RESUMEN
Duchenne muscular dystrophy (DMD) is a severe hereditary myopathy. Standard treatment by glucocorticosteroids is limited because of numerous side effects. The aim of this study was to test immunomodulation by human immunoglobulin G (IgG) as treatment in the experimental mouse model (mdx) of DMD. 2 g/kg human IgG compared to human albumin was injected intraperitoneally in mdx mice at the age of 3 and 7 weeks. Advanced voluntary wheel running parameters were recorded continuously. At the age of 11 weeks, animals were killed so that blood, diaphragm, and lower limb muscles could be removed for quantitative PCR, histological analysis and ex vivo muscle contraction tests. IgG compared to albumin significantly improved the voluntary running performance and reduced muscle fatigability in an ex vivo muscle contraction test. Upon IgG treatment, serum creatine kinase values were diminished and mRNA expression levels of relevant inflammatory markers were reduced in the diaphragm and limb muscles. Macrophage infiltration and myopathic damage were significantly ameliorated in the quadriceps muscle. Collectively, this study demonstrates that, in the early disease course of mdx mice, human IgG improves the running performance and diminishes myopathic damage and inflammation in the muscle. Therefore, IgG may be a promising approach for treatment of DMD. Two monthly intraperitoneal injections of human immunoglobulin G (IgG) improved the early 11-week disease phase of mdx mice. Voluntary running was improved and serum levels of creatine kinase were diminished. In the skeletal muscle, myopathic damage was ameliorated and key inflammatory markers such as mRNA expression of SPP1 and infiltration by macrophages were reduced. The study suggests that IgG could be explored as a potential treatment option for Duchenne muscular dystrophy and that pre-clinical long-term studies should be helpful.
Asunto(s)
Inmunoglobulina G/uso terapéutico , Factores Inmunológicos/uso terapéutico , Distrofia Muscular de Duchenne/tratamiento farmacológico , Factores de Edad , Animales , Antígenos CD/metabolismo , Peso Corporal/efectos de los fármacos , Creatina Quinasa/sangre , Modelos Animales de Enfermedad , Femenino , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Actividad Motora/efectos de los fármacos , Fuerza Muscular/efectos de los fármacos , Fuerza Muscular/genética , Músculos/metabolismo , Músculos/patología , Distrofia Muscular de Duchenne/sangre , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
The neuromodulator dopamine plays an important role in synaptic plasticity. The effects depend on receptor subtypes, affinity, concentration level, and the kind of neuroplasticity induced. In animal experiments, dopamine D2-like receptor stimulation revealed partially antagonistic effects on plasticity, which might be explained by dosage dependency. In humans, D2 receptor block abolishes plasticity, and the D2/D3, but predominantly D3, receptor agonist ropinirol has a dosage-dependent nonlinear affect on plasticity. Here we aimed to determine the specific affect of D2 receptor activation on neuroplasticity in humans, because physiological effects of D2 and D3 receptors might differ. Therefore, we combined application of the selective D2 receptor agonist bromocriptine (2.5, 10, and 20 mg or placebo medication) with anodal and cathodal transcranial direct current stimulation (tDCS), which induces nonfocal plasticity, and with paired associative stimulation (PAS) generating a more focal kind of plasticity in the motor cortex of healthy humans. Plasticity was monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. For facilitatory tDCS, bromocriptine prevented plasticity induction independent from drug dosage. However, its application resulted in an inverted U-shaped dose-response curve on inhibitory tDCS, excitability-diminishing PAS, and to a minor degree on excitability-enhancing PAS. These data support the assumption that modulation of D2-like receptor activity exerts a nonlinear dose-dependent effect on neuroplasticity in the human motor cortex that differs from predominantly D3 receptor activation and that the kind of plasticity-induction procedure is relevant for its specific impact.
