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Clifford J Woolf – One of the best experts on this subject based on the ideXlab platform.
replicate high density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injuryBMC Neuroscience, 2002Co-Authors: Michael Costigan, Katia Befort, Laurie A Karchewski, Robert S Griffin, Donatella Durso, Andrew Allchorne, Joanne Sitarski, James W Mannion, Richard E Pratt, Clifford J WoolfAbstract:
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.
a role for hsp27 in sensory neuron survivalThe 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.
role of p38 mitogen activated protein kinase in Axotomy induced apoptosis of rat retinal ganglion cellsThe Journal of Neuroscience, 2000Co-Authors: Masashi Kikuchi, Stuart A Lipton, Lalitha TennetiAbstract:
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.
Axotomy induced target disconnection promotes an additional death mechanism involved in motoneuron degeneration in amyotrophic lateral sclerosis transgenic miceThe 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.
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).
gonadal steroid attenuation of developing hamster facial motoneuron loss by Axotomy equal efficacy of testosterone dihydrotestosterone and 17 β estradiolThe 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.