Antikinetoplastid SAR study in 3-nitroimidazopyridine series: identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program

Artificial Gravity Reveals that Economy of Action Determines the Stability of Sensorimotor Coordination

Background: When we move along in time with a piece of music, we synchronise the downward phase of our gesture with the beat. While it is easy to demonstrate this tendency, there is considerable debate as to its neural origins. It may have a structural basis, whereby the gravitational field acts as an orientation reference that biases the formulation of motor commands. Alternatively, it may be functional, and related to the economy with which motion assisted by gravity can be generated by the motor system

Deciphering the functional role of spatial and temporal muscle synergies in whole-body movements

International audienceVoluntary movement is hypothesized to rely on a limited number of muscle synergies, the recruitment of which translates task goals into effective muscle activity. In this study, we investigated how to analytically characterize the functional role of different types of muscle synergies in task performance. To this end, we recorded a comprehensive dataset of muscle activity during a variety of whole-body pointing movements. We decomposed the electromyographic (EMG) signals using a space-by-time modularity model which encompasses the main types of synergies. We then used a task decoding and information theoretic analysis to probe the role of each synergy by mapping it to specific task features. We found that the temporal and spatial aspects of the movements were encoded by different temporal and spatial muscle synergies, respectively, consistent with the intuition that there should a correspondence between major attributes of movement and major features of synergies. This approach led to the development of a novel computational method for comparing muscle synergies from different participants according to their functional role. This functional similarity analysis yielded a small set of temporal and spatial synergies that describes the main features of whole-body reaching movements

Hand use predicts the structure of representations in sensorimotor cortex.

Fine finger movements are controlled by the population activity of neurons in the hand area of primary motor cortex. Experiments using microstimulation and single-neuron electrophysiology suggest that this area represents coordinated multi-joint, rather than single-finger movements. However, the principle by which these representations are organized remains unclear. We analyzed activity patterns during individuated finger movements using functional magnetic resonance imaging (fMRI). Although the spatial layout of finger-specific activity patterns was variable across participants, the relative similarity between any pair of activity patterns was well preserved. This invariant organization was better explained by the correlation structure of everyday hand movements than by correlated muscle activity. This also generalized to an experiment using complex multi-finger movements. Finally, the organizational structure correlated with patterns of involuntary co-contracted finger movements for high-force presses. Together, our results suggest that hand use shapes the relative arrangement of finger-specific activity patterns in sensory-motor cortex

Robot-assisted image-guided transcranial magnetic stimulation for somatotopic mapping of the motor cortex: a clinical pilot study

Shape and exact location of motor cortical areas varies among individuals. The exact knowledge of these locations is crucial for planning of neurosurgical procedures. In this study, we have used robot-assisted image-guided transcranial magnetic stimulation (Ri-TMS) to elicit MEP response recorded for individual muscles and reconstruct functional motor maps of the primary motor cortex

Rhaponticum acaule (L) DC essential oil: chemical composition, in vitro antioxidant and enzyme inhibition properties

