220 research outputs found
Genes and miRNAs as Hurdles and Promoters of Corticospinal Tract Regeneration in Spinal Cord Injury
Spinal cord injury (SCI) is a devastating lesion to the spinal cord, which determines the interruption of ascending/descending axonal tracts, the loss of supraspinal control of sensory-motor functions below the injured site, and severe autonomic dysfunctions, dramatically impacting the quality of life of the patients. After the acute inflammatory phase, the progressive formation of the astrocytic glial scar characterizes the acute-chronic phase: such scar represents one of the main obstacles to the axonal regeneration that, as known, is very limited in the central nervous system (CNS). Unfortunately, a cure for SCI is still lacking: the current clinical approaches are mainly based on early vertebral column stabilization, anti-inflammatory drug administration, and rehabilitation programs. However, new experimental therapeutic strategies are under investigation, one of which is to stimulate axonal regrowth and bypass the glial scar. One major issue in axonal regrowth consists of the different genetic programs, which characterize axonal development and maturation. Here, we will review the main hurdles that in adulthood limit axonal regeneration after SCI, describing the key genes, transcription factors, and miRNAs involved in these processes (seen their reciprocal influencing action), with particular attention to corticospinal motor neurons located in the sensory-motor cortex and subjected to axotomy in case of SCI. We will highlight the functional complexity of the neural regeneration programs. We will also discuss if specific axon growth programs, that undergo a physiological downregulation during CNS development, could be reactivated after a spinal cord trauma to sustain regrowth, representing a new potential therapeutic approach
Functional integration of complex miRNA networks in central and peripheral lesion and axonal regeneration
The Dual Nature of Onuf’s Nucleus: Neuroanatomical Features and Peculiarities, in Health and Disease
Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy
Spinal cord injury (SCI) constitutes an inestimable public health issue. The most crucial phase in the pathophysiological process of SCI concerns the well-known secondary injury, which is the uncontrolled and destructive cascade occurring later with aberrant molecular signaling, inflammation, vascular changes, and secondary cellular dysfunctions. The use of mesenchymal stem cells (MSCs) represents one of the most important and promising tested strategies. Their appeal, among the other sources and types of stem cells, increased because of their ease of isolation/preservation and their properties. Nevertheless, encouraging promise from preclinical studies was followed by weak and conflicting results in clinical trials. In this review, the therapeutic role of MSCs is discussed, together with their properties, application, limitations, and future perspectives
Pharmacological c-Jun NH2-Terminal Kinase (JNK) Pathway Inhibition Reduces Severity of Spinal Muscular Atrophy Disease in Mice
Spinal muscular atrophy (SMA) is a severe neurodegenerative disorder that occurs in early childhood. The disease is caused by the deletion/mutation of the survival motor neuron 1 (SMN1) gene resulting in progressive skeletal muscle atrophy and paralysis, due to the degeneration of spinal motor neurons (MNs). Currently, the cellular and molecular mechanisms underlying MN death are only partly known, although recently it has been shown that the c-Jun NH2-terminal kinase (JNK)-signaling pathway might be involved in the SMA pathogenesis. After confirming the activation of JNK in our SMA mouse model (SMN2+/+; SMN\u3947+/+; Smn-/-), we tested a specific JNK-inhibitor peptide (D-JNKI1) on these mice, by chronic administration from postnatal day 1 to 10, and histologically analyzed the spinal cord and quadriceps muscle at age P12. We observed that D-JNKI1 administration delayed MN death and decreased inflammation in spinal cord. Moreover, the inhibition of JNK pathway improved the trophism of SMA muscular fibers and the size of the neuromuscular junctions (NMJs), leading to an ameliorated innervation of the muscles that resulted in improved motor performances and hind-limb muscular tone. Finally, D-JNKI1 treatment slightly, but significantly increased lifespan in SMA mice. Thus, our results identify JNK as a promising target to reduce MN cell death and progressive skeletal muscle atrophy, providing insight into the role of JNK-pathway for developing alternative pharmacological strategies for the treatment of SMA
Increasing agrin function antagonizes muscle atrophy and motor impairment in spinal muscular atrophy
