficient to support signaling, blocking VEGFR1 via antibody or tamoxifen-induced knockout did not reduce pain or lesion size in mice. Targeting BDNF-TrkB with an anti-BDNF antibody also proved ineffective. Notably, changing dosing schedule to once weekly eliminated entrectinib-induced bone-loss without decreasing efficacy against pain. CONCLUSIONS: This suggests NGF-TrkA signaling, but not BDNF-TrkB or VEGF-VEGFR1, mediates endometriosis-associated pain. Moreover, entrectinib blocks endometriosis-associated pain and reduces lesion sizes. Our results also indicated that entrectinib-like molecules are promising candidates for endometriosis treatment.

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OBJECTIVES: Mycobacterium leprae is able to infect Schwann cells leading to neural damage. Neurotrophins are involved in nervous system plasticity and impact neural integrity during diseases. Investigate the association between single nucleotide polymorphisms in neurotrophin genes and leprosy phenotypes, especially neural damage. DESIGN: We selected single nucleotide polymorphisms in neurotrophins or their receptors genes associated with neural disorders: rs6265 and rs11030099 of brain-derived neurotrophic factor (BDNF), rs6330 of BDNF, rs6332 in NT3 and rs2072446 of P75NTR. The association of genetic frequencies with leprosy phenotypes was investigated in a case-control study. RESULTS: An association of the BDNF single nucleotide polymorphism rs11030099 with the number of affected nerves was demonstrated. The "AA+AC" genotypes were demonstrated to be protective against nerve impairment. However, this variation does not affect BDNF serum levels. BDNF is an important factor for myelination of Schwann cells and polymorphisms in this gene can be associated with leprosy outcome. Moreover, rs11030099 is located in the binding region for micro-RNA (miRNA) 26a that could be involved in control of BDNF expression. We demonstrated different expression levels of this miRNA in polar forms of leprosy. CONCLUSION: Our findings demonstrate for the first time an association between the polymorphism rs11030099 in the BDNF gene and neural commitment in leprosy and may indicate a possible role of miRNA-26a acting synergistically to these genetic variants in neural damage development.

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Stroke represents one of the main causes of death and disability in the world; despite this, pharmacological therapies against stroke remain insufficient. Ischemic stroke is the leading etiology of stroke. Different molecular mechanisms, such as excitotoxicity, oxidative stress, and inflammation, participate in cell death and tissue damage. At a preclinical level, different garlic compounds have been evaluated against these mechanisms. Additionally, there is evidence supporting the participation of garlic compounds in other mechanisms that contribute to brain tissue recovery, such as neuroplasticity. After ischemia, neuroplasticity is activated to recover cognitive and motor function. Some garlic-derived compounds and preparations have shown the ability to promote neuroplasticity under physiological conditions and, more importantly, in cerebral damage models. This work describes damage/repair mechanisms and the importance of garlic as a source of antioxidant and anti-inflammatory agents against damage. Moreover, we examine the less-explored neurotrophic properties of garlic, culminating in proposals and observations based on our review of the available information. The aim of the present study is to propose that garlic compounds and preparations could contribute to the treatment of ischemic stroke through their neurotrophic effects.

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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.

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Addiction is a serious public health problem, and the current pharmacotherapy is unable to prevent drug use reinstatement. Studies have focused on physical exercise as a promising coadjuvant treatment. Our research group recently showed beneficial neuroadaptations in the dopaminergic system related to amphetamine-relapse prevention involving physical exercise-induced endogenous opioid system activation (EXE-OS activation). In this context, additional mechanisms were explored to understand the exercise benefits on drug addiction. Male rats previously exposed to amphetamine (AMPH, 4.0 mg/kg) for 8 days were submitted to physical exercise for 5 weeks. EXE-OS activation was blocked by naloxone administration (0.3 mg/kg) 5 min before each physical exercise session. After the exercise protocol, the rats were re-exposed to AMPH for 3 days, and in sequence, euthanasia was performed and the VTA and NAc were dissected. In the VTA, our findings showed increased immunocontent of proBDNF, BDNF, and GDNF and decreased levels of AMPH-induced TrkB; therefore, EXE-OS activation increased all these markers and naloxone administration prevented this exercise-induced effect. In the NAc, the same molecular markers were also increased by AMPH and decreased by EXE-OS activation. In this study, we propose a close relation between EXE-OS activation beneficial influence and a consequent neuroadaptation on neurotrophins and dopaminergic system levels in the mesolimbic brain area, preventing the observed AMPH-relapse behavior. Our outcomes bring additional knowledge concerning addiction neurobiology understanding and show that EXE-OS activation may be a potential adjuvant tool in drug addiction therapy.

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Brain-derived neurotrophic factor (BDNF) has been studied as a biomarker of major depressive disorder (MDD). Besides diagnostic biomarkers, clinically useful biomarkers can inform response to treatment. We aimed to review all studies that sought to relate BDNF baseline levels, or BDNF polymorphisms, with response to treatment in MDD. In order to achieve this, we performed a systematic review of studies that explored the relation of BDNF with both pharmacological and non-pharmacological treatment. Finally, we reviewed the evidence that relates peripheral levels of BDNF and BDNF polymorphisms with the development and management of treatment-resistant depression.

