Izabel Cristina Custodio de Souza

Neurobiological Effects of Transcranial Direct Current Stimulation: A Review

Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation technique that is affordable and easy to operate compared to other neuromodulation techniques. Anodal stimulation increases cortical excitability, while the cathodal stimulation decreases it. Although tDCS is a promising treatment approach for chronic pain as well as for neuropsychiatric diseases and other neurological disorders, several complex neurobiological mechanisms that are not well understood are involved in its effect. The purpose of this systematic review is to summarize the current knowledge regarding the neurobiological mechanisms involved in the effects of tDCS. The initial search resulted in 171 articles. After applying inclusion and exclusion criteria, we screened 32 full-text articles to extract findings about the neurobiology of tDCS effects including investigation of cortical excitability parameters. Overall, these findings show that tDCS involves a cascade of events at the cellular and molecular levels. Moreover, tDCS is associated with glutamatergic, GABAergic, dopaminergic, serotonergic, and cholinergic activity modulation. Though these studies provide important advancements toward the understanding of mechanisms underlying tDCS effects, further studies are needed to integrate these mechanisms as to optimize clinical development of tDCS.

Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial.

&NA; Melatonin reduced pain scores and analgesic use, and improved sleep quality in endometriosis‐associated chronic pelvic pain. Melatonin modulates the secretion of brain‐derived neurotrophic factor independently of its analgesic effect in endometriosis. &NA; Endometriosis‐associated chronic pelvic pain (EACPP) presents with an intense inflammatory reaction. Melatonin has emerged as an important analgesic, antioxidant, and antiinflammatory agent. This trial investigates the effects of melatonin compared with a placebo on EACPP, brain‐derived neurotrophic factor (BDNF) level, and sleep quality. Forty females, aged 18 to 45 years, were randomized into the placebo (n = 20) or melatonin (10 mg) (n = 20) treatment groups for a period of 8 weeks. There was a significant interaction (time vs group) regarding the main outcomes of the pain scores as indexed by the visual analogue scale on daily pain, dysmenorrhea, dysuria, and dyschezia (analysis of variance, P < 0.01 for all analyses). Post hoc analysis showed that compared with placebo, the treatment reduced daily pain scores by 39.80% (95% confidence interval [CI] 12.88–43.01%) and dysmenorrhea by 38.01% (95% CI 15.96–49.15%). Melatonin improved sleep quality, reduced the risk of using an analgesic by 80%, and reduced BNDF levels independently of its effect on pain. This study provides additional evidence regarding the analgesic effects of melatonin on EACPP and melatonin’s ability to improve sleep quality. Additionally, the study revealed that melatonin modulates the secretion of BDNF and pain through distinct mechanisms.

Cross-Cultural Adaptation and Validation of the Brazilian Portuguese Version of the Pain Catastrophizing Scale

