Transcranial Direct Current Stimulation (tDCS) Promotes state-dependent Effects on Neuroinflammatory and Behavioral Parameters in rats Chronically Exposed to Stress and a Hyper-Palatable Diet.

Chronic stress is a common condition affecting health, often associated with unhealthy eating habits. Transcranial direct current stimulation (tDCS) has been proposed to address these issues. Thus, this research investigated the effects of tDCS on biometric, behavioral, and neurochemical parameters in chronically stressed rats fed a hyper-palatable cafeteria diet (CAFD). The study lasted 8 weeks, with CAFD exposure and/or chronic restraint stress model (CRS - 1 h/day, 5 days/week, for 7 weeks) started concurrently. tDCS or sham sessions were applied between days 42 and 49 (0.5 mA, 20 min/day). CAFD increased body weight, caloric consumption, adiposity, and liver weight. It also altered central parameters, reducing anxiety and cortical levels of IL-10 and BDNF. In turn, the CRS resulted in increased adrenals in rats with standard diet (SD), and anxiety-like and anhedonic behaviors in rats with CAFD. tDCS provided neurochemical shifts in CAFD-fed stressed rats increasing central levels of TNF-α and IL-10, while in stressed rats SD-fed induced a decrease in the adrenals weight, relative visceral adiposity, and serum NPY levels. These data demonstrated the anxiolytic effect of CAFD and anxiogenic effect of stress in CAFD-fed animals. In addition, tDCS promoted state-dependent effects on neuroinflammatory and behavioral parameters in rats chronically exposed to stress and a hyper-palatable diet. These findings provide primary evidence for additional mechanistic and preclinical studies of the tDCS technique for stress-related eating disorders, envisioning clinical applicability.

Evidence of Anti-Inflammatory Effect of Transcranial Direct Current Stimulation in a CFA-Induced Chronic Inflammatory Pain Model in Wistar Rats.

INTRODUCTION: Given that chronic inflammatory pain is highly prevalent worldwide, it is important to study new techniques to treat or relieve this type of pain. The present study evaluated the effect of transcranial direct current stimulation (tDCS) in rats submitted to a chronic inflammatory model by nociceptive response, biomarker levels (brain-derived neurotrophic factor [BDNF] and interleukin [IL]-6 and IL-10), and by histological parameters. METHODS: Sixty-day-old male Wistar rats were used in this study and randomized by weight into 6 major groups: total control, control + sham-tDCS, control + active tDCS, total CFA, CFA + sham-tDCS, and CFA + active tDCS. After inflammatory pain was established, the animals were submitted to the treatment protocol for 8 consecutive days, according to the experimental group. The nociceptive tests (von Frey and hot plate) were assessed, and euthanasia by decapitation occurred at day 8 after the end of tDCS treatment, and the blood serum and central nervous structures were collected for BDNF and IL measurements. All experiments and procedures were approved by the Institutional Committee for Animal Care and Use (UFPel #4538). RESULTS: The tDCS treatment showed a complete reversal of the mechanical allodynia induced by the pain model 24 h and 8 days after the last tDCS session, and there was partial reversal of the thermal hyperalgesia at all time points. Serum BDNF levels were decreased in CFA + sham-tDCS and CFA + tDCS groups compared to the control + tDCS group. The control group submitted to tDCS exhibited an increase in serum IL-6 levels in relation to the other groups. In addition, there was a significant decrease in IL-10 striatum levels in control + tDCS, CFA, and CFA + sham-tDCS groups in relation to the control group, with a partial tDCS effect on the CFA pain model. Local histology demonstrated tDCS effects in decreasing lymphocytic infiltration and neovascularization and tissue regeneration in animals exposed to CFA. CONCLUSION: tDCS was able to reverse the mechanical allodynia and decrease thermal hyperalgesia and local inflammation in a chronic inflammatory pain model, with a modest effect on striatum IL-10 levels. As such, we suggest that analgesic tDCS mechanisms may be related to tissue repair by modulating the local inflammatory process.

Increased Oxidative Parameters and Decreased Cytokine Levels in an Animal Model of Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous disorder characterized by impairing levels of hyperactivity, impulsivity and inattention. Oxidative and inflammatory parameters have been recognized among its multiple predisposing pathways, and clinical studies indicate that ADHD patients have increased oxidative stress. In this study, we aimed to evaluate oxidative (DCFH oxidation, glutathione levels, glutathione peroxidase, catalase and superoxide dismutase activities) and inflammatory (TNF-α, IL-1ß and IL-10) parameters in the most widely accepted animal model of ADHD, the spontaneously hypertensive rats (SHR). Prefrontal cortex, cortex (remaining regions), striatum and hippocampus of adult male SHR and Wistar Kyoto rats were studied. SHR presented increased reactive oxygen species (ROS) production in the cortex, striatum and hippocampus. In SHR, glutathione peroxidase activity was decreased in the prefrontal cortex and hippocampus. TNF-α levels were reduced in the prefrontal cortex, cortex (remaining regions), hippocampus and striatum of SHR. Besides, IL-1ß and IL-10 levels were decreased in the cortex of the ADHD model. Results indicate that SHR presented an oxidative profile that is characterized by an increase in ROS production without an effective antioxidant counterbalance. In addition, this strain showed a decrease in cytokine levels, mainly TNF-α, indicating a basal deficit. These results may present a new approach to the cognitive disturbances seen in the SHR.

