Role of calcitonin gene-related peptide and brain natriuretic peptide to modulate the excitability state of trigeminal neurons : relevance to migraine pathology and treatment

Sandra Vilotti,1 Elsa Fabbretti,2 Andrea Nistri1 1Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy; 2Center for Biomedical Sciences and Engineering, University of Nova Gorica, Nova Gorica, Slovenia Abstract: Hyperactivity of trigeminal sensory neurons is a major process to generate recurrent headache, typical of migraine attacks. How physiological nociception is converted into strong pathological pain remains, however, poorly understood. In recent years, certain neuropeptides and their receptors have been shown to modulate sensory neuron nociception and to contribute to the persistent hyperalgesia due to the sensory stimulus sensitization that defines the clinical experience of chronic pain syndromes, including migraine. Using calcitonin gene-related peptide (CGRP) and brain natriuretic peptide (BNP) as examples, this review addresses the mechanisms through which neuropeptides might modulate nociceptor activity. One attractive notion is that pain signaling by trigeminal sensory neurons is potently regulated by the ambient levels of these peptides: CGRP is thought to facilitate neuronal firing responsible for trigeminal sensitization necessary to trigger headache, whereas BNP is proposed to act as a negative regulator of trigeminal neuron activity. For either peptide, the key target appears to be the ATP-gated P2X3 receptor that, widely expressed by trigeminal sensory neurons, generates fast, large excitation to release glutamate onto second-order brain neurons. The fine balance between the activities of these peptides is suggested to ultimately determine whether nociception is perceived at higher center as a physiological or pathological response. Hence, the clinical goal of CGRP antagonism using either pharmacological receptor blockers or monoclonal antibodies (to sequester this peptide or to directly inhibit its receptor) is currently considered a novel approach for migraine prophylaxis and to treat acute headache attacks. Keywords: trigeminal ganglion, headache, sensory neurons, P2X3, TRPV

Bimodal Action of Protons on ATP Currents of Rat PC12 Cells

The mode of action of extracellular protons on ATP-gated P2X2 receptors remains controversial as either enhancement or depression of ATP-mediated currents has been reported. By investigating, at different pH, the electrophysiological effect of ATP on P2X2 receptors and complementing it with receptor modelling, the present study suggests a unified mechanism for both potentiation and inactivation of ATP receptors by protons. Our experiments on patch-clamped PC12 cells showed that, on the same cell, mild acidification potentiated currents induced by low ATP concentrations (<0.1 mM) and attenuated responses to high ATP concentrations (>1 mM) with emergence of current fading and rebound. To clarify the nature of the ATP/H+ interaction, we used the Ding and Sachs's “loop” receptor model which best describes the behavior of such receptors with two open states linked via one inactivated state. No effects by protons could be ascribed to H+-mediated open channel block. However, by assuming that protons facilitated binding of ATP to resting as well as open receptors, the model could closely replicate H+-induced potentiation of currents evoked by low ATP doses plus fading and rebound induced by high ATP doses. The latter phenomenon was due to receptor transition to the inactive state. The present data suggest that the high concentration of protons released with ATP (and catecholamines) from secretory vesicles may allow a dual action of H+ on P2X2 receptors. This condition might also occur on P2X2 receptors of central neurons exposed to low pH during ischemia

How the discovery of neuronal stem cells have changed neuroscience and perspective for the therapy for central nervous system illnesses

Mostly-incurable central nervous system diseases and disorders, such as neurodegenerative diseases, stroke, brain and spinal cord injuries and psychiatric illnesses, represent one of the most difficult health problems today, in terms of mortality, disability, productivity loss and health-care costs. After disappointing results regarding the translational value of neuroprotective molecules and protocols from preclinical research on animals to clinic, a new hope for the developing effective treatments for brain and spinal cord disorders came with the discovery of neuronal stem and progenitor cells, which have the potential to differentiate into a myriad of different glial and neuronal cell types. The basic biology behind the neuronal stem cells is becoming discovered, paving the way to possibilities for their manipulation and reprograming and for their clinical applications. Some of those protocols and clinical trials are described in this paper, with the emphasis on spinal cord injury treatments

Molecular Mechanisms Underlying Cell Death in Spinal Networks in Relation to Locomotor Activity After Acute Injury in vitro

Understanding the pathophysiological changes triggered by an acute spinal cord injury is a primary goal to prevent and treat chronic disability with a mechanism-based approach. After the primary phase of rapid cell death at the injury site, secondary damage occurs via autodestruction of unscathed tissue through complex cell-death mechanisms that comprise caspase-dependent and caspase-independent pathways. To devise novel neuroprotective strategies to restore locomotion, it is, therefore, necessary to focus on the death mechanisms of neurons and glia within spinal locomotor networks. To this end, the availability of in vitro preparations of the rodent spinal cord capable of expressing locomotor-like oscillatory patterns recorded electrophysiologically from motoneuron pools offers the novel opportunity to correlate locomotor network function with molecular and histological changes long after an acute experimental lesion. Distinct forms of damage to the in vitro spinal cord, namely excitotoxic stimulation or severe metabolic perturbation (with oxidative stress, hypoxia/aglycemia), can be applied with differential outcome in terms of cell types and functional loss. In either case, cell death is a delayed phenomenon developing over several hours. Neurons are more vulnerable to excitotoxicity and more resistant to metabolic perturbation, while the opposite holds true for glia. Neurons mainly die because of hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) with subsequent DNA damage and mitochondrial energy collapse. Conversely, glial cells die predominantly by apoptosis. It is likely that early neuroprotection against acute spinal injury may require tailor-made drugs targeted to specific cell-death processes of certain cell types within the locomotor circuitry. Furthermore, comparison of network size and function before and after graded injury provides an estimate of the minimal network membership to express the locomotor program

