Glial cell responses, complement, and clusterin in the central nervous system following dorsal root transection

Liu, Li; Persson, Jonas; Svensson, Mikael; Aldskogius, Håkan

doi:10.1002/(sici)1098-1136(199807)23:3<221::aid-glia5>3.0.co;2-7

Cited by 78 publications

(34 citation statements)

References 61 publications

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“…Two weeks after rhizotomy, significant increases in ED1 immunoreactivity were observed in the CNS part of the root as well as the cuneate fasciculus (to 38%), but not in the dorsal horn (Fig. 3G,H ), in agreement with previous studies (Liu et al, 1998). Figure 4 shows the relationship between regenerating CTB-labeled axons and ED1 immunoreactivity in the spinal cord after immediate and delayed NT-3 treatment.…”

Section: Non-neuronal Cell Responsessupporting

confidence: 90%

“…Dorsal roots regenerate at a rate of 2-2.5 mm/d (Wujek and Lasek, 1983;Oblinger and Lasek, 1984;Richardson and Verge, 1986), hence most axons would have reached the DREZ by 3 d after lesion. Astrocytic hypertrophy and proliferation are well underway by 2 d after injury (Liu et al, 1998). However, outright degeneration (implicit in the appearance of ED1-positive cells) does not begin until after the first postoperative week.…”

Section: Discussionmentioning

confidence: 98%

“…3A). Rhizotomy gives rise to a gliotic response involving proliferation and hypertrophy of astrocytes in the CNS portion of the root as well as the dorsal gray matter (Liu et al, 1998). Additionally, glial processes extend into the dorsal root for many tens of micrometers (Fig.…”

Section: Non-neuronal Cell Responsesmentioning

confidence: 99%

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Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

Ramer

Duraisingam²,

Priestley

et al. 2001

J. Neurosci.

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Glial-derived inhibitory molecules and a weak cell-body response prevent sensory axon regeneration into the spinal cord after dorsal root injury. Neurotrophic factors, particularly neurotrophin-3 (NT-3), may increase the regenerative capacity of sensory neurons after dorsal rhizotomy, allowing regeneration across the dorsal root entry zone (DREZ). Intrathecal NT-3, delivered at the time of injury, promoted an upregulation of the growth-associated protein GAP-43 primarily in large-diameter sensory profiles (which did not occur after rhizotomy alone), as well as regeneration of cholera toxin B-labeled sensory axons across the DREZ and deep into the dorsal horn. However, delaying treatment for 1 week compromised regeneration: although axons still penetrated the DREZ, growth within white matter was qualitatively and quantitatively restricted. This was not associated with an impaired cell-body response (GAP-43 upregulation was equivalent for both immediate and delayed treatments), or with astrogliosis at the DREZ, which begins almost immediately after rhizotomy, but with the delayed appearance of mature ED1-expressing phagocytes in the dorsal white matter between 1 and 2 weeks after lesion, marking the beginning of myelin breakdown. After rhizotomy with immediate NT-3 treatment, regeneration continues beyond 2 weeks, but in the dorsal gray matter rather than in the degenerating dorsal columns. The ability of NT-3 to promote regeneration across the DREZ, but not after the beginning of degeneration after delayed treatment reveals a hierarchy of inhibitory influences: the astrogliotic, but not the degenerative barrier is surmountable by NT-3 treatment. Key words: neurotrophin-3; regeneration; degeneration; astrocytes; oligodendrocytes; myelin; dorsal root ganglionThe differential abilities of peripheral and central nervous tissue to support regeneration is exemplified at the dorsal root entry zone (DREZ), which marks the entry point of primary afferent axons into the spinal cord. Here, the environment changes abruptly from consisting of growth-permissive Schwann cells, to astrocytes, oligodendrocytes, and microglia, which may all inhibit regeneration (Fawcett and Asher, 1999). On contact with the DREZ, regenerating axons form club-like end bulbs or synapselike structures, (Ramon y Cajal, 1928;Carlstedt, 1985), but because of the prohibitive environment of the CNS and a paltry regenerative response of sensory neurons to rhizotomy, they never re-enter the adult cord.One strategy to encourage regeneration is to enhance the growth response of the rhizotomized neurons. GAP-43 is induced in nearly all neurons during peripheral nerve regeneration (Verge et al., 1990b), but in few neurons after rhizotomy (Schreyer and Skene, 1993), unless the root is severed very close to the DRG (Chong et al., 1996). Dorsal root axonal growth occurs at about half the rate of peripheral axons (Wujek and Lasek, 1983;Oblinger and Lasek, 1984). An experimental "conditioning" lesion to a peripheral nerve before dorsal rhizotomy doubles the rate of ...