Spinal muscular atrophy (SMA) is a pediatric genetic disease, characterized by motor neuron (MN) death, leading to progressive muscle weakness, respiratory failure, and, in the most severe cases, to death. Abnormalities at the neuromuscular junction (NMJ) have been reported in SMA, including neurofilament (NF) accumulation at presynaptic terminals, immature and smaller than normal endplates, reduced transmitter release, and, finally, muscle denervation. Here we have studied the role of agrin in SMAΔ7 mice, the experimental model of SMAII. We observed a 50% reduction in agrin expression levels in quadriceps of P10 SMA mice compared to age-matched WT controls. To counteract such condition, we treated SMA mice from birth onwards with therapeutic agrin biological NT-1654, an active splice variant of agrin retaining synaptogenic properties, which is also resistant to proteolytic cleavage by neurotrypsin. Mice were analyzed for behavior, muscle and NMJ histology, and survival. Motor behavior was significantly improved and survival was extended by treatment of SMA mice with NT-1654. At P10, H/E-stained sections of the quadriceps, a proximal muscle early involved in SMA, showed that NT-1654 treatment strongly prevented the size decrease of muscle fibers. Studies of NMJ morphology on whole-mount diaphragm preparations revealed that NT-1654-treated SMA mice had more mature NMJs and reduced NF accumulation, compared to vehicle-treated SMA mice. We conclude that increasing agrin function in SMA has beneficial outcomes on muscle fibers and NMJs as the agrin biological NT-1654 restores the crosstalk between muscle and MNs, delaying muscular atrophy, improving motor performance and extending survival
Molecular diversity within clones of cv. Tannat (Vitis vinifera)
DNAs from 9 clones of cv. Tannat (Vitis vinifera) were analyzed at 89 microsatellite loci. Only one, VMCNg 1d12, showed a differential pattern that separated the clones in two groups. The statistical analysis of concentrations for aroma compounds from microvinifications also resulted in the same two groupings of clones. Many analyzed microsatellite loci amplified only one allele, implying that Tannat is a highly homozygous variety. For a given set of 15 microsatellites the level of homozygosity was 53 % for Tannat, in contrast to 6 % for Pinot, 20 % for both Cabernet Franc and Chardonnay and 33 % for Cabernet Sauvignon. We provide molecular data for Tannat, originating from southwestern France and nowadays becoming the emblematic cultivar of Uruguayan fine red wines. We also report a correlation between aroma-related compounds and molecular markers within clones of a cultivar.
Updating Prospective Self-Efficacy Beliefs About Cardiac Interoception in Anorexia Nervosa: An Experimental and Computational Study.
Patients with anorexia nervosa (AN) typically hold altered beliefs about their body that they struggle to update, including global, prospective beliefs about their ability to know and regulate their body and particularly their interoceptive states. While clinical questionnaire studies have provided ample evidence on the role of such beliefs in the onset, maintenance, and treatment of AN, psychophysical studies have typically focused on perceptual and 'local' beliefs. Across two experiments, we examined how women at the acute AN (N = 86) and post-acute AN state (N = 87), compared to matched healthy controls (N = 180) formed and updated their self-efficacy beliefs retrospectively (Experiment 1) and prospectively (Experiment 2) about their heartbeat counting abilities in an adapted heartbeat counting task. As preregistered, while AN patients did not differ from controls in interoceptive accuracy per se, they hold and maintain 'pessimistic' interoceptive, metacognitive self-efficacy beliefs after performance. Modelling using a simplified computational Bayesian learning framework showed that neither local evidence from performance, nor retrospective beliefs following that performance (that themselves were suboptimally updated) seem to be sufficient to counter and update pessimistic, self-efficacy beliefs in AN. AN patients showed lower learning rates than controls, revealing a tendency to base their posterior beliefs more on prior beliefs rather than prediction errors in both retrospective and prospective belief updating. Further explorations showed that while these differences in both explicit beliefs, and the latent mechanisms of belief updating, were not explained by general cognitive flexibility differences, they were explained by negative mood comorbidity, even after the acute stage of illness
Synthesis and CNS activities of pyridopyrazinone and pyridodiazepinone derivatives
New tricyclic derivatives with cyclocondensed pyrido-pyrazine 7,10 and pyrido-diazepine 20a,20b skeletons were synthetized and biologically investigated. The compounds, preliminarily tested on explorative, muscle relaxing, antinociceptive, spontaneous motor activities and influence on the narcotic effect of Evipan, revealed interesting CNS depressant and analgesic activities. The pyrido[2,3-e]pyrrolo[1,2-a]pyrazine structure of 7 appeared the most promising for analgesic and neuroleptic activities. The above compounds were assayed also for their capacity to inhibit DNA synthesis in Ehrlich ascites tumor cells; 20a appeared to be able of inducing a significant inhibition
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