Nicotine Neurotoxicity Involves Low Wnt1 Signaling in Spinal Locomotor Networks of the Postnatal Rodent Spinal Cord

The postnatal rodent spinal cord in-vitro is a useful model to investigate early pathophysi-ological changes after injury. While low dose nicotine (1 µM) induces neuroprotection, how higher doses affect spinal networks is unknown. Using spinal preparations of postnatal wild-type Wistar rat and Wnt1Cre2:Rosa26Tom double-transgenic mouse, we studied the effect of nicotine (0.5–10 µM) on locomotor networks in-vitro. Nicotine 10 µM induced motoneuron depolarization, suppressed monosynaptic reflexes, and decreased fictive locomotion in rat spinal cord. Delayed fall in neuronal numbers (including motoneurons) of central and ventral regions emerged without loss of dorsal neurons. Conversely, nicotine (0.5–1 µM) preserved neurons throughout the spinal cord and strongly activated the Wnt1 signaling pathway. High-dose nicotine enhanced expression of S100 and GFAP in astrocytes indicating a stress response. Excitotoxicity induced by kainate was contrasted by nicotine (10 µM) in the dorsal area and persisted in central and ventral regions with no change in basal Wnt signaling. When combining nicotine with kainate, the activation of Wnt1 was reduced compared to kainate/sham. The present results suggest that high dose nicotine was neurotoxic to central and ventral spinal neurons as the neuroprotective role of Wnt signaling became attenuated. This also corroborates the risk of cigarette smoking for the foetus/newborn since tobacco contains nicotine.Fil: Kaur, Jaspreet. Universidad de Copenhagen; DinamarcaFil: Mazzone, Graciela Luján. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Nistri, Andrea. International School For Advanced Studies; Itali

Biomass Carbonization: Process Options and Economics for Small Scale Forestry Farms☆

Abstract Bioenergy represents a unique opportunity for forestry companies to diversify the sources of income and create new stable business opportunities: a large number of initiatives has started in the last decades especially regarding decentralized power generation; nevertheless the conversion of the farmers to energy producers is not a trivial issue. The present work has focused on a possible alternative to biopower generation for forestry farms: the biomass carbonization (i.e. biomass slow pyrolysis). Charcoal making presents good prerequisite conditions for successful biomass based systems in the forestry sector: the system results incentive-independent, the power generation represents the co-product of a different primary production (resulting a real additional income), the plant capital cost is affordable for small scale farmers, operations requires technical skills normally available in the forestry sector and the reliability of the system is proven and credible, reducing the risks contained in business plans based on "number of hours of operation over several years". Moreover charcoal is a well known product, familiar to forestry companies for a very long time, the market is well defined, the technology is known but still offers opportunities for further improvements (in terms of efficiency, costs and environmental impacts), the technology does not present major risk, the investment is well suited to small farmers and the process and technology gives a great opportunity for small scale and local supply chain development. Based on these considerations, the present work investigated the technological opportunities for small scale charcoal making systems. Various process configurations have been examined, focusing on advantages and disadvantages representative of each solution in view of small scale application suitable for the Italian case and a designed pilot plant has been proposed

How the discovery of neuronal stem cells have changed neuroscience and perspective for the therapy for central nervous system illnesses

Mostly-incurable central nervous system diseases and disorders, such as neurodegenerative diseases, stroke, brain and spinal cord injuries and psychiatric illnesses, represent one of the most difficult health problems today, in terms of mortality, disability, productivity loss and health-care costs. After disappointing results regarding the translational value of neuroprotective molecules and protocols from preclinical research on animals to clinic, a new hope for the developing effective treatments for brain and spinal cord disorders came with the discovery of neuronal stem and progenitor cells, which have the potential to differentiate into a myriad of different glial and neuronal cell types. The basic biology behind the neuronal stem cells is becoming discovered, paving the way to possibilities for their manipulation and reprograming and for their clinical applications. Some of those protocols and clinical trials are described in this paper, with the emphasis on spinal cord injury treatments

GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks

Correct operation of neuronal networks depends on the interplay between synaptic excitation and inhibition processes leading to a dynamic state termed balanced network. In the spinal cord, balanced network activity is fundamental for the expression of locomotor patterns necessary for rhythmic activation of limb extensor and flexor muscles. After spinal cord lesion, paralysis ensues often followed by spasticity. These conditions imply that, below the damaged site, the state of balanced networks has been disrupted and that restoration might be attempted by modulating the excitability of sublesional spinal neurons. Because of the widespread expression of inhibitory GABAergic neurons in the spinal cord, their role in the early and late phases of spinal cord injury deserves full attention. Thus, an early surge in extracellular GABA might be involved in the onset of spinal shock while a relative deficit of GABAergic mechanisms may be a contributor to spasticity. We discuss the role of GABA A receptors at synaptic and extrasynaptic level to modulate network excitability and to offer a pharmacological target for symptom control. In particular, it is proposed that activation of GABA A receptors with synthetic GABA agonists may downregulate motoneuron hyperexcitability (due to enhanced persistent ionic currents) and, therefore, diminish spasticity. This approach might constitute a complementary strategy to regulate network excitability after injury so that reconstruction of damaged spinal networks with new materials or cell transplants might proceed more successfully

Autothermal biochar production and characterization at pilot scale

The present work reports on the results from the validation campaign of an autothermal pilot carbonization unit (CarbON) and on the characterization of the produced biochar and pyrolysis vapors. The proposed pilot plant leverages the simplicity and effectiveness of autothermal operations together with open top, downdraft design, to bring to the small scale the performance of larger installations. In autothermal operation, heat for the process is internally provided by combusting part of the feedstock and evolved volatiles inside the reactor, the so called “oxidative pyrolysis”. Please click on the file below for full content of the abstract