Background: α-glucosidase is a therapeutic target for diabetes mellitus (DM) and α-glucosidase inhibitors play a vital role in the treatments for the disease. Furthermore, xanthine oxidase (XO) is a key enzyme that catalyzes hypoxanthine and xanthine to uric acid which at high levels can lead to hyperuricemia which is an important cause of gout. Pancreatic lipase (PL) secreted into the duodenum plays a key role in the digestion and absorption of fats. For its importance in lipid digestion, PL represents an attractive target for obesity prevention. Methods: The flowers essential oil of Rhaponticum acaule (L) DC (R. acaule) was characterized using gas chromatography-mass spectrometry (GC-MS). The antioxidant activities of R. acaule essential oil (RaEO) were also determined using 2,2’-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), reducing power, phosphomolybdenum, and DNA nicking assays. The inhibitory power of RaEO against α-glucosidase, xanthine oxidase and pancreatic lipase was evaluated. Enzyme kinetic studies using Michaelis-Menten and the derived Lineweaver-Burk (LB) plots were performed to understand the possible mechanism of inhibition exercised by the components of this essential oil. Results: The result revealed the presence of 26 compounds (97.4%). The main constituents include germacrene D (49.2%), methyl eugenol (8.3%), (E)-β-ionone (6.2%), β-caryophyllene (5.7%), (E,E)-α-farnesene (4.2%), bicyclogermacrene (4.1%) and (Z)-α-bisabolene (3.7%). The kinetic inhibition study showed that the essential oil demonstrated a strong α-glucosidase inhibiton and it was a mixed inhibitor. On the other hand, our results evidenced that this oil exhibited important xanthine oxidase inhibitory effect, behaving as a non-competitive inhibitor. The essential oil inhibited the turkey pancreatic lipase, with maximum inhibition of 80% achieved at 2 mg/mL. Furthermore, the inhibition of turkey pancreatic lipase by RaEO was an irreversible one. Conclusion: The results revealed that the RaEO is a new promising potential source of antioxidant compounds, endowed with good practical applications for human health. Keywords: α-glucosidase, Antioxidant activity, Chemical composition, Pancreatic lipase inhibition, Rhaponticum acaule essential oil, Xanthine oxidase

Gene Expression Changes in the Motor Cortex Mediating Motor Skill Learning

The primary motor cortex (M1) supports motor skill learning, yet little is known about the genes that contribute to motor cortical plasticity. Such knowledge could identify candidate molecules whose targeting might enable a new understanding of motor cortical functions, and provide new drug targets for the treatment of diseases which impair motor function, such as ischemic stroke. Here, we assess changes in the motor-cortical transcriptome across different stages of motor skill acquisition. Adult rats were trained on a gradually acquired appetitive reach and grasp task that required different strategies for successful pellet retrieval, or a sham version of the task in which the rats received pellet reward without needing to develop the reach and grasp skill. Tissue was harvested from the forelimb motor-cortical area either before training commenced, prior to the initial rise in task performance, or at peak performance. Differential classes of gene expression were observed at the time point immediately preceding motor task improvement. Functional clustering revealed that gene expression changes were related to the synapse, development, intracellular signaling, and the fibroblast growth factor (FGF) family, with many modulated genes known to regulate synaptic plasticity, synaptogenesis, and cytoskeletal dynamics. The modulated expression of synaptic genes likely reflects ongoing network reorganization from commencement of training till the point of task improvement, suggesting that motor performance improves only after sufficient modifications in the cortical circuitry have accumulated. The regulated FGF-related genes may together contribute to M1 remodeling through their roles in synaptic growth and maturation.McGovern Institute for Brain Research at MITNational Institutes of Health (U.S.) ((NIH grant 1-RC1-NS068103-01)National Institutes of Health (U.S.) (NIH grant R01-MH084966)Roberto Rocca Education Program (Fellowship)Massachusetts Institute of Technology. Undergraduate Research Opportunities Program (Fellowship)Italy. Ministero dell'istruzione, dell'università e della ricerca (MIUR grant RBIN04H5AS)Italy. Ministero dell'istruzione, dell'università e della ricerca (MIUR grant RBLA03FLJC)Italy. Ministero dell'istruzione, dell'università e della ricerca (FIRB n. RBAP10L8TY

Source analysis of beta-synchronisation and cortico-muscular coherence after movement termination based on high resolution electroencephalography