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A reduced dendritic complexity, especially in regions such as the hippocampus and the prefrontal cortex, has been linked to the pathophysiology of some neuropsychiatric disorders, in which synaptic plasticity and functions such as emotional and cognitive processing are compromised. For this reason, the identification of new therapeutic strategies would be enriched by the search for metabolites that promote structural plasticity. The present study evaluated the dendritogenic potential of the ethanol extract of Lippia alba, an aromatic plant rich in flavonoids and terpenes, which has been widely used in traditional medicine for its presumed analgesic, anxiolytic, and antidepressant potential. An in vitro model of rat cortical neurons was used to determine the kinetics of the plant's effect at different time intervals. Changes in morphological parameters of the neurons were determined, as well as the dendritic complexity, by Sholl analysis. The extract promotes the outgrowth of dendritic branching in a rapid and sustained fashion, without being cytotoxic to the cells. We found that this effect could be mediated by the phosphatidylinositol 3-kinase pathway, which is involved in mechanisms of neuronal plasticity, differentiation, and survival. The evidence presented in this study provides a basis for further research that, through in vivo models, can delve into the plant's therapeutic potential.

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Despite cognitive symptoms being very important in schizophrenia, not every schizophrenic patient has a significant cognitive deficit. The molecular mechanisms underlying the different degrees of cognitive functioning in schizophrenic patients are not sufficiently understood. We studied the relation between brain-derived neurotrophic factor (BDNF) and cognitive functioning in two groups of schizophrenic patients with different cognitive statuses. According to the Montreal Cognitive Assessment (MoCA) results, the schizophrenic patients were classified into two subgroups: normal cognition (26 or more) and cognitive deficit (25 or less). We measured their plasma BDNF levels using ELISAs. The statistical analyses were performed using Spearman's Rho and Kruskal-Wallis tests. We found a statistically significant positive correlation between the plasma BDNF levels and MoCA score (p = 0.04) in the subgroup of schizophrenic patients with a cognitive deficit (n = 29). However, this correlation was not observed in the patients with normal cognition (n = 11) and was not observed in the total patient group (n = 40). These results support a significant role for BDNF in the cognitive functioning of schizophrenics with some degree of cognitive deficit, but suggest that BDNF may not be crucial in patients with a normal cognitive status. These findings provide information about the molecular basis underlying cognitive deficits in this illness.

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Epidural motor cortex stimulation (MCS) is an effective treatment for refractory neuropathic pain; however, some individuals are unresponsive. In this study, we correlated the effectiveness of MCS and refractoriness with the expression of cytokines, neurotrophins, and nociceptive mediators in the dorsal root ganglion (DRG), sciatic nerve, and plasma of rats with sciatic neuropathy. MCS inhibited hyperalgesia and allodynia in two-thirds of the animals (responsive group), and one-third did not respond (refractory group). Chronic constriction injury (CCI) increased IL-1ß in the nerve and DRG, inhibited IL-4, IL-10, and IL-17A in the nerve, decreased ß-endorphin, and enhanced substance P in the plasma, compared to the control. Responsive animals showed decreased NGF and increased IL-6 in the nerve, accompanied by restoration of local IL-10 and IL-17A and systemic ß-endorphin. Refractory animals showed increased TNF-α and decreased IFNγ in the nerve, along with decreased TNF-α and IL-17A in the DRG, maintaining low levels of systemic ß-endorphin. Our findings suggest that the effectiveness of MCS depends on local control of inflammatory and neurotrophic changes, accompanied by recovery of the opioidergic system observed in neuropathic conditions. So, understanding the refractoriness to MCS may guide an improvement in the efficacy of the technique, thus benefiting patients with persistent neuropathic pain.

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Glucocorticoids (GC) affect neuronal plasticity, development and function of the nervous system by inhibiting neurotrophin-induced Trk signaling. It has been established that pretreatment with dexamethasone (DEX) restricts Neurotrophin-induced neurite outgrowth by inhibiting Trk-dependent activation of Ras-Erk1/2 signaling pathways. However, the precise molecular mechanism through which DEX interferes with neurotrophin signaling and Trk-mediated neurite outgrowth has not been clearly defined yet. Here, we observed that in PC12 cells DEX treatment promotes the transcription of Sprouty4, a regulatory molecule that is part of a negative feedback module that specifically abrogates Ras to Erk1/2 signaling in response to NGF. In line with this, either knockdown of Sprouty4 or overexpression of a dominant negative form of Sprouty4 (Y53A), rescue the inhibition of NGF/TrkA-promoted neurite outgrowth and Erk1/2 phosphorylation induced by DEX. Likewise, treatment of hippocampal neurons with DEX induces the expression of Sprouty4 and its knockdown abrogates the inhibitory effect of DEX on primary neurite formation, dendrite branching and Erk1/2 activation induced by BDNF. Thus, these results suggest that the induction of Sprouty4 mRNA by DEX translates into a significant inhibition of Trk to Erk1/2 signaling pathway. Together, these findings bring new insights into the crosstalk between DEX and neurotrophin signaling and demonstrate that Sprouty4 mediates the inhibitory effects of DEX on neurotrophin function.