The Experts below are selected from a list of 300 Experts worldwide ranked by ideXlab platform
Clifford J Woolf - One of the best experts on this subject based on the ideXlab platform.
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replicate high density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury
BMC Neuroscience, 2002Co-Authors: Michael Costigan, Laurie A Karchewski, Robert S Griffin, Donatella Durso, James W Mannion, Katia Befort, Richard E Pratt, Andrew Allchorne, Joanne Sitarski, Clifford J WoolfAbstract:Background Rat oligonucleotide microarrays were used to detect changes in gene expression in the dorsal root ganglion (DRG) 3 days following sciatic nerve transection (Axotomy). Two comparisons were made using two sets of triplicate microarrays, naive versus naive and naive versus Axotomy.
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a role for hsp27 in sensory neuron survival
The Journal of Neuroscience, 1999Co-Authors: Susan E Lewis, Michael Costigan, Richard J Mannion, Fletcher A White, Richard E Coggeshall, Simon Beggs, Jody L Martin, Wolfgang H Dillmann, Clifford J WoolfAbstract:Peripheral nerve injury in neonatal rats results in the death of the majority of the axotomized sensory neurons by 7 d after injury. In adult animals, however, all sensory neurons survive for at least 4 months after Axotomy. How sensory neurons acquire the capacity to survive axonal injury is not known. Here we describe how the expression of the small heat shock protein 27 (HSP27) is correlated with neuronal survival after Axotomy in vivo and after NGF withdrawal in vitro. The number of HSP27-immunoreactive neurons in the L4 DRG is low at birth and does not change significantly for 21 d after postnatal day 0 (P0) sciatic nerve Axotomy. In contrast, in the adult all axotomized neurons begin to express HSP27. One week after P0 sciatic nerve section the total number of neurons in the L4 DRG is dramatically reduced, but all surviving axotomized neurons, as identified by c-jun immunoreactivity, are immunoreactive for HSP27. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling reveals that very few HSP27-expressing neurons are dying 48 hr after neonatal Axotomy. In vitro , a similar correlation exists between HSP27 expression and survival; in P0 DRG cultures, neurons that express HSP27 preferentially survive NGF withdrawal. Finally, overexpression of human HSP27 in neonatal rat sensory and sympathetic neurons significantly increases survival after NGF withdrawal, with nearly twice as many neurons surviving at 48 hr. Together these results suggest that HSP27 in sensory neurons plays a role in promoting survival after Axotomy or neurotrophin withdrawal.
Stuart A Lipton - One of the best experts on this subject based on the ideXlab platform.
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role of p38 mitogen activated protein kinase in Axotomy induced apoptosis of rat retinal ganglion cells
The Journal of Neuroscience, 2000Co-Authors: Masashi Kikuchi, Lalitha Tenneti, Stuart A LiptonAbstract:p38 is a member of the mitogen-activated protein (MAP) kinase superfamily and mediates intracellular signal transduction. Recent studies suggest that p38 is involved in apoptotic signaling in several cell types, including neurons. In the mammalian retina, ∼50% of the retinal ganglion cells (RGCs) die by apoptosis during development. Additionally, transection of the optic nerve close to the eye bulb causes apoptotic cell death of RGCs in adulthood. We investigated the role of p38 in Axotomy-induced apoptosis of RGCs. One day after Axotomy, activated (phosphorylated) p38 was visualized by immunocytochemistry in the nuclei of RGCs, but not in control retinas. Phosphorylated p38 was first detected on immunoblots 12 hr after Axotomy, reached a maximum at 1 d, and then decreased. To investigate possible roles of p38 in RGC death, a p38 MAP kinase inhibitor, SB203580, was administered intravitreally at the time of Axotomy and repeated at 5 and 10 d. Assayed 14 d after Axotomy, SB203580 increased the number of surviving RGCs in a dose-dependent manner (the minimum effective concentration was 1.6 μm). Furthermore, MK801, a selective inhibitor of NMDA receptors, not only showed protective effects against RGC apoptosis but also attenuated p38 MAP kinase activation in a dose-dependent manner. Our findings imply that p38 is in the signaling pathway to RGC apoptosis mediated by glutamate neurotoxicity through NMDA receptors after damage to the optic nerve. p38 inhibitors could be potentially useful for the treatment of optic nerve trauma and neurodegenerative diseases that affect RGCs, such as glaucoma.
Kathryn J Jones - One of the best experts on this subject based on the ideXlab platform.
