Gentle Touch Therapy, Pain Relief and Neuroplasticity at Baseline in Fibromyalgia Syndrome: A Randomized, Multicenter Trial with Six-Month Follow-Up.

BACKGROUND: Fibromyalgia (FM) is considered a stress-related disorder characterized mainly by chronic widespread pain. Its pathogenesis is unknown, but cumulative evidence points at dysfunctional transmitter systems and inflammatory biomarkers that may underlie the major symptoms of the condition. This study aimed to evaluate pain scores (primary outcome), quality of life, inflammatory biomarkers and neurotransmitter systems in women with FM (secondary outcomes) subjected to gentle touch therapy (GTT) or placebo. METHODS: A total of 64 female patients with FM were randomly assigned to two groups, namely GTT (n = 32) or Placebo (n = 32). Clinical assessments were conducted at baseline and post-intervention with six-month follow-up. We measured serum catecholamines (dopamine), indolamines and intermediary metabolites (serotonin or 5-hydroxyindolacetic acid (5-HIAA)), as well as tetrahydrobiopterin (BH4), which is a cofactor for the synthesis of neurotransmitters and inflammatory biomarkers in women with FM. A group of healthy individuals with no intervention (control group) was used to compare biochemical measurements. Intervention effects were analyzed using repeated measures (RM) two-way ANOVA followed by Bonferroni post hoc test and mixed ANCOVA model with intention to treat. RESULTS: Compared to placebo, the GTT group presented lower pain scores and brain-derived neurotrophic factor (BDNF) levels without altering the quality of life of women with FM. Changes in BDNF had a mediating role in pain. Higher baseline serum BDNF and 5-HIAA or those with a history of anxiety disorder showed a higher reduction in pain scores across time. However, women with higher serum dopamine levels at baseline showed a lower effect of the intervention across the observation period revealed by an ANCOVA mixed model. CONCLUSIONS: In conclusion, lower pain scores were observed in the GTT group compared to the placebo group without altering the quality of life in women with FM. Reductions in BDNF levels could be a mechanism of FM pain status improvement. In this sense, the present study encourages the use of these GTT techniques as an integrative and complementary treatment of FM.

Effects of photobiomodulation on mitochondria of brain, muscle, and C6 astroglioma cells.

The purpose of this study was to investigate the effect of different doses of photobiomodulation (PBM) on mitochondrial respiratory complexes and oxidative cellular energy metabolic enzymes in the mitochondria of brain, muscle, and C6 glioma cells after different time intervals. C6 cells were irradiated with an AlGaInP laser at 10, 30, and 60 J/cm2 for 20, 60, and 120 s, respectively. After irradiation, the cells were maintained in serum-free Dulbecco's Modified Eagle's medium for 24 h, and biochemical measurements were made subsequently. Mitochondrial suspensions from adult rat skeletal muscles/brains were irradiated with an AlGaInP laser at the abovementioned doses. In one group, the reaction was stopped 5 min after irradiation and in the other 60 min after irradiation. Both the C6 cells that received the doses of 10 and 30 J/cm² showed increased complex I activity; the cells that were irradiated at 30 J/cm2 showed increased hexokinase activity. Five minutes after the introduction of PBM of the muscle mitochondria (at 30 and 60 J/cm2), the activity of complex I increased, while the activity of complex IV increased only at 60 J/cm2. One hour after the laser session, complex II activity increased in the cells treated with 10 and 60 J/cm²; however, complex IV activity showed an increase in all PBM groups. In brain mitochondria, 5 min after irradiation only the activity of complex IV increased in all PBM groups. One hour after the laser session, complex II activity increased at 60 J/cm2, and complex IV activity increased for all PBM groups when compared to controls. PBM could increase the activity of respiratory chain complexes in an apparently dose- and time-dependent manner.

Low-level laser therapy attenuates the acute inflammatory response induced by muscle traumatic injury.

