Author
Elizabeth J. Bradbury
Other affiliations: St Thomas' Hospital, King's College London, University of Cambridge
Bio: Elizabeth J. Bradbury is an academic researcher from Wolfson Centre for Age-Related Diseases. The author has contributed to research in topics: Spinal cord injury & Spinal cord. The author has an hindex of 47, co-authored 73 publications receiving 8923 citations. Previous affiliations of Elizabeth J. Bradbury include St Thomas' Hospital & King's College London.
Papers published on a yearly basis
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TL;DR: It is demonstrated that CSPGs are important inhibitory molecules in vivo and suggested that their manipulation will be useful for treatment of human spinal injuries.
Abstract: The inability of axons to regenerate after a spinal cord injury in the adult mammalian central nervous system (CNS) can lead to permanent paralysis. At sites of CNS injury, a glial scar develops, containing extracellular matrix molecules including chondroitin sulphate proteoglycans (CSPGs). CSPGs are inhibitory to axon growth in vitro, and regenerating axons stop at CSPG-rich regions in vivo. Removing CSPG glycosaminoglycan (GAG) chains attenuates CSPG inhibitory activity. To test the functional effects of degrading chondroitin sulphate (CS)-GAG after spinal cord injury, we delivered chondroitinase ABC (ChABC) to the lesioned dorsal columns of adult rats. We show that intrathecal treatment with ChABC degraded CS-GAG at the injury site, upregulated a regeneration-associated protein in injured neurons, and promoted regeneration of both ascending sensory projections and descending corticospinal tract axons. ChABC treatment also restored post-synaptic activity below the lesion after electrical stimulation of corticospinal neurons, and promoted functional recovery of locomotor and proprioceptive behaviours. Our results demonstrate that CSPGs are important inhibitory molecules in vivo and suggest that their manipulation will be useful for treatment of human spinal injuries.
2,150 citations
TL;DR: Glial cell line-derived neurotrophic factor (GDNF), delivered intrathecally, completely reversed axotomy-induced down-regulation of the P2X3 receptor and it is concluded that P2x3 receptors are normally expressed in nociceptive primary sensory neurons, predominantly the nonpeptidergic nocICEptors.
440 citations
TL;DR: BDNF is appropriately localized and regulated in inflammatory states and is sufficient and necessary for the expression of central sensitization in the spinal cord, and pharmacological antagonism of BDNF may prove an effective and novel analgesic strategy for the treatment of persistent inflammatory pain states.
Abstract: Central sensitization, the hyperexcitability of spinal processing that often accompanies peripheral injury, is a major component of many persistent pain states. Here we report that the neurotrophin, brain-derived neurotrophic factor (BDNF), is a modulator of excitability within the spinal cord and contributes to the mechanism of central sensitization. BDNF, localized in primary sensory neuron cell bodies and central terminals, potentiates nociceptive spinal reflex responses in an in vitro spinal cord preparation and induces c-fos expression in dorsal horn neurons. NMDA receptor-mediated responses, known as a major contributor to central sensitization, were significantly enhanced by exogenous BDNF. Systemic NGF treatment, a procedure that mimics peripheral inflammatory states, raises BDNF levels in sensory neurons and increases nociceptive spinal reflex excitability. This increased central excitability is reduced by trkB-IgG, a BDNF "antagonist." We also show directly that inflammatory pain-related behavior depends on BDNF release in vivo. Thus behavioral nociceptive responses induced by intraplantar formalin and by intraplantar carageenan are significantly attenuated by trkB-IgG. Hence BDNF is appropriately localized and regulated in inflammatory states and is sufficient and necessary for the expression of central sensitization in the spinal cord. We propose that BDNF may function as a modulator of central sensitization in pathological states, and our results suggest that pharmacological antagonism of BDNF may prove an effective and novel analgesic strategy for the treatment of persistent inflammatory pain states.
415 citations
TL;DR: Robust sprouting is found of both injured and intact descending projections as well as uninjured primary afferents after a cervical dorsal column injury and ChABC treatment and CSPG degradation; compensatory sprouting of descending systems could be a key mechanism underlying functional recovery.