Transcranial direct current stimulation (tDCS) has beneficial effects on liver lipid accumulation and hepatic inflammatory parameters in obese rats.

Obesity is key to liver steatosis development and progression. Transcranial direct current stimulation (tDCS) is a promising tool for eating disorders management but was not yet evaluated in steatosis. This study investigated tDCS' effects on liver steatosis and inflammation in an experimental obesity model. Male Wistar rats (60 days-old) were randomly allocated (n = 10/group) as follows: standard-diet/sham tDCS (SDS), standard-diet/tDCS (SDT), hypercaloric-cafeteria-diet/sham tDCS (HDS), and hypercaloric-cafeteria-diet/tDCS (HDT). After 40 days of diet, animals received active or sham tDCS for eight days and were euthanized for liver fat deposition and inflammation analysis. HDS and HDT animals showed cumulative food consumption, total liver lipid deposits, IL-1ß, TNF-α levels, IL-1ß/IL-10 and TNF-α/IL-10 ratios significantly higher than the SDS and SDT groups (p < 0.001 for all parameters). tDCS (SDT and HDT) reduced liver lipid deposits (0.7 times for both, p < 0.05), IL-1ß (0.7 times and 0.9 times, respectively, p < 0.05) and IL-1ß/IL-10 index (0.6 times and 0.8 times, respectively, p < 0.05) in relation to sham (SDS and HDS). There was an interaction effect on the accumulation of hepatic triglycerides (p < 0.05). tDCS reduced 0.8 times the average liver triglyceride concentration in the HDT vs. HDS group (p < 0.05). In this obesity model, tDCS significantly decreased liver steatosis and hepatic inflammation. These results may justify looking into tDCS utility for human steatosis.

Single exercise stress reduces central neurotrophins levels and adenosine A1 and A2 receptors expression, but does not revert opioid-induced hyperalgesia in rats.

BACKGROUND: This study assessed the effects of an acute stress model upon the long-term hyperalgesia induced by repeated morphine administration in neonatal rats. We also evaluated neurotrophins and cytokines levels; expressions of adenosine and acetylcholine receptors, and acetylcholinesterase enzyme at the spinal cord. MATERIAL AND METHODS: Male Wistar rats were subjected to morphine or saline administration from P8 to P14. Thermal hyperalgesia and mechanical hyperesthesia were assessed using the hot plate (HP) and von Frey (vF) tests, respectively, at postnatal day P30 and P60. After baseline measurements, rats were subjected to a single exercise session, as an acute stress model, at P30 or P60. We measured the levels of BDNF and NGF, interleukin-6, and IL-10 in the cerebral cortex and the brainstem; and the expression levels of adenosine and muscarinic receptors, as well as acetylcholinesterase (AChE) enzyme at the spinal cord. RESULTS: A stress exercise session was not able to revert the morphine-induced hyperalgesia. The morphine and exercise association in rats induced a decrease in the neurotrophins brainstem levels, and A1 , A2A , A2B receptors expression in the spinal cord, and an increase in the IL-6 cortical levels. The exercise reduced M2 receptors expression in the spinal cord of naive rats, while morphine prevented this effect. CONCLUSIONS: Single session of exercise does not revert hyperalgesia induced by morphine in rats; however, morphine plus exercise modulate neurotrophins, IL-6 central levels, and expression of adenosine receptors.

Transcranial direct current stimulation (tDCS) modulates biometric and inflammatory parameters and anxiety-like behavior in obese rats.

Obesity is a multifactorial disease associated with metabolic dysfunction and the prevention and treatment of obesity are often unsatisfactory. Transcranial direct-current stimulation (tDCS) is a non-invasive brain stimulation technique that has proven promising in the treatment of eating disorders such as obesity. We investigate the effects of tDCS on locomotor and exploratory activities, anxiety-like and feeding behavior, and levels of brain-derived neurotrophic factor (BDNF), IL (interleukin)-10, IL-1ß, and tumor necrosis factor-alpha (TNF-α) in the cerebral cortex of obese rats. A total of 40 adult male Wistar rats were used in our study. Animals were divided into groups of three or four animals per cage and allocated to four treatment groups: standard diet plus sham tDCS treatment (SDS), standard diet plus tDCS treatment (SDT), hypercaloric diet plus sham tDCS treatment (HDS), hypercaloric diet plus tDCS treatment (HDT). After 40 days on a hypercaloric diet and/or standard diet were to assessed the locomotor and exploratory activity and anxiety-like behavior to by the open field (OF) and elevated plus maze (EPM) tests respectively before and after exposure to tDCS treatment. The experimental groups were submitted to active or sham treatment tDCS during eight days. Palatable food consumption test (PFT) was performed 24 h after the last tDCS session under fasting and feeding conditions. Obese animals submitted to tDCS treatment showed a reduction in the Lee index, visceral adipose tissue weight, and food craving. In addition, bicephalic tDCS decreased the cerebral cortex levels of IL-1ß and TNF-α in these animals. Exposure to a hypercaloric diet produced an anxiolytic effect, which was reversed by bicephalic tDCS treatment. These results suggest that, in accordance with studies in humans, bicephalic tDCS could modulate biometric and inflammatory parameters, as well as anxiety-like and feeding behavior, of rats subjected to the consumption of a hypercaloric diet.