The purpose of this work was to investigate the effect of early and long-term low-level laser therapy (LLLT) on oxidative stress and inflammatory biomarkers after acute-traumatic muscle injury in Wistar rats. Animals were randomly divided into the following four groups: control group (CG), muscle injury group (IG), CG + LLLT, and IG + LLLT: laser treatment with doses of 3 and 5 J/cm(2). Muscle traumatic injury was induced by a single-impact blunt trauma in the rat gastrocnemius. Irradiation for 3 or 5 J/cm(2) was initiated 2, 12, and 24 h after muscle trauma induction, and the treatment was continued for five consecutive days. All the oxidant markers investigated. namely thiobarbituric acid-reactive substance, carbonyl, superoxide dismutase, glutathione peroxidase, and catalase, were increased as soon as 2 h after muscle injury and remained increased up to 24 h. These alterations were prevented by LLLT at a 3 J/cm(2) dose given 2 h after the trauma. Similarly, LLLT prevented the trauma-induced proinflammatory state characterized by IL-6 and IL-10. In parallel, trauma-induced reduction in BDNF and VEGF, vascular remodeling and fiber-proliferating markers, was prevented by laser irradiation. In order to test whether the preventive effect of LLLT was also reflected in muscle functionality, we tested the locomotor activity, by measuring distance traveled and the number of rearings in the open field test. LLLT was effective in recovering the normal locomotion, indicating that the irradiation induced biostimulatory effects that accelerated or resolved the acute inflammatory response as well as the oxidant state elicited by the muscle trauma.

Differential effects of insulin on peripheral diabetes-related changes in mitochondrial bioenergetics: involvement of advanced glycosylated end products.

Large scale clinical trials have demonstrated that an intensive antihyperglycemic treatment in diabetes mellitus (DM) in individuals reduces the incidence of micro- and macrovascular complications, e.g. nephropathy, retinopathy, DM-accelerated atherosclerosis, myocardial infarction, or limb amputations. Here, we investigated the effect of short- and long-term insulin administration on mitochondrial function in peripheral tissues of streptozotocin (STZ)-induced hyperglycemic rats. In addition, the in vitro effect of methylglyoxal (MG), advanced glycation end products (AGEs) and human diabetic plasma on mitochondrial activity was investigated in skeletal muscle and liver mitochondria and in rat skin primary fibroblasts. Hyperglycemic STZ rats showed tissue-specific patterns of energy deficiency, evidenced by reduced activities of complexes I, II and/or IV after 30 days of hyperglycemia in heart, skeletal muscle and liver; moreover, cardiac tissue was found to be the most sensitive to the diabetic condition, since energy metabolism was impaired after 10 days of the hyperglycemia. Insulin-induced tight glycemic control was effective in protecting against the hyperglycemia-induced inhibition of mitochondrial enzyme activities. Furthermore, the long-term hormone replacement (30 days) also increased these activities in kidney from STZ-treated animals, where the hyperglycemic state did not modify the electron transport activity. Results from in vitro experiments indicate that mitochondrial impairment could result from oxidative stress-induced accumulation of MG and/or AGEs. Further investigations demonstrated that human plasma AGE accumulation elicits reduced mitochondrial function in skin fibroblast. These data suggest that persistent hyperglycemia results in tissue-specific patterns of energy deficiency and that early and continuous insulin therapy is necessary to maintain proper mitochondrial metabolism.

The intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a new rodent model to test palliative and neuroprotective agents for Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting approximately 1% of the population older than 60 years. Classically, PD is considered to be a motor system disease and its diagnosis is based on the presence of a set of cardinal motor signs that are consequence of a pronounced death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Nowadays there is considerable evidence showing that non-dopaminergic degeneration also occurs in other brain areas which seems to be responsible for the deficits in olfactory, emotional and memory functions that precede the classical motor symptoms in PD. Dopamine-replacement therapy has dominated the treatment of PD and although the currently approved antiparkinsonian agents offer effective relief of the motor deficits, they have not been found to alleviate the non-motor features as well as the underlying dopaminergic neuron degeneration and thus drug efficacy is gradually lost. Another major limitation of chronic dopaminergic therapy is the numerous adverse effects such as dyskinesias, psychosis and behavioral disturbance. The development of new therapies in PD depends on the existence of representative animal models to facilitate the evaluation of new pharmacological agents before they are applied in clinical trials. We have recently proposed a new experimental model of PD consisting of a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 1 mg/nostril) in rodents. Our findings demonstrated that rats and mice treated intranasally with MPTP suffer impairments in olfactory, cognitive, emotional and motor functions conceivably analogous to those observed during different stages of PD. Such infusion causes time-dependent loss of tyrosine hydroxylase in the olfactory bulb and SNc, resulting in significant dopamine depletion in different brain areas. We have also identified some pathogenic mechanisms possibly involved in the neurodegeneration induced by i.n. administration of MPTP including mitochondrial dysfunction, oxidative stress, activation of apoptotic cell death mechanisms and glutamatergic excitotoxicity. Therefore, the present review attempts to provide a comprehensive picture of the i.n. MPTP model and to highlight recent findings from our group showing its potential as a valuable rodent model for testing novel drugs that may provide alternative or adjunctive treatment for both motor and non-motor symptoms relief with a reduced side-effect profile as well as the discovery of compounds to modify the course of PD.