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Potenciales Evocados Motores/fisiología , Corteza Motora/fisiología , Plasticidad Neuronal/fisiología , Receptores de Dopamina D2/metabolismo , Adulto , Análisis de Varianza , Biofisica , Bromocriptina/farmacología , Domperidona/farmacología , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Electromiografía , Potenciales Evocados Motores/efectos de los fármacos , Femenino , Humanos , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/inervación , Plasticidad Neuronal/efectos de los fármacos , Tractos Piramidales/fisiología , Estimulación Magnética TranscranealRESUMEN
Recent proof-of-principle data showed that the haematopoietic growth factor granulocyte colony-stimulating factor (filgrastim) mediates neuroprotection in rodent models of Parkinson's disease. In preparation for future clinical trials, we performed a preclinical characterization of a pegylated derivative of granulocyte colony-stimulating factor (pegfilgrastim) in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. We determined serum and cerebrospinal fluid drug levels after subcutaneous injection. A single injection of pegfilgrastim was shown to achieve stable levels of granulocyte colony-stimulating factor in both serum and cerebrospinal fluid with substantially higher levels compared to repetitive filgrastim injections. Leucocyte blood counts were only transiently increased after repeated injections. We demonstrated substantial dose-dependent long-term neuroprotection by pegfilgrastim in both young and aged mice, using bodyweight-adjusted doses that are applicable in clinical settings. Importantly, we found evidence for the functionally relevant preservation of nigrostriatal projections by pegfilgrastim in our model of Parkinson's disease, which resulted in improved motor performance. The more stable levels of pegylated neuroprotective proteins in serum and cerebrospinal fluid may represent a general advantage in the treatment of chronic neurodegenerative diseases and the resulting longer injection intervals are likely to improve patient compliance. In summary, we found that pegylation of a neuroprotective growth factor improved its pharmacokinetic profile over its non-modified counterpart in an in vivo model of Parkinson's disease. As the clinical safety profile of pegfilgrastim is already established, these data suggest that evaluation of pegfilgrastim in further Parkinson's disease models and ultimately clinical feasibility studies are warranted.
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Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/metabolismo , Ácido Homovanílico/metabolismo , Inyecciones Subcutáneas , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/líquido cefalorraquídeo , Enfermedad de Parkinson/etiología , Polietilenglicoles/metabolismo , Ratas , Ratas Wistar , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapéutico , Prueba de Desempeño de Rotación con Aceleración Constante , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Restless legs syndrome (RLS) is a common neurological disorder whose exact pathophysiological mechanism remains unclear despite the successful use of dopaminergic treatment and recent discovery of predisposing genetic factors. As iron deficiency has been associated with RLS for some patients and there is evidence for decreased spinal dopamine D(3)-receptor (D3R) signaling in RLS, we aimed at establishing whether D3R activity and iron deficiency share common pathways within the pathophysiology of RLS sensory and motor symptoms. Using a combined mouse model of iron deficiency and dopamine D(3)-receptor deficiency (D3R-/-), circadian motor symptoms were evaluated by continuous recording of spontaneous wheel running activity. Testing the acute and persistent pain responses with the hot-plate test and formalin test, respectively, assessed sensory symptoms. A 15 week iron-deficient (ID) diet alone increased acute and persistent pain responses as compared to control diet. As compared to C57BL/6 (WT), homozygous D3R-/- mice already exhibited elevated responses to acute and persistent pain stimuli, where the latter was further elevated by concurrent iron deficiency. ID changed the circadian activity pattern toward an increased running wheel usage before the resting period, which resembled the RLS symptom of restlessness before sleep. Interestingly, D3R-/- shifted this effect of iron deficiency to a time point 3-4 h earlier. The results confirm the ability of iron deficiency and D3R-/- to evoke sensory and motor symptoms in mice resembling those observed in RLS patients. Furthermore this study suggests an increase of ID-related sensory symptoms and modification of ID-related motor symptoms by D3R-/-.