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Axotomy induced target disconnection promotes an additional death mechanism involved in motoneuron degeneration in amyotrophic lateral sclerosis transgenic mice
The Journal of Comparative Neurology, 2014Co-Authors: Kathryn J Jones, Melissa M Haulcomb, Nichole A Mesnard, Richard J Batka, Thomas D Alexander, Virginia M SandersAbstract:The target disconnection theory of amyotrophic lateral sclerosis (ALS) pathogenesis suggests that disease onset is initiated by a peripheral pathological event resulting in neuromuscular junction loss and motoneuron (MN) degeneration. Presymptomatic mSOD1G93A mouse facial MN (FMN) are more susceptible to Axotomy-induced cell death than wild-type (WT) FMN, which suggests additional CNS pathology. We have previously determined that the mSOD1 molecular response to facial nerve Axotomy is phenotypically regenerative and indistinguishable from WT, whereas the surrounding microenvironment shows significant dysregulation in the mSOD1 facial nucleus. To elucidate the mechanisms underlying the enhanced mSOD1 FMN loss after Axotomy, we superimposed the facial nerve Axotomy model on presymptomatic mSOD1 mice and investigated gene expression for death receptor pathways after target disconnection by Axotomy vs. disease progression. We determined that the TNFR1 death receptor pathway is involved in Axotomy-induced FMN death in WT and is partially responsible for the mSOD1 FMN death. In contrast, an inherent mSOD1 CNS pathology resulted in a suppressed glial reaction and an upregulation in the Fas death pathway after target disconnection. We propose that the dysregulated mSOD1 glia fail to provide support the injured MN, leading to Fas-induced FMN death. Finally, we demonstrate that, during disease progression, the mSOD1 facial nucleus displays target disconnection-induced gene expression changes that mirror those induced by Axotomy. This validates the use of Axotomy as an investigative tool in understanding the role of peripheral target disconnection in the pathogenesis of ALS. J. Comp. Neurol. 522:2349–2376, 2014. © 2014 Wiley Periodicals, Inc.
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Toll-like receptor 2 and facial motoneuron survival after facial nerve Axotomy.
Neuroscience Letters, 2010Co-Authors: Derek A. Wainwright, Virginia M Sanders, Nichole A Mesnard, Kathryn J JonesAbstract:Abstract We have previously demonstrated that CD4 + Th2 lymphocytes are required to rescue facial motoneuron (FMN) survival after facial nerve Axotomy through interaction with peripheral antigen presenting cells, as well as CNS resident microglia. Furthermore, the innate immune molecule, toll-like receptor 2 (TLR2), has been implicated in the development of Th2-type immune responses and can be activated by intracellular components released by dead or dying cells. The role of TLR2 in the FMN response to Axotomy was explored in this study, using a model of facial nerve Axotomy at the stylomastoid foramen in the mouse, in which blood–brain-barrier (BBB) permeability does not occur. After facial nerve Axotomy, TLR2 mRNA was significantly upregulated in the facial motor nucleus and co-immunofluorescence localized TLR2 to CD68 + microglia, but not GFAP + astrocytes. Using TLR2-deficient (TLR2 −/− ) mice, it was determined that TLR2 does not affect FMN survival levels after Axotomy. These data contribute to understanding the role of innate immunity after FMN death and may be relevant to motoneuron diseases, such as amyotrophic lateral sclerosis (ALS).
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gonadal steroid attenuation of developing hamster facial motoneuron loss by Axotomy equal efficacy of testosterone dihydrotestosterone and 17 β estradiol
The Journal of Neuroscience, 2005Co-Authors: Christopher B Huppenbauer, Lisa Tanzer, Lydia L Doncarlos, Kathryn J JonesAbstract:In the hamster facial nerve injury paradigm, we have established that androgens enhance both functional recovery from facial nerve paralysis and the rate of regeneration in the adult, through intrinsic effects on the nerve cell body response to injury and via an androgen receptor (AR)-mediated mechanism. Whether these therapeutic effects of gonadal steroids encompass neuroprotection from Axotomy-induced cell death is the focus of the present study. Virtually 100% of adult hamster facial motoneurons (FMNs) survive Axotomy at the stylomastoid foramen (SMF), whereas, before postnatal day 15 (P15), developing FMNs undergo substantial Axotomy-induced cell death. The first part of the present study focuses on determining when ARs are first expressed in developing hamster FMNs. Using AR immunocytochemistry, it was found that males express ARs by P2 and females by P4, which is the earliest demonstration of AR expression in mammalian motoneurons reported thus far in the literature. The second half examines the neuroprotective effects of testosterone propionate, 17-β estradiol, and dihydrotestosterone on FMNs of P7 hamsters after facial nerve transection at the SMF. The results demonstrate that androgens and estrogens are equally able to rescue ∼20% of FMNs from Axotomy-induced cell death, with the effects permanent. This study is the first to investigate the effects of both androgens and estrogens on Axotomy-induced cell death in one system and, with our previously published work, to validate the hamster FMN injury paradigm as a model of choice in the investigation of both neurotherapeutic and neuroprotective actions of gonadal steroids.