Morphine exposure during early life alters thermal and mechanical thresholds in rats.

BACKGROUND: Morphine is an opioid analgesic used to relieve moderate-to-severe pain, including pain in neonates at the intensive care unit. In our previous study, we showed that repeated morphine exposure during early life could trigger long-lasting implications on the developing nervous system, such as long-term neurochemical and behavioral alterations in adult rats. AIMS: The aim of our study was to determine the short-, intermediate-, and long-term effects of repeated morphine administration during early life on the thermal and mechanical thresholds and on the central levels (cerebral cortex and brainstem) of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and cytokines (interleukin-6 [IL-6] and IL-10). METHODS: Male Wistar rats were administered morphine (5µg/day, s.c.) or saline for 7days from postnatal day 8 (P8) until P14. The nociceptive effect was assessed by evaluating the thermal response using the hot plate test (HPT) and the mechanical response by Von Frey (VFT) and Randall-Selitto (RST) tests at P16, P30, and P60. BDNF, NGF, IL-6, and IL-10 levels were measured in the cerebral cortex and brainstem. RESULTS: In HPT, no difference in latency was observed at P16; however, at P30 and P60, the morphine-treated group exhibited a less increase in the nociceptive threshold compared to the saline group. VFT and RST demonstrated an interaction between group and age, where the morphine group showed a less pronounced increase in latency with age, which is indicative of allodynia. In the cerebral cortex, an association between BDNF and NGF levels and age was observed, where neurotrophin level increased with age in the saline group, and decreased with age in the morphine group. In addition, IL-10 levels decreased with age in both groups; however, there was no significant difference in IL-6 levels. In the brainstem, BDNF, NGF, IL-6, and IL-10 levels increased with age. DISCUSSION: Repeated morphine exposure during neonatal life triggered alterations in the nociceptive behavior, including thermal hyperalgesia and mechanical allodynia, as well as decreased levels of BDNF and NGF in the cerebral cortex. Our study highlights the importance of extensive comprehension of the pharmacological interventions during CNS maturation.

Anti-inflammatory effect of an adhesive resin containing indomethacin-loaded nanocapsules.

OBJECTIVE: To analyze the anti-inflammatory and analgesic effects of an adhesive resin containing indomethacin-loaded nanocapsules in rat model. DESIGN: Adhesive resin disks with or without indomethacin-loaded nanocapsules were subcutaneously implanted into right hind paw of rats. A week after surgical procedure, 2% formalin solution was intradermally injected into plantar surface of paw. Nociceptive and inflammatory responses were evaluated by formalin test. Paw edema by pletismometer and mechanical hyperalgesia by von Frey test were performed on day 2, day 4, day 6, day 8, day 10 and day 12 after surgery. IL-6, IL-10, and lactate dehydrogenase (LDH) serum levels were determined by ELISA-sandwich test. RESULTS: Group containing indomethacin-loaded nanocapsules (NC) presented lower edema in the right hind paw at 24h after formalin injection than those of the control group (CT) (P<0.01). NC group showed decrease in the nociceptive response in phase I (neurogenic pain) compared to CT group (NC - 66.86±22.83s X CT - 130.17±35.83s, P<0.001). NC group presented supporting higher intensity of stimulus on days 8 and 12 (24h and 72h after formalin injection) (P<0.01 and P<0.02 respectively). The IL-6 serum level was also significantly higher in the NC group than CT group (p<0.001). CONCLUSIONS: These results indicate that an adhesive resin containing indomethacin-loaded nanocapsules has anti-inflammatory and nociceptive activities in a chemical model of acute inflammation. The present investigation confirms an adhesive resin with drug-loaded nanocapsules may be useful for improving therapeutic effect for adhesives to be used in deep cavities.

The Influence of Palatable Diets in Reward System Activation: A Mini Review.

The changes in eating patterns that have occurred in recent decades are an important cause of obesity. Food intake and energy expenditure are controlled by a complex neural system involving the hypothalamic centers and peripheral satiety system (gastrointestinal and pancreatic hormones). Highly palatable and caloric food disrupts appetite regulation; however, palatable foods induce pleasure and reward. The cafeteria diet is such a palatable diet and has been shown consistently to increase body weight and induce hyperplasia in animal obesity models. Moreover, palatable high-fat foods (such as those of the cafeteria diet) can induce addiction-like deficits in brain reward function and are considered to be an important source of motivation that might drive overeating and contribute to the development of obesity. The mechanism of neural adaptation triggered by palatable foods is similar to those that have been reported for nondrug addictions and long-term drug use. Thus, this review attempts to describe the potential mechanisms that might lead to highly palatable diets, such as the cafeteria diet, triggering addiction, or compulsion through the reward system.