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Deficiencias de Hierro , Trastornos del Movimiento/etiología , Dolor/etiología , Receptores de Dopamina D3/fisiología , Síndrome de las Piernas Inquietas/complicaciones , Análisis de Varianza , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Lateralidad Funcional/genética , Hierro/sangre , Locomoción/genética , Locomoción/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Trastornos del Movimiento/genética , Dolor/genética , Dimensión del Dolor/métodos , Estimulación Física/efectos adversos , Células del Asta Posterior/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Tiempo de Reacción/genética , Receptores de Dopamina D3/deficiencia , Síndrome de las Piernas Inquietas/sangre , Síndrome de las Piernas Inquietas/genética , Médula Espinal/patologíaRESUMEN
Physical exercise has been shown to increase neurogenesis, to decrease neuronal injury and to improve memory in animal models of stroke and head trauma. Therefore, we investigated the effect of voluntary wheel running on survival, neuronal damage and cell proliferation in a mouse model of pneumococcal meningitis. Mice were housed in cages equipped with voluntary running wheels or in standard cages before induction of bacterial meningitis by a subarachnoid injection of a Streptococcus pneumoniae type 3 strain. 24 hours later antibiotic treatment was initiated with ceftriaxone (100 mg/kg twice daily). Experiments were terminated either 30 hours or 4 days (short-term) or 7 weeks (long-term) after infection, and the survival time, inflammatory cytokines and corticosterone levels, neurogenesis in the dentate gyrus of the hippocampal formation and the cognitive function were evaluated in surviving mice. Survival time was significantly increased in running mice compared to control animals (p = 0.0087 in short-term and p = 0.016 in long-term experiments, log-rank test). At the end of the long-term experiment, mortality was lower in trained than in sedentary animals (p = 0.031, Fisher's Exact test). Hippocampal neurogenesis--assessed by the density of doublecortin-, TUC-4- and BrdU + NeuN-colabeled cells--was significantly increased in running mice in comparison to the sedentary group after meningitis. However, Morris water maze performance of both groups 6 weeks after bacterial meningitis did not reveal differences in learning ability. In conclusion, physical exercise prior to infection increased survival in a mouse model of bacterial meningitis and stimulated neurogenesis in the dentate gyrus of the hippocampal formation.
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Meningitis Bacterianas/mortalidad , Meningitis Bacterianas/patología , Neurogénesis , Condicionamiento Físico Animal/fisiología , Animales , Giro Dentado/citología , Giro Dentado/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Neurogénesis/fisiología , Tasa de Supervivencia/tendencias , Factores de TiempoRESUMEN
For Duchenne muscular dystrophy (DMD), a common myopathy that leads to severe disability, no causal therapy is available. Glucocorticosteroids improve patients' muscle strength, but their long-term use is limited by negative side effects. Thus, pharmacological modifications of glucocorticosteroids are required to increase the efficacy by drug targeting. Liposomal encapsulation augments systemic half-life and local tissue concentrations of glucocorticosteroids and, at the same time, reduces systemic side effects. In this study, the efficacy of novel, long-circulating, polyethylene-glycol-coated liposomes encapsulating prednisolone was compared with free prednisolone in the treatment of mdx mice, a well-established animal model for DMD. Using an objective and sensitive computerized 24-hr detection system of voluntary wheel-running in single cages, we demonstrate a significant impairment of the running performance in mdx compared with black/10 control mice aged 3-6 weeks. Treatment with liposomal or free prednisolone did not improve running performance compared with saline control or empty liposomes. Histopathological parameters, including the rate of internalized nuclei and fiber size variation, and mRNA and protein expression levels of transforming growth factor (TGF)-ß and monocytes chemotactic protein (MCP)-1 also remained unchanged. Bioactivity in skeletal muscle of liposomal and free prednisolone was demonstrated by elevated mRNA expression of muscle ring finger protein 1 (MuRF1), a mediator of muscle atrophy, and its forkhead box transcription factors (Foxo1/3). Our data support the assessment of voluntary running to be a robust and reproducible outcome measure of skeletal muscle performance during the early disease course of mdx mice and suggest that liposomal encapsulation is not superior in treatment efficacy compared with conventional prednisolone. Our study helps to improve the future design of experimental treatment in animal models of neuromuscular diseases.