Giorgio Terenghi - One of the best experts on this subject based on the ideXlab platform.
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Quantification of N‐CAM and N‐cadherin expression in axotomized and crushed rat sciatic nerve
Journal of Anatomy, 2020Co-Authors: M. R. Thornton, Cristina Mantovani, Martin A Birchall, Giorgio TerenghiAbstract:Adhesion molecules are important in supporting axonal regeneration. Qualitative studies have described increased expression of neural cell adhesion molecule (NCAM) and N-cadherin in models of nerve injury allowing active regeneration. In this study we have used quantitative immunohistochemistry to compare expression of NCAM and N-cadherin after nerve injury either with active regeneration (crush) into the distal stump or without (Axotomy and capping). Quantification was performed 15 days after Axotomy in proximal and distal stumps. Quantification after crush either proximal, distal or within the crushed area was performed at 2, 7, 15 and 30 days after injury. Axotomy induced increases in expression in proximal stumps between two and three times those in uninjured nerves for both molecules. In distal stumps, N-cadherin levels increased seven-fold, yet NCAM levels did not exceed control values. After crush, NCAM immunoreactivity increased in the crushed area and distal stump in contrast to Axotomy and NCAM-positive axons co-localized with PGP9.5. N-cadherin levels in the distal stump increased above control levels, but the magnitude of the increase seen after crush was different to those seen after Axotomy. In conclusion, increased expression of adhesion molecules, particularly NCAM, in the distal stump of injured nerves is dependent upon the presence of regenerating axons.
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Quantification of N-CAM and N-cadherin expression in axotomized and crushed rat sciatic nerve
J ANAT, 2005Co-Authors: Giorgio TerenghiAbstract:Adhesion molecules are important in supporting axonal regeneration. Qualitative studies have described increased expression of neural cell adhesion molecule (NCAM) and N-cadherin in models of nerve injury allowing active regeneration. In this study we have used quantitative immunohistochemistry to compare expression of NCAM and N-cadherin after nerve injury either with active regeneration (crush) into the distal stump or without (Axotomy and capping). Quantification was performed 15 days after Axotomy in proximal and distal stumps. Quantification after crush either proximal, distal or within the crushed area was performed at 2, 7, 15 and 30 days after injury. Axotomy induced increases in expression in proximal stumps between two and three times those in uninjured nerves for both molecules. In distal stumps, N-cadherin levels increased seven-fold, yet NCAM levels did not exceed control values. After crush, NCAM immunoreactivity increased in the crushed area and distal stump in contrast to Axotomy and NCAM-positive axons co-localized with PGP9.5. N-cadherin levels in the distal stump increased above control levels, but the magnitude of the increase seen after crush was different to those seen after Axotomy. In conclusion, increased expression of adhesion molecules, particularly NCAM, in the distal stump of injured nerves is dependent upon the presence of regenerating axons.
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primary sensory neurons and satellite cells after peripheral Axotomy in the adult rat timecourse of cell death and elimination
Experimental Brain Research, 2002Co-Authors: Andrew Hart, Thomas Brannstrom, Mikael Wiberg, Giorgio TerenghiAbstract:The timecourse of cell death in adult dorsal root ganglia after peripheral Axotomy has not been fully characterised. It is not clear whether neuronal death begins within 1 week of Axotomy or continues beyond 2 months after Axotomy. Similarly, neither the timecourse of satellite cell death in the adult, nor the effect of nerve repair has been described. L4 and L5 dorsal root ganglia were harvested at 1–14 days, 1–6 months after sciatic nerve division in the adult rat, in accordance with the Animals (Scientific Procedures) Act 1986. In separate groups the nerve was repaired either immediately or following a 1-week delay, and the ganglia were harvested 2 weeks after the initial transection. Microwave permeabilisation and triple staining enabled combined TUNEL staining, morphological examination and neuron counting by the stereological optical dissector technique. TUNEL-positive neurons, exhibiting a range of morphologies, were seen at all timepoints (peak 25 cells/group 2 weeks after Axotomy) in axotomised ganglia only. TUNEL-positive satellite cell numbers peaked 2 months after Axotomy and were more numerous in axotomised than control ganglia. L4 control ganglia contained 13,983 (SD 568) neurons and L5, 16,285 (SD 1,313). Neuron loss was greater in L5 than L4 axotomised ganglia, began at 1 week (15%, P=0.045) post-Axotomy, reached 35% at 2 months (P<0.001) and was not significantly greater at 4 months or 6 months. Volume of axotomised ganglia fell to 19% of control by 6 months (P<0.001). In animals that underwent nerve repair, both the number of TUNEL-positive neurons and neuron loss were reduced. Immediate repair was more protective than repair after a 1-week delay. Thus TUNEL positivity precedes actual neuron loss, reflecting the time taken to complete cell death and elimination. Neuronal death begins within 1 day of peripheral Axotomy, the majority occurs within the first 2 months, and limited death is still occurring at 6 months. Neuronal death is modulated by peripheral nerve repair and by its timing after Axotomy. Secondary satellite cell death also occurs, peaking 2 months after Axotomy. These results provide a logical framework for future research into neuronal and satellite cell death within the dorsal root ganglia and provide further insight into the process of Axotomy induced neuronal death.