Abstract: Chondroitin sulfate proteoglycans (CSPGs) are inhibitory extracellular matrix molecules that are upregulated after CNS injury. Degradation of CSPGs using the enzyme chondroitinase ABC (ChABC) can promote functional recovery after spinal cord injury. However, the mechanisms underlying this recovery are not clear. Here we investigated the effects of ChABC treatment on promoting plasticity within the spinal cord. We found robust sprouting of both injured (corticospinal) and intact (serotonergic) descending projections as well as uninjured primary afferents after a cervical dorsal column injury and ChABC treatment. Sprouting fibers were observed in aberrant locations in degenerating white matter proximal to the injury in regions where CSPGs had been degraded. Corticospinal and serotonergic sprouting fibers were also observed in spinal gray matter at and below the level of the lesion, indicating increased innervation in the terminal regions of descending projections important for locomotion. Spinal-injured animals treated with a vehicle solution showed no significant sprouting. Interestingly, ChABC treatment in uninjured animals did not induce sprouting in any system. Thus, both denervation and CSPG degradation were required to promote sprouting within the spinal cord. We also examined potential detrimental effects of ChABC-induced plasticity. However, although primary afferent sprouting was observed after lumbar dorsal column lesions and ChABC treatment, there was no increased connectivity of nociceptive neurons or development of mechanical allodynia or thermal hyperalgesia. Thus, CSPG digestion promotes robust sprouting of spinal projections in degenerating and denervated areas of the spinal cord; compensatory sprouting of descending systems could be a key mechanism underlying functional recovery.
398 citations
TL;DR: There are now numerous preclinical reports of various experimental treatments promoting some functional recovery after spinal cord injury, but the evidence that regeneration of damaged pathways or compensatory collateral sprouting can promote recovery is critically evaluated.
Abstract: There are now numerous preclinical reports of various experimental treatments promoting some functional recovery after spinal cord injury. Surprisingly, perhaps, the mechanisms that underlie recovery have rarely been definitively established. Here, we critically evaluate the evidence that regeneration of damaged pathways or compensatory collateral sprouting can promote recovery. We also discuss several more speculative mechanisms that might putatively explain or confound some of the reported outcomes of experimental interventions.
357 citations
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TL;DR: Here, a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain is developed, identifying distinct forms of Plasticity, which are term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.
Abstract: We describe those sensations that are unpleasant, intense, or distressing as painful. Pain is not homogeneous, however, and comprises three categories: physiological, inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which is subject to or an expression of neural plasticity-the capacity of neurons to change their function, chemical profile, or structure. Here, we develop a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain, identifying distinct forms of plasticity, which we term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.
3,543 citations
TL;DR: In this paper, pH-induced self-assembly of a peptide-amphiphile was used to make a nanostructured fibrous scaffold reminiscent of extracellular matrix.
Abstract: We have used the pH-induced self-assembly of a peptide-amphiphile to make a nanostructured fibrous scaffold reminiscent of extracellular matrix. The design of this peptide-amphiphile allows the nanofibers to be reversibly cross-linked to enhance or decrease their structural integrity. After cross-linking, the fibers are able to direct mineralization of hydroxyapatite to form a composite material in which the crystallographic c axes of hydroxyapatite are aligned with the long axes of the fibers. This alignment is the same as that observed between collagen fibrils and hydroxyapatite crystals in bone.
3,125 citations
TL;DR: Chondroitin and keratan sulphate proteoglycans are among the main inhibitory extracellular matrix molecules that are produced by reactive astrocytes in the glial scar, and they are believed to play a crucial part in regeneration failure.
Abstract: After injury to the adult central nervous system (CNS), injured axons cannot regenerate past the lesion. In this review, we present evidence that this is due to the formation of a glial scar. Chondroitin and keratan sulphate proteoglycans are among the main inhibitory extracellular matrix molecules that are produced by reactive astrocytes in the glial scar, and they are believed to play a crucial part in regeneration failure. We will focus on this role, as well as considering the behaviour of regenerating neurons in the environment of CNS injury.
2,838 citations
TL;DR: The major triggers that initiate and maintain central sensitization in healthy individuals in response to nociceptor input and in patients with inflammatory and neuropathic pain are reviewed, emphasizing the fundamental contribution and multiple mechanisms of synaptic plasticity caused by changes in the density, nature, and properties of ionotropic and metabotropic glutamate receptors.
2,803 citations
TL;DR: P2X receptors are membrane ion channels that open in response to the binding of extracellular ATP and are involved in the initiation of afferent signals in several viscera and play a key role in sensing tissue-damaging and inflammatory stimuli.
Abstract: P2X receptors are membrane ion channels that open in response to the binding of extracellular ATP. Seven genes in vertebrates encode P2X receptor subunits, which are 40–50% identical in amino acid ...
2,800 citations