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Glucocorticoides/administración & dosificación , Liposomas/uso terapéutico , Actividad Motora/efectos de los fármacos , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/fisiopatología , Prednisolona/administración & dosificación , Análisis de Varianza , Animales , Creatina Quinasa/sangre , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Fuerza Muscular/efectos de los fármacos , Fuerza Muscular/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/sangre , Distrofia Muscular de Duchenne/genética , Polietilenglicoles/administración & dosificación , ARN Mensajero/metabolismo , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
INTRODUCTION: To test the hypothesis that the efficacy of botulinum toxin depends on the activity of the neuromuscular junction, we developed an in vivo paradigm to determine the degree and duration of low-dose botulinum toxin-induced focal paresis in mice. METHODS: We combined an automated wheel-running paradigm with low-dose botulinum toxin injections into the calf muscles of wild-type mice. Half of the mice were injected either before the nightly running or before the daily resting period. RESULTS: After botulinum toxin injections, running distance and maximum velocity decreased dose-dependently. The degree and duration of decrease between the respective groups with regard to the time-points of injection were identical. CONCLUSIONS: This in vivo paradigm quantifies the degree of otherwise clinically inapparent botulinum toxin-induced focal calf muscle paresis. Increased muscle activity after low-dose injections does not influence the efficacy of botulinum toxin in normal muscles.
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Toxinas Botulínicas/toxicidad , Músculo Esquelético/fisiología , Paresia/inducido químicamente , Paresia/fisiopatología , Carrera/fisiología , Animales , Prueba de Esfuerzo/efectos de los fármacos , Prueba de Esfuerzo/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/efectos de los fármacos , Unión Neuromuscular/efectos de los fármacos , Unión Neuromuscular/fisiología , Distribución AleatoriaRESUMEN
OBJECTIVE: Cortical myelin can be severely affected in patients with demyelinating disorders of the central nervous system. However, the functional implication of cortical demyelination remains elusive. In this study, we investigated whether cortical myelin influences cortical spreading depression (CSD). METHODS: CSD measurements were performed in rodent models of toxic and autoimmune induced cortical demyelination, in neuregulin-1 type I transgenic mice displaying cortical hypermyelination, and in glial fibrillary acidic protein-transgenic mice exhibiting pronounced astrogliosis. RESULTS: Cortical demyelination, but not astrogliosis or inflammation per se, was associated with accelerated CSD. In contrast, hypermyelinated neuregulin-1 type I transgenic mice displayed a decelerated CSD propagation. INTERPRETATION: Cortical myelin may be crucially involved in the stabilization and buffering of extracellular ion content that is decisive for CSD propagation velocity and cortical excitability, respectively. Our data thus indicate that cortical involvement in human demyelinating diseases may lead to relevant alterations of cortical function.
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Corteza Cerebral/fisiopatología , Depresión de Propagación Cortical/fisiología , Enfermedades Desmielinizantes/fisiopatología , Encefalomielitis Autoinmune Experimental/fisiopatología , Proteína Básica de Mielina/análisis , Vaina de Mielina/fisiología , Animales , Astrocitos , Corteza Cerebral/química , Corteza Cerebral/efectos de los fármacos , Depresión de Propagación Cortical/efectos de los fármacos , Cuprizona/farmacología , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/genética , Electroencefalografía , Femenino , Lateralidad Funcional/fisiología , Proteína Ácida Fibrilar de la Glía/genética , Gliosis , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Esclerosis Múltiple/fisiopatología , Proteína Básica de Mielina/fisiología , Vaina de Mielina/genética , Neurregulina-1/genética , Ratas , Ratas Endogámicas LewRESUMEN
Background: Low intensity, high-frequency transcranial alternating current stimulation (tACS) applied over the motor cortex decreases the amplitude of motor evoked potentials. This double-blind, placebo-controlled parallel group study aimed to test the efficacy of this method for acute management of migraines. Methods: The patients received either active (0.4 mA, 140 Hz) or sham stimulation for 15 min over the visual cortex with the number of terminated attacks two hours post-stimulation as the primary endpoint, as a home therapy option. They were advised to treat a maximum of five migraine attacks over the course of six weeks. Results: From forty patients, twenty-five completed the study, sixteen in the active and nine in the sham group with a total of 102 treated migraine attacks. The percentage of terminated migraine attacks not requiring acute rescue medication was significantly higher in the active (21.5%) than in the sham group (0%), and the perceived pain after active stimulation was significantly less for 2-4 h post-stimulation than after sham stimulation. Conclusion: tACS over the visual cortex has the potential to terminate migraine attacks. Nevertheless, the high drop-out rate due to compliance problems suggests that this method is impeded by its complexity and time-consuming setup.
