28 research outputs found
Neurotrophins and sensory neuron development and plasticity
No full textSIGLEAvailable from British Library Document Supply Centre-DSC:DXN024134 / BLDSC - British Library Document Supply CentreGBUnited Kingdo
Neuregulin/ErbB signaling in developmental myelin formation and nerve repair
No full textMyelin is essential for rapid and accurate conduction of electrical impulses by axons in the central and peripheral nervous system (PNS). Myelin is formed in the early postnatal period, and developmental myelination in the PNS depends on axonal signals provided by Nrg1/ErbB receptors. In addition, Nrg1 is required for effective nerve repair and remyelination in adulthood. We discuss here similarities and differences in Nrg1/ErbB functions in developmental myelination and remyelination after nerve injury
Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation
No full textThe goal of the current work was to profile positive (mTORC1 activation, autocrine/paracrine growth factors) and negative [AMPK, unfolded protein response (UPR)] pathways that might regulate overload-induced mTORC1 activation with the hypothesis that a number of negative regulators of mTORC1 will be engaged during a supra-physiological model of hypertrophy. To achieve this, mTORC1-IRS1/2 signaling, BiP/CHOP/IRE1a, and AMPK activation were determined in rat plantaris muscle following synergist ablation (SA). SA resulted in significant increases in muscle mass of ~4% per day throughout the 21 days of the experiment. The expression of the insulin-like growth factors were high throughout the 21d of overload. However, IGF signaling was limited since IRS1 and 2 were undetectable in the overloaded muscle from day 3 to day 9. The decreases in IRS1/2 protein were paralleled by increases in GRB10(Ser501/503) and S6K1(Thr389) phosphorylation, two mTORC1 targets that can destabilize IRS proteins. PKB(Ser473) phosphorylation was higher from 3-6 days and this was associated with increased TSC2(Thr939) phosphorylation. The phosphorylation of TSC2(Thr1345) (an AMPK site) was also elevated whereas phosphorylation at the other PKB site, Thr(1462), was unchanged at 6d. In agreement with the phosphorylation of Thr(1345), synergist ablation led to activation of a1-AMPK during the initial growth phase, lasting the first 9 days before returning to baseline by day 12. The UPR markers CHOP and BiP were elevated over the first 12 days following ablation, whereas IRE1a levels decreased. These data suggest that during supra-physiological muscle loading, at least three potential molecular brakes engage to down-regulate mTORC1
TRP-channels as key integrators of lipid pathways in nociceptive neurons
No full textS.93-107TRP-channels are the most prominent family of ligand-gated ion channels for pain perception. In sensory neurons, TRPV1-V4, TRPA1 and TRPM8 are expressed and are responsible for the conversion of external stimuli to painful sensations. Under pathophysiological conditions, excessive activity of TRP-channels leads to mechanical allodynia and thermal hyperalgesia. Among the endogenous TRP-channel sensitizers, activators and inhibitors, more than 50 arachidonic acid- and linoleic acid-metabolites from the COX-, LOX- and CYP-pathways, as well as lysophospholipids and isoprenoids can be found. As a consequence, these lipids represent the vast majority of endogenous TRP-channel modulators in sensory neurons. Although the precise mechanisms of TRP-channel modulation by most lipids are still unknown, it became clear that lipids can either bind directly to the target TRP-channel or modulate TRP-channels indirectly by activating G-protein coupled receptors. Thus, TRP-channels seem to be key sensors for lipids, integrating and interpreting incoming signals from the different metabolic lipid pathways. Here, we discuss the specific properties of the currently known endogenous lipid-derived TRP-channel modulators concerning their ability to activate or inhibit TRP-channels, the molecular mechanisms of lipid/TRP-channel interactions and specific TRP-regulatory characteristics of the individual lipid families.5
Development of MRC Centre MRI calf muscle fat fraction protocol as a sensitive outcome measure in Hereditary Sensory Neuropathy Type 1