We hypothesized that post-movement beta synchronization (PMBS) and cortico-muscular coherence (CMC) during movement termination relate to each other and have similar role in sensorimotor integration. We calculated the parameters and estimated the sources of these phenomena.We measured 64-channel EEG simultaneously with surface EMG of the right first dorsal interosseus muscle in 11 healthy volunteers. In Task1, subjects kept a medium-strength contraction continuously; in Task2, superimposed on this movement, they performed repetitive self-paced short contractions. In Task3 short contractions were executed alone. Time-frequency analysis of the EEG and CMC was performed with respect to the offset of brisk movements and averaged in each subject. Sources of PMBS and CMC were also calculated.High beta power in Task1, PMBS in Task2-3, and CMC in Task1-2 could be observed in the same individual frequency bands. While beta synchronization in Task1 and PMBS in Task2-3 appeared bilateral with contralateral predominance, CMC in Task1-2 was strictly a unilateral phenomenon; their main sources did not differ contralateral to the movement in the primary sensorimotor cortex in 7 of 11 subjects in Task1, and in 6 of 9 subjects in Task2. In Task2, CMC and PMBS had the same latency but their amplitudes did not correlate with each other. In Task2, weaker PMBS source was found bilaterally within the secondary sensory cortex, while the second source of CMC was detected in the premotor cortex, contralateral to the movement. In Task3, weaker sources of PMBS could be estimated in bilateral supplementary motor cortex and in the thalamus. PMBS and CMC appear simultaneously at the end of a phasic movement possibly suggesting similar antikinetic effects, but they may be separate processes with different active functions. Whereas PMBS seems to reset the supraspinal sensorimotor network, cortico-muscular coherence may represent the recalibration of cortico-motoneuronal and spinal systems

Direction of Movement Is Encoded in the Human Primary Motor Cortex

The present study investigated how direction of hand movement, which is a well-described parameter in cerebral organization of motor control, is incorporated in the somatotopic representation of the manual effector system in the human primary motor cortex (M1). Using functional magnetic resonance imaging (fMRI) and a manual step-tracking task we found that activation patterns related to movement in different directions were spatially disjoint within the representation area of the hand on M1. Foci of activation related to specific movement directions were segregated within the M1 hand area; activation related to direction 0° (right) was located most laterally/superficially, whereas directions 180° (left) and 270° (down) elicited activation more medially within the hand area. Activation related to direction 90° was located between the other directions. Moreover, by investigating differences between activations related to movement along the horizontal (0°+180°) and vertical (90°+270°) axis, we found that activation related to the horizontal axis was located more anterolaterally/dorsally in M1 than for the vertical axis, supporting that activations related to individual movement directions are direction- and not muscle related. Our results of spatially segregated direction-related activations in M1 are in accordance with findings of recent fMRI studies on neural encoding of direction in human M1. Our results thus provide further evidence for a direct link between direction as an organizational principle in sensorimotor transformation and movement execution coded by effector representations in M1

Optimization of Muscle Activity for Task-Level Goals Predicts Complex Changes in Limb Forces across Biomechanical Contexts

Optimality principles have been proposed as a general framework for understanding motor control in animals and humans largely based on their ability to predict general features movement in idealized motor tasks. However, generalizing these concepts past proof-of-principle to understand the neuromechanical transformation from task-level control to detailed execution-level muscle activity and forces during behaviorally-relevant motor tasks has proved difficult. In an unrestrained balance task in cats, we demonstrate that achieving task-level constraints center of mass forces and moments while minimizing control effort predicts detailed patterns of muscle activity and ground reaction forces in an anatomically-realistic musculoskeletal model. Whereas optimization is typically used to resolve redundancy at a single level of the motor hierarchy, we simultaneously resolved redundancy across both muscles and limbs and directly compared predictions to experimental measures across multiple perturbation directions that elicit different intra- and interlimb coordination patterns. Further, although some candidate task-level variables and cost functions generated indistinguishable predictions in a single biomechanical context, we identified a common optimization framework that could predict up to 48 experimental conditions per animal (n = 3) across both perturbation directions and different biomechanical contexts created by altering animals' postural configuration. Predictions were further improved by imposing experimentally-derived muscle synergy constraints, suggesting additional task variables or costs that may be relevant to the neural control of balance. These results suggested that reduced-dimension neural control mechanisms such as muscle synergies can achieve similar kinetics to the optimal solution, but with increased control effort (≈2×) compared to individual muscle control. Our results are consistent with the idea that hierarchical, task-level neural control mechanisms previously associated with voluntary tasks may also be used in automatic brainstem-mediated pathways for balance