RESUMEN
BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by mutations in the dystrophin gene, which leads to structural instability of the dystrophin-glycoprotein-complex with subsequent muscle degeneration. In addition, muscle inflammation has been implicated in disease progression and therapeutically addressed with glucocorticosteroids. These have numerous adverse effects. Treatment with human immunoglobulin G (IgG) improved clinical and para-clinical parameters in the early disease phase in the well-established mdx mouse model. The aim of the present study was to confirm the efficacy of IgG in a long-term pre-clinical study in mdx mice. METHODS: IgG (2 g/kg body weight) or NaCl solution as control was administered monthly over 18 months by intraperitoneal injection in mdx mice beginning at 3 weeks of age. Several clinical outcome measures including endurance, muscle strength, and echocardiography were assessed. After 18 months, the animals were sacrificed, blood was collected for analysis, and muscle samples were obtained for ex vivo muscle contraction tests, quantitative PCR, and histology. RESULTS: IgG significantly improved the daily voluntary running performance (1.9 m more total daily running distance, P < 0.0001) and slowed the decrease in grip strength by 0.1 mN, (P = 0.018). IgG reduced fatigability of the diaphragm (improved ratio to maximum force by 0.09 ± 0.04, P = 0.044), but specific tetanic force remained unchanged in the ex vivo muscle contraction test. Cardiac function was significantly better after IgG, especially fractional area shortening (P = 0.012). These results were accompanied by a reduction in cardiac fibrosis and the infiltration of T cells (P = 0.0002) and macrophages (P = 0.0027). In addition, treatment with IgG resulted in a significant reduction of the infiltration of T cells (P ≤ 0.036) in the diaphragm, gastrocnemius, quadriceps, and a similar trend in tibialis anterior and macrophages (P ≤ 0.045) in gastrocnemius, quadriceps, tibialis anterior, and a similar trend in the diaphragm, as well as a decrease in myopathic changes as reflected by a reduced central nuclear index in the diaphragm, tibialis anterior, and quadriceps (P ≤ 0.002 in all). CONCLUSIONS: The present study underscores the importance of an inflammatory contribution to the disease progression of DMD. The data demonstrate the long-term efficacy of IgG in the mdx mouse. IgG is well tolerated by humans and could preferentially complement gene therapy in DMD. The data call for a clinical trial with IgG in DMD.
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Corazón/fisiopatología , Inmunoglobulina G/uso terapéutico , Músculo Esquelético/fisiopatología , Distrofia Muscular de Duchenne/complicaciones , Animales , Modelos Animales de Enfermedad , Humanos , Inmunoglobulina G/farmacología , RatonesRESUMEN
Iron deficiency has been described as a risk factor in secondary restless legs syndrome (RLS), although it has not been investigated whether iron deficiency induces sensory symptoms in RLS patients. In this study, we established a mouse model of iron deficiency by administering a purified iron-deficient (ID) diet (<8 mg/kg iron) or nonpurified standard diet [normal diet (ND)] (<179 mg/kg iron) to male C57Bl/6 mice from postnatal d 28 for 1, 4, or 15 wk. The level of iron deficiency was assessed by the plasma iron concentration. After varying durations of iron deficiency, both acute and chronic sensory components of pain were measured using hot-plate and formalin tests, which preferentially assess Adelta- and C-fibers, respectively. Based on hot-plate reaction time, ID mice had a lower acute pain threshold than the ND mice after 4 and 15 wk but not after 1 wk. In addition, ID mice had an increased chronic pain response compared with the ND mice only in the late phase of the formalin-test after 1, 4, and 15 wk of iron deficiency. This increased pain response was accompanied by an elevated expression of c-Fos immunoreactive cells at the ipsilateral dorsal horn, suggesting that iron deficiency indirectly increases cell activity at the spinal cord level. These results demonstrate that iron deficiency increases acute and chronic pain responses in mice and may cause similar alterations to the acute pain threshold and sensitivity to C-fiber-mediated chronic pain in ID RLS patients.