No full textObjectives: Hereditary sensory neuropathy type 1 (HSN1) is a rare, slowly progressive neuropathy causing profound sensory deficits and often severe motor loss. L-serine supplementation is a possible candidate therapy but the lack of responsive outcome measures is a barrier for undertaking clinical trials in HSN1. We performed a 12-month natural history study to characterise the phenotype of HSN1 and to identify responsive outcome measures. Methods: Assessments included Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), CMTNSv2-Rasch modified, nerve conduction studies, quantitative sensory testing, intraepidermal nerve fibre density (thigh), computerised myometry (lower limbs), plasma 1-deoxysphingolipid levels, calf-level intramuscular fat accumulation by MRI and patient-based questionnaires (Neuropathic Pain Symptom Inventory and 36-Short Form Health Survey version 2 [SF-36v2]). Results: 35 patients with HSN1 were recruited. There was marked heterogeneity in the phenotype mainly due to differences between the sexes: males generally more severely affected. The outcome measures that significantly changed over 1 year and correlated with CMTNSv2, SF-36v2-physical component and disease duration were MRI determined calf intramuscular fat accumulation (mean change in overall calf fat fraction 2.36%, 95% CI 1.16 to 3.55, p=0.0004), pressure pain threshold on the hand (mean change 40 kPa, 95% CI 0.7 to 80, p=0.046) and myometric measurements of ankle plantar flexion (median change '0.5 Nm, IQR '9.5 to 0, p=0.0007), ankle inversion (mean change '0.89 Nm, 95% CI '1.66 to '0.12, p=0.03) and eversion (mean change '1.61 Nm, 95% CI '2.72 to '0.51, p=0.006). Intramuscular calf fat fraction was the most responsive outcome measure. Conclusion: MRI determined calf muscle fat fraction shows validity and high responsiveness over 12 months and will be useful in HSN1 clinical trials
THE SPINAL NERVE TRANSECTION MODEL OF NEUROPATHIC PAIN IS ASSOCIATED WITH ALTERATIONS OF THE MOLECULAR ORGANISATION OF THE NODAL REGIONS OF MYELINATED SENSORY AXONS WITHIN THE DORSAL ROOT
No full textSaltatory conduction in myelinated fibres depends on a specific molecular organization of axonal domains: the nodal, paranodal and juxtaparanodal regions. During development, shaker-type Kvchannels (STKC: Kv1.1 and Kv 1.2) at nodal and paranodal regions are essential to prevent hyperexcitation. At later stages, they cluster at juxtaparanodal regions and become ‘‘silent’’. Neuropathic pain (NP) develops following peripheral nerve injury and a critical event is the development of hyperexcitability in damaged myelinated sensory fibres. It
is known that at the site of injury glial and axonal architecture are disrupted. In this study, we aimed to investigate sensory fibres’ nodal architecture at a site remote from the nerve injury: the dorsal root (DR). L5 spinal nerve transection (SNT) was performed in rats and the L5 DR harvested at day 7 or 21 post injury. We used a pan-Nav channel antibody to label the node, Caspr and Neurofascin antibodies to label the paranode and a Kv1.2 antibody to label the juxtaparanode. Acutely after SNT the structure of the nodal region was preserved, but at a later time point we noted movement of Kv1.2 channels into the paranodal region such as there was co-labelling of Caspr and Kv1.2. There was a significant reduction in the longitudinal distance between the node and Kv1.2 immunostaining (p=0.04). There was no apparent change in nodal or paranodal architecture. Ongoing studies with electron microscopy will provide information about ultrastructural changes that may be associated to redistribution of Kv1.2. Quantification of juxtaparanodal protein expression after SNT will be done using Western blots. Redistribution of Kv1.2 after SNT might be a protective mechanism to counteract the nerve hyperexcitability that follows nerve injury. To test this hypothesis we are currently investigating the electrophysiological properties of the injured nerve fibres using an ex vivo DRG intracellular recording technique and probing the function of STKC by using the specific blocker α-dendrotoxin. Preliminary data shows that α-dendrotoxin significantly prolonged the action potential half width as well as refractory period in the injured but not in uninjured A-fibre neurons. Thismight suggest upon injury, STKC become actively involved in action potentials from a ‘‘hibernating’’ state in uninjured neurons
Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity
No full textThe study of rare families with inherited pain insensitivity can identify new human-validated analgesic drug targets. Here, a 66-yr-old female presented with nil requirement for postoperative analgesia after a normally painful orthopaedic hand surgery (trapeziectomy). Further investigations revealed a lifelong history of painless injuries, such as frequent cuts and burns, which were observed to heal quickly. We report the causative mutations for this new pain insensitivity disorder: the co-inheritance of (i) a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, which we cloned from the fatty-acid amide hydrolase (FAAH) chromosomal region; and (ii) a common functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity. Circulating concentrations of anandamide and related fatty-acid amides (palmitoylethanolamide and oleoylethanolamine) that are all normally degraded by FAAH were significantly elevated in peripheral blood compared with normal control carriers of the hypomorphic single-nucleotide polymorphism. The genetic findings and elevated circulating fatty-acid amides are consistent with a phenotype resulting from enhanced endocannabinoid signalling and a loss of function of FAAH. Our results highlight previously unknown complexity at the FAAH genomic locus involving the expression of FAAH-OUT, a novel pseudogene and long non-coding RNA. These data suggest new routes to develop FAAH-based analgesia by targeting of FAAH-OUT, which could significantly improve the treatment of postoperative pain and potentially chronic pain and anxiety disorders. - 2019 The Author(s)Medical Research Council (Career Development Award G1100340 to JJC); Wellcome Trust ( 200183/Z/15/Z to JJC, 095698Z/11/Z and 202747/Z/16/Z to DLHB); Alzheimer's Society (research fellowship to JTB), University of Cambridge Academic Foundation Programme (to MCL); Molecular Nociception Group (to MCL); National Institutes of Health (Bethesda, MD, USA) Ruth L. Kirschstein Institutional National Research Service Award (to MCL); Wellcome Trust funded London Pain Consortium (to JDR); Colciencias through a Francisco Jose de Caldas Scholarship (LASPAU, Harvard University) (to JDR); Canadian Institutes of Health Research (CIHR; to MNH); CIHR (postdoctoral funding to MM).Scopu
O07 Neuregulin-1 is required for axoglial signalling following peripheral nerve injury to ensure normal re-myelination and functional recovery
No full textNucleophilic substitution and cyclisation reactions of some polyfluoro-heteroaromatic and polyfluoroaromatic compounds
No full textThis thesis describes the reactions of some highly fluorinated aromatic and heteroaromatic compounds, in particular derivatives of naphthalene, quinoline and isoquinoline. Chapter 1 provides a general introduction to the preparation, reactions and applications of fluorine containing organic materials. Chapter 2 describes the reactions of some quinoline- and isoquinoline- thiolates with dimethyl acetylenedicarboxylate in an attempt to form six membered heterocycles. Chapter 3 describes nucleophilic substitution reactions of heptafluoro- quinoline and -isoquinoline with sulphur and oxygen nucleophiles. The sulphur nucleophiles are found to attack the 6- site in the isoquinoline and the 4- site in the quinoline. The oxygen nucleophiles attack the 1- site in the isoquinoline and 2- and 4- sites in the quinoline. Chapter 4 describes competition experiments of heptafluoro-quinoline and -isoquinoline with nucleophiles. Relative rates of attack at the 1- position and 6- position in the isoquinoline are determined for a variety of nucleophiles. The relative rates of two nucleophiles are determined for 4- attack in the quinoline. The relative reactivities of the two heterocycles are determined for two different nucleophiles. Chapter 5 describes the pyrolysis of heptafluoro-2-naphtiiyl propynoate which yield two difluoro-butenone derivatives. These decarbonylate under further pyrolysis to yield a 1,1-difluorocyclopropene. All the products were identified by X-ray crystallography. Chapter 6 gives experimental details for Chapter 2 to Chapter 5