Effects of low-power laser irradiation (LPLI) at different wavelengths and doses on oxidative stress and fibrogenesis parameters in an animal model of wound healing.

Gallium-arsenide (GaAs) and helium-neon (HeNe) lasers are the most commonly used low-energy lasers in physiotherapy for promoting wound healing and pain modulation. The aim of this study was investigate the effect of low-power laser irradiation (LPLI) at different wavelengths and doses on oxidative stress and fibrogenesis parameters in an animal model of wound healing. The animals were randomly divided into five groups (n=6): Controls (skin injured animals without local or systemic treatment), skin injury treated with HeNe 1 J/cm(2) (two seg); skin injury treated with HeNe 3 J/cm(2) (six seg); skin injury treated with GaAs 1 J/cm(2) (three seg); skin injury treated with GaAs 3 J/cm(2) (nine seg). A single circular wound measuring 8 mm in diameter was surgically created on the back of the animal. The rats were irradiated at 2, 12, 24, 48, 72, 96, and 120 h after skin injury. The parameters, namely hydroxyproline content, activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and lipid (TBARS) and protein oxidation (carbonyl groups) measurements were assessed. In addition, wound size regression was also analyzed. The results showed an improvement in the wound healing reflected by the reduction in wound size and increased collagen synthesis. Moreover, a significant reduction in TBARS levels, carbonyl content, and SOD and CAT activities were observed after laser irradiation, particularly with the treatments HeNe laser 1 and 3 J/cm(2) dose and GaAs 3 J/cm(2) dose. The data strongly indicate that LPLI therapy is efficient in accelerating the skin wound healing process after wounding, probably by reducing the inflammatory phase and inducing collagen synthesis.

Proanthocyanidin-rich fraction from Croton celtidifolius Baill confers neuroprotection in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine rat model of Parkinson's disease.

We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered impairments in olfactory, cognitive and motor functions associated with time-dependent disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). On the other hand, the proanthocyanidin-rich fraction (PRF) obtained from the bark of Croton celtidifolius Baill (Euphorbiaceae), a tree frequently found in the Atlantic forest in south Brazil, has been described to have several neurobiological activities including antioxidant and anti-inflammatory properties, which may be of interest in the treatment of PD. The present data indicated that the pretreatment with PRF (10 mg/kg, i.p.) during five consecutive days was able to prevent mitochondrial complex-I inhibition in the striatum and olfactory bulb, as well as a decrease of the enzyme tyrosine hydroxylase expression in the olfactory bulb and substantia nigra of rats infused with a single intranasal administration of MPTP (1 mg/nostril). Moreover, pretreatment with PRF was found to attenuate the short-term social memory deficits, depressive-like behavior and reduction of locomotor activity observed at different periods after intranasal MPTP administration in rats. Altogether, the present findings provide strong evidence that PRF from C. celtidifolius may represent a promising therapeutic tool in PD, thus being able to prevent both motor and non-motor early symptoms of PD, together with its neuroprotective potential.

Acute exposure of rabbits to diphenyl diselenide: a toxicological evaluation.

The simple organoselenium compound diphenyl diselenide (PhSe)(2) is a promising new pharmacological agent. However, few toxicological evaluations of this molecule have been reported. We evaluated the effects of acute administration of (PhSe)(2) on toxicological parameters in rabbits. Adult New Zealand rabbits were exposed to (PhSe)(2) (5-500 micromol kg(-1) , intraperitoneally) once a day for 5 days. Exposure to 500 micromol kg(-1) caused 85% mortality. Exposure to 50 micromol kg(-1) of (PhSe)(2) increased the glutathione levels in the hippocampus, kidney, heart, muscle and blood, whereas lipoperoxidation (TBARS) decreased in the cerebellum and kidney after exposure to 5 micromol kg(-1) . The activity of glutathione peroxidase increased in the heart and muscle of rabbits treated with 50 micromol kg(-1) of (PhSe)(2) and glutathione reductase activity was reduced in the cerebellum, cerebral cortex and kidney. Treatment with (PhSe)(2) reduced the activity of δ-aminolevulinate dehydratase in the hippocampus and increased this activity in the heart, but did not alter the activity of complexes I and II of the respiratory chain in the liver and brain. Hepatic and renal biochemical and histological parameters were not modified by (PhSe)(2) and apoptosis was not detected in these tissues; however, the hepatic cells tended to accumulate fat vacuoles. These results indicated that acute toxicology to (PhSe)(2) in rabbit is dependent on the dose, which should motivate further experiments on the therapeutic properties of this compound.