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Formaldehído/farmacología , Deficiencias de Hierro , Dimensión del Dolor/efectos de los fármacos , Dolor/fisiopatología , Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Animales , Animales Recién Nacidos , Biotinilación/efectos de los fármacos , Dieta , Genes fos/efectos de los fármacos , Calor , Inmunohistoquímica , Hierro/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Tiempo de Reacción/efectos de los fármacosRESUMEN
Sexual dimorphism has been described in various aspects of physiological and pathophysiological processes involving dopaminergic signaling. This might account for the different disease characteristics in men and women in e.g. Parkinson's disease or ADHD. A better understanding might contribute to the future individualization of therapy. We examined spontaneous wheel running activity of male and female mice, homo- and heterozygote for dopamine D3 receptor deficiency (D3R -/- and D3R+/-), and compared them to wild type controls. We found higher wheel running activity in female mice than in their male littermates. D3-/- mice, irrespective of sex, were also hyperactive compared to both D3+/- and wild type animals. Hyperactivity of D3-/- female mice was pronounced during the first days of wheel running but then decreased while their male counterparts continued to be hyperactive. Physical activity was menstrual cycle-dependent. Activity fluctuations were also seen in D3 receptor knockout mice and are therefore presumably independent of D3 receptor activation. Our data underscore the complex interaction of dopaminergic signaling and gonadal hormones that leads to specific running behavior. Furthermore, we detected sex- and D3 receptor status-specific reactions during novel exposure to the running wheel. These findings suggest the need for adapting dopaminergic therapies to individual factors such as sex or even menstrual cycle to optimize therapeutic success.
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Actividad Motora/fisiología , Receptores de Dopamina D3/metabolismo , Carrera/fisiología , Caracteres Sexuales , Animales , Femenino , Masculino , Ciclo Menstrual , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Dopamina D3/genética , Estadísticas no ParamétricasRESUMEN
The present study aimed to investigate the efficacy of repetitive cathodal direct current stimulation (rctDCS) over the visual cortex as a prophylactic treatment in patients with menstrual migraine. 20 female patients were recruited in this double-blind, placebo-controlled study and were assigned to receive either cathodal or sham stimulation. Over 3 menstrual cycles, tDCS with 2mA intensity and 20 min duration was applied to the visual cortex of the patients, in 5 consecutive sessions 1-5 days prior to the first day of their menstruation. The primary endpoint of the study was the frequency of the migraine attacks at the end of the treatment period, however, additional parameters, such as the number of migraine related days and the intensity of pain were also recorded 3 months before, during and 3 months post-treatment. Visual cortex excitability was determined by measuring the phosphene thresholds (PTs) using single pulse transcranial magnetic stimulation (TMS) over the visual cortex. Sixteen patients completed the study. A significant decrease in the number of migraine attacks (p=0.04) was found in the cathodal group compared to baseline but not compared to sham (p=0.053). In parallel the PTs increased significantly in this group, compared to the sham group (p<0.05). Our results indicate that prophylactic treatment with rctDCS over the visual cortex might be able to decrease the number of attacks in patients with menstrual migraine, probably by modifying cortical excitability.