OBJECTIVE Catastrophizing is a maladaptive response to pain and is one of the factors that contribute to the chronicity of some pain syndromes. The Pain Catastrophizing Scale (PCS) assists both treatment planning and outcome assessment. Its use is limited in Portuguese-speaking countries because of the lack of a validated translated version. We conducted the validation of the Brazilian Portuguese (BP)-PCS and explored its psychometric properties. This study reports the internal consistency, factor structure, and its capability to discriminate pain reported by patients with specific chronic pain conditions. METHODS Three hundred eighty-four patients, 317 women (82.55%), aged 18-79 years with chronic nonmalignant pain attending an outpatient multidisciplinary pain center participated in this cross-sectional study. The instruments were the BP-PCS, pain intensity, pain interference in functional capacity, and a sociodemographic questionnaire. One subsample with chronic tensional headache (CTH) according to the criteria of the International Headache Society (N = 19), and another with a diagnosis of fibromyalgia according to the American College of Rheumatology criteria (N = 50) were selected to assess the discriminative properties of BP-PCS. RESULTS We observed good internal consistency (Cronbachs α values of 0.91 for the total BP-PCS, and 0.93 [helplessness], 0.88 [magnification], and 0.86 [rumination] for the respective subdomains). The item-total correlation coefficients ranged from 0.91 to 0.94. Confirmatory factor analysis (CFA) supported the three factors structure, with the comparative fit index = 0.98, root mean square error of approximation = 0.09, and normed fit index = 0.98. Significant correlations were found for pain intensity, pain interference, and patients mood (correlation coefficients ranged from 0.48 to 0.66, P < 0.01). No significant gender difference was observed for BP-PCS scores. When comparing scores of BP-PCS scale and subscales between the selected control group (patients with pain scores on visual analog scale equal or lower than 40 mm in the most part of the day in the last 6 months) and patients with fibromyalgia or CTH, we observed lower scores for the former group. CONCLUSION Our findings support the validity and reliability of the BP-PCS. The scale showed satisfactory psychometric properties. CFA provides support for the three-factor structure reported in previous studies. This factor structure presented good discriminative properties to identify catastrophizers who present with mild chronic pain, fibromyalgia, and CTH. The BP-PCS is a valuable tool for use in scientific studies and in the clinical setting in patients with chronic pain in Brazilian Portuguese-speaking countries.

Analgesic and Sedative Effects of Melatonin in Temporomandibular Disorders: A Double-Blind, Randomized, Parallel-Group, Placebo-Controlled Study

CONTEXT The association between myofascial temporomandibular disorder (TMD) and nonrestorative sleep supports the investigation of therapies that can modulate the sleep/wake cycle. In this context, melatonin becomes an attractive treatment option for myofascial TMD pain. OBJECTIVES To investigate the effects of melatonin on pain (primary aim) and sleep (secondary aim) as compared with placebo in a double-blind, randomized, parallel-group trial. METHODS Thirty-two females, aged 20-40 years, with myofascial TMD pain were randomized into placebo or melatonin (5mg) treatment groups for a period of four weeks. RESULTS There was a significant interaction (time vs. group) for the main outcomes of pain scores as indexed by the visual analogue scale and pressure pain threshold (analysis of variance; P<0.05 for these analyses). Post hoc analysis showed that the treatment reduced pain scores by -44% (95% CI -57%, -26%) compared with placebo, and it also increased the pressure pain threshold by 39% (95% CI 14%, 54%). The use of analgesic doses significantly decreased with time (P<0.01). The daily analgesic doses decreased by -66% (95% CI -94%, -41%) when comparing the two groups. Additionally, melatonin improved sleep quality, but its effect on pain was independent of the effect on sleep quality. CONCLUSION This study provides additional evidence supporting the analgesic effects of melatonin on pain scores and analgesic consumption in patients with mild-to-moderate chronic myofascial TMD pain. Furthermore, melatonin improves sleep quality but its effect on pain appears to be independent of changes in sleep quality.

BDNF as an effect modifier for gender effects on pain thresholds in healthy subjects

BDNF is an important marker of neuronal plasticity. It has also been associated with pain processing. Increased BDNF levels are observed in chronic pain syndromes. In order to understand the role of BDNF associated with other factors such as gender on experimental pain we aimed to determine whether experimental heat or pressure pain threshold is correlated with brain derived neurotrophic factor (BDNF) level, gender and age. Heat pain threshold and pressure pain threshold were measured in 49 healthy volunteers (27 females). The multivariate linear regression models (on heat and pressure pain thresholds) revealed a significant effect of gender (p=0.001 for both models), serum BDNF (p<0.004 for both models) and interaction between BDNF and gender (<0.001 for both models). In fact, when adjusting for BDNF levels and age, heat and pressure pain thresholds were significantly reduced in women as compared to men (p<0.001 for both models). These effects were not observed when gender was analyzed alone. These finding suggests that experimental heat and pressure pain threshold is gender-related and BDNF dependent. In fact BDNF has a facilitatory effect on pain threshold in females but has an opposite effect in males; supporting the notion that BDNF is an effect modifier of the gender effects on pain threshold in healthy subjects.