Anatoly B. Uzdensky - One of the best experts on this subject based on the ideXlab platform.
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HDAC1 Expression, Histone Deacetylation, and Protective Role of Sodium Valproate in the Rat Dorsal Root Ganglia After Sciatic Nerve Transection
Molecular Neurobiology, 2020Co-Authors: V. A. Dzreyan, S. V. Rodkin, M. A. Pitinova, Anatoly B. UzdenskyAbstract:Nerve injury is an important reason of human disability and death. We studied the role of histone deacetylation in the response of the dorsal root ganglion (DRG) cells to sciatic nerve transection. Sciatic nerve transection in the rat thigh induced overexpression of histone deacetylase 1 (HDAC1) in the ipsilateral DRG at 1–4 h after Axotomy. In the DRG neurons, HDAC1 initially upregulated at 1 h but then redistributed from the nuclei to the cytoplasm at 4 h after Axotomy. Histone H3 was deacetylated at 24 h after Axotomy. Deacetylation of histone H4, accumulation of amyloid precursor protein, a nerve injury marker, and GAP-43, an axon regeneration marker, were observed in the axotomized DRG on day 7. Neuronal injury occurred on day 7 after Axotomy along with apoptosis of DRG cells, which were mostly the satellite glial cells remote from the site of sciatic nerve transection. Administration of sodium valproate significantly reduced apoptosis not only in the injured ipsilateral DRG but also in the contralateral ganglion. It also reduced the deacetylation of histones H3 and H4, prevented Axotomy-induced accumulation of amyloid precursor protein, which indicated nerve injury, and overexpressed GAP-43, a nerve regeneration marker, in the axotomized DRG. Therefore, HDAC1 was involved in the Axotomy-induced injury of DRG neurons and glial cells. HDAC inhibitor sodium valproate demonstrated the neuroprotective activity in the axotomized DRG.
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The effect of Axotomy on firing and ultrastructure of the crayfish mechanoreceptor neurons and satellite glial cells.
Molecular and Cellular Neuroscience, 2020Co-Authors: M. V. Rudkovskii, A.g. Fedorenko, Andrey Khaitin, Maria Pitinova, Anatoly B. UzdenskyAbstract:Abstract Neurotrauma is among main causes of human disability and death. We studied effects of Axotomy on ultrastructure and neuronal activity of a simple model object – an isolated crayfish stretch receptor that consists of single mechanoreceptor neurons (MRN) enwrapped by multilayer glial envelope. After isolation, MRN regularly fired until spontaneous activity cessation. Axotomy did not change significantly MRN spike amplitude and firing rate. However, the duration of neuron activity from MRN isolation to its spontaneous cessation decreased in axotomized MRN relative to intact neuron. [Ca2+] in MRN axon and soma increased 3–10 min after Axotomy. Ca2+ entry through ion channels in the axolemma accelerated Axotomy-stimulated firing cessation. MRN incubation with Ca2+ionophore ionomycin accelerated MRN inactivation, whereas Ca2+-channel blocker Cd2+ prolonged firing. Activity duration of either intact, or axotomized MRN did not change in the presence of ryanodine or dantrolene, inhibitors of ryanodin-sensitive Ca2+ channels in endoplasmic reticulum. Thapsigargin, inhibitor of endoplasmic reticulum Ca2+-ATPase, or its activator ochratoxin were ineffective. Ultrastructural study showed that the defect in the axon transected by thin scissors is sealed by fused axolemma, glial and collagen layers. Only the 30–50 μm long segment completely lost microtubules and contained swelled mitochondria. The microtubular bundle remained undamaged at 300 μm away from the Axotomy site. However, mitochondria within the 200–300 μm segment were strongly condensed and lost matrix and cristae. Glial and collagen layers exhibited greater damage. Swelling and edema of glial layers, collagen disorganization and rupture occurred within this segment. Thus, Axotomy stronger damages glia/collagen envelope, axonal microtubules and mitochondria.