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Menstruación/fisiología , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/terapia , Estimulación Transcraneal de Corriente Directa/métodos , Corteza Visual/fisiología , Adulto , Método Doble Ciego , Femenino , Humanos , Profilaxis Pre-Exposición , Resultado del Tratamiento , Adulto JovenRESUMEN
Dopaminergic signaling influences physical activity. Notably impaired D2 receptor (D2R) function has been associated with decreased voluntary physical activity. Most animal models investigating effects of genetic or pharmacological dopaminergic modulation measure physical activity for a limited time of up to few hours. The aim of this study is to investigate the impact of chronic or acute D2R dysfunction on physical activity over several days. For this purpose, we used a highly automated running wheel system to continuously record physical activity in mice. We found that D2R-knockout status led to a permanent decrease of running wheel activity. In contrast, acute D2R blockade by raclopride (1.5-5mg/kg) resulted in an initial dose-dependent reduction of running wheel usage and a compensating increase of activity in later stages of the activity phase. This indicates that D2R dysfunction reduces physical activity. Our data indicate that this reduction to a large extent cannot be explained by motor deficits. The delayed increase of activity after D2R blockade might be due to a rebound effect.
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Antagonistas de Dopamina/farmacología , Locomoción/efectos de los fármacos , Locomoción/genética , Racloprida/farmacología , Receptores de Dopamina D2/deficiencia , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Factores de TiempoRESUMEN
Tetanus neurotoxin (TeNT) enhances activity of motoneurons by blocking spinal inhibitory interneurons. Based on this pathomechanism, we propose that low-dosage intramuscular injections of TeNT could serve as a specific treatment for central paretic muscles. However in vivo TeNT research is restricted because of the fear of triggering widespread muscle spasms. In addition, no reliable test to measure the in vivo toxicity of low-dosage TeNT is available. We introduce a novel wheel running-based paradigm with mice to quantify functional effects and thus the toxicity of low-dosage TeNT in vivo. We accustomed three groups of wildtype mice (n=14) to using a complex running wheel with irregularly spaced crossbars. Each group received an injection with a different low-dosage of TeNT (0.15 ng, 0.1 ng or 0.05 ng TeNT) into both tibialis anterior muscles. The maximum running velocity and accumulative running time of the groups were recorded during the following weeks. Three days after TeNT injections, the mice exhibited an increase in muscle tone of the injected tibialis anterior muscles but no generalized symptoms. However, we found that normal running in the complex wheel set-up was disturbed such that the maximum running velocity and running time of the mice decreased with the size of the dose. This effect peaked on the fifth and sixth nights after injection and returned to baseline level again within the next two weeks. With this novel in vivo automated paradigm we can accurately and objectively quantify the duration and degree of TeNT-induced focal increase in muscle tone.
Asunto(s)
Metaloendopeptidasas/toxicidad , Espasticidad Muscular/inducido químicamente , Espasticidad Muscular/fisiopatología , Carrera/fisiología , Toxina Tetánica/toxicidad , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Fenómenos Biomecánicos , Relación Dosis-Respuesta a Droga , Miembro Posterior/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas Motoras/efectos de los fármacos , Tono Muscular/efectos de los fármacos , Tono Muscular/fisiología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Parálisis/inducido químicamente , Parálisis/fisiopatologíaRESUMEN
In preterm infants, the risk to develop attention-deficit/hyperactivity disorder is 3 to 4-fold higher than in term infants. Moreover, preterm infants exhibit deficits in motor coordination and balance. Based on clinical data, higher oxygen levels in preterm infants lead to worse neurological outcome, and experimental hyperoxia causes wide-ranging cerebral changes in neonatal rodents. We hypothesize that hyperoxia in the immature brain may affect motor activity in preterm infants. We subjected newborn mice from P6 to P8 to 48 h of hyperoxia (80% O(2)) and tested motor activity in running wheels starting at adolescent age P30. Subsequently, from P44 to P53, regular wheels were replaced by complex wheels with variable crossbar positions to assess motor coordination deficits. MRI with diffusion tensor imaging was performed in the corpus callosum to determine white matter diffusivity in mice after hyperoxia at ages P30 and P53 in comparison to control animals. Adolescent mice after neonatal hyperoxia revealed significantly higher values for maximum velocity and mean velocity in regular wheels than controls (P<0.05). In the complex running wheels, however, maximum velocity was decreased in animals after hyperoxia, as compared to controls (P<0.05). Decreased fractional anisotropy and increased radial diffusion coefficient were observed in the corpus callosum of P30 and P53 mice after neonatal hyperoxia compared to control mice. Hyperoxia in the immature brain causes hyperactivity, motor coordination deficits, and impaired white matter diffusivity in adolescent and young adult mice.