The Concept of the Immune-Pineal Axis Tested in Patients Undergoing an Abdominal Hysterectomy

Objective: Activation of the immune-pineal axis induces a transient reduction in nocturnal melatonin in the plasma during the proinflammatory phase of an innate immune response to allow the proper migration of leukocytes to the lesion site. This transient reduction should be regulated by inflammatory mediators, which are responsible for the fine-tuning of the process. In the present study, we measured the pre- and postoperative serum concentrations of melatonin, tumor necrosis factor (TNF) and cortisol in women who underwent an elective hysterectomy and correlated the variation in melatonin with postoperative pain. Methods: We evaluated 12 women who had an abdominal hysterectomy. Blood was collected at 10.00 and 22.00 h 1 week and 1 day before the surgery, on the 1st and 2nd days after the surgery and at 22.00 h on the day of the surgery. Results: On the night after the surgery, there was no melatonin detected at 22.00 h. High TNF levels were accompanied by a lower nocturnal melatonin output, higher postoperative pain according to a visual analog scale and the request of higher doses of analgesics. In addition, low cortisol levels were accompanied by a lower nocturnal melatonin output. Conclusion: Our results confirm that the same antagonistic pattern between TNF and glucocorticoids observed in cultured pineal glands also occurs in humans. This integrative pattern suggests that the cross talk between the immune and endocrine system orchestrates longitudinal changes in pineal activity, reinforcing the hypothesis of an immune-pineal axis.

Resveratrol Regulates the Quiescence-Like Induction of Activated Stellate Cells by Modulating the PPARγ/SIRT1 Ratio

The activation of hepatic stellate cell (HSC), from a quiescent cell featuring cytoplasmic lipid droplets to a proliferative myofibroblast, plays an important role in liver fibrosis development. The GRX line is an activated HSC model that can be induced by all‐trans‐retinol to accumulate lipid droplets. Resveratrol is known for activating Sirtuin1 (SIRT1), a NAD+‐dependent deacetylase that suppresses the activity of peroxisome proliferator‐activated receptor gamma (PPARγ), an important adipogenic transcription factor involved in the quiescence maintenance of HSC. We evaluated the effects of 0.1 μM of resveratrol in retinol‐induced GRX quiescence by investigating the interference of SIRT1 and PPARγ on cell lipogenesis. GRX lipid accumulation was evaluated through Oil‐red O staining, triacylglycerides quantification, and [14C] acetate incorporation into lipids. mRNA expression and protein content of SIRT1 and PPARγ were measured by RT‐PCR and immunoblotting, respectively. Resveratrol‐mediated SIRT1 stimuli did not induce lipogenesis and reduced the retinol‐mediated fat‐storing capacity in GRX. In order to support our results, we established a cell culture model of transgenic super expression of PPARγ in GRX cells (GRXPγ). Resveratrol reduced lipid droplets accumulation in GRXPγ cells. These results suggest that the PPARγ/SIRT1 ratio plays an important role in the fate of HSC. Thus, whenever the PPARγ activity is greater than SIRT1 activity the lipogenesis is enabled. J. Cell. Biochem. 116: 2304–2312, 2015.

An Mn2+-stimulated neutral-sphingomyelinase in seminiferous tubules of immature Wistar rats

Mammalian sphingomyelinases have been implicated in many important physiological and pathophysiological processes. The seminiferous tubules of immature (19 day-old) Wistar rats have at least three types of sphingomyelinases, a lysosomal one and two microsomal ones. One of the microsomal sphingomyelinases is active at pH 6.5 and is stimulated by Mn2+ > Co2+ > Mg2+, and the other is active at pH 7.4 and is stimulated by Mn2+ > Mg2+ and inhibited by Co2+. The two microsomal enzymes are only slightly inhibited by EDTA and at pH 7.4 the stimulatory effects of Mn2+ and Mg2+ are additive. These data characterize the existence of two different membrane-bound sphingomyelinases in the seminiferous tubules of the rat.