Asunto(s)
Cuerpo Calloso/fisiopatología , Hipercinesia/fisiopatología , Hiperoxia/fisiopatología , Actividad Motora/fisiología , Animales , Cuerpo Calloso/patología , Hipercinesia/etiología , Hipercinesia/patología , Hiperoxia/complicaciones , Hiperoxia/patología , Imagen por Resonancia Magnética , RatonesRESUMEN
The type I interferons, interferon-beta and alpha (IFN-beta, IFN-alpha), are widely used for the treatment of autoimmune demyelination in the central nervous system (CNS). Their effects on de- and remyelination through the broadly expressed type I IFN receptor (IFNAR), however, are highly speculative. In order to elucidate the role of endogenous type I interferons for myelin damage and recovery we induced toxic demyelination in the absence of IFNAR1. We demonstrate that IFNAR signalling was induced during acute demyelination since the cytokine IFN-beta as well as the IFN-dependent genes IRF7, ISG15 and UBP43 were strongly upregulated. Myelin damage, astrocytic and microglia response, however, were not significantly reduced in the absence of IFNAR1. Furthermore, motor skills of IFNAR1-deficient animals during non-immune demyelination were unaltered. Finally, myelin recovery was found to be independent from endogenous IFNAR signalling, indicating a redundant role of this receptor for non-inflammatory myelin damage and repair.
Asunto(s)
Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/fisiopatología , Vaina de Mielina/metabolismo , Receptor de Interferón alfa y beta/metabolismo , Transducción de Señal/fisiología , Animales , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Sistema Nervioso Central/ultraestructura , Cuprizona/toxicidad , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Destreza Motora/fisiología , Vaina de Mielina/patología , Receptor de Interferón alfa y beta/deficiencia , Receptor de Interferón alfa y beta/genética , Transducción de Señal/efectos de los fármacos , Organismos Libres de Patógenos EspecíficosRESUMEN
PURPOSE: Weak direct currents induce lasting alterations of cortical excitability in animals and humans, which are controlled by polarity, duration of stimulation, and current strength applied. To evaluate its anticonvulsant potential, transcranial direct current stimulation (tDCS) was tested in a modified cortical ramp-stimulation model of focal epilepsy. METHODS: The threshold for localized seizure activity (TLS) was determined in freely moving rats by applying a single train of rising bipolar pulses through a unilateral epicranial electrode. After tDCS, TLS was determined repeatedly for 120 min at intervals of 15 min. The first group of animals received two sessions of cathodal tDCS at 100 microA, one for 30 and one for 60 min. A third session consisted of 60 min of anodal tDCS. A second group received cathodal tDCS at 200 microA for 15 and for 30 min, as well as anodal tDCS for 30 min. RESULTS: Sixty minutes of cathodal tDCS at 100 microA resulted in a TLS increase lasting for >or=2 h. When the intensity was increased to 200 microA, a similar lasting TLS elevation occurred after a stimulation of just 30-min duration. In contrast, anodal tDCS at identical stimulation durations and current strengths had no significant effect on TLS. CONCLUSIONS: The anticonvulsive effect induced by cathodal tDCS depends on stimulation duration and current strength and may be associated with the induction of alterations of cortical excitability that outlast the actual stimulation. The results lead to the reasonable assumption that cathodal tDCS could evolve as a therapeutic tool in drug-refractory partial epilepsy.