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Section: Non-neuronal Cell Responsessupporting

confidence: 90%

Section: Discussionmentioning

confidence: 98%

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Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

Ramer

Duraisingam²,

Priestley

et al. 2001

J. Neurosci.

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“…As glia and inflammatory cells have been shown to play a role in neuropathic pain (Liu et al, 1998, Liu et , we quantitatively examined immunohistochemical markers for astrocytes, microglia, and macrophages in the L5 dorsal horn region. The present experiments differ from the L5 VRT studies in two important ways.…”

Section: Introductionmentioning

confidence: 99%

At-level neuropathic pain is induced by lumbosacral ventral root avulsion injury and ameliorated by root reimplantation into the spinal cord

Bigbee

Hoang

Havton

2007

Experimental Neurology

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Neuropathic pain is common after traumatic injuries to the cauda equina/conus medullaris and brachial plexus. Clinically, this pain is difficult to treat and its mechanisms are not well understood. Lesions to the ventral roots are common in these injuries, but are rarely considered as potential contributors to pain. We examined whether a unilateral L6-S1 ventral root avulsion (VRA) injury in adult female rats might elicit pain within the dermatome projecting to the adjacent, uninjured L5 spinal segment. Additionally, a subset of subjects had the avulsed L6-S1 ventral roots reimplanted (VRA+Imp) into the lateral funiculus post-avulsion to determine whether this neural repair strategy elicits or ameliorates pain. Behavioral tests for mechanical allodynia and hyperalgesia were performed weekly over 7 weeks post-injury at the hind paw plantar surface. Allodynia developed early and persisted post-VRA, whereas VRA+Imp rats exhibited allodynia only at 1 week postoperatively. Hyperalgesia was not observed at any time in any experimental group. Quantitative immunohistochemistry showed increased levels of inflammatory markers in laminae III-V and in the dorsal funiculus of the L5 spinal cord of VRA, but not VRA+Imp rats, specific to areas that receive projections from mechanoreceptive, but not nociceptive, primary afferents. These data suggest that sustained at-level neuropathic pain can develop following a pure motor lesion, whereas the pain may be ameliorated by acute root reimplantation. We believe that our findings are of translational research interest, as root implantation surgery is emerging as a potentially useful strategy for the repair of cauda equina/conus medullaris injuries.

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“…Astrogliosis begins within days of a dorsal rhizotomy, whereas frank Wallerian degeneration does not begin until 1 week later. 73,74 It is clear that activated astrocytes, whether part of a scar following SCI or as a component of the reactive DREZ following rhizotomy, deter regeneration. Following SCI, axons retract from the lesion site and are surrounded by CNS myelin.…”

Section: Myelin and Myelin Signaling: An Inhibitory Chorus Linementioning

confidence: 99%

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

2005

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Here we review mechanisms and molecules that necessitate protection and oppose axonal growth in the injured spinal cord, representing not only a cast of villains but also a company of therapeutic targets, many of which have yet to be fully exploited. We next discuss recent progress in the fields of bridging, overcoming conduction block and rehabilitation after spinal cord injury (SCI), where several treatments in each category have entered the spotlight, and some are being tested clinically. Finally, studies that combine treatments targeting different aspects of SCI are reviewed. Although experiments applying some treatments in combination have been completed, auditions for each part in the much-sought combination therapy are ongoing, and performers must demonstrate robust anatomical regeneration and/or significant return of function in animal models before being considered for a lead role.Spinal Cord (2005) 43, 134-161.

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Glial cell responses, complement, and clusterin in the central nervous system following dorsal root transection

Cited by 78 publications

References 61 publications

Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

At-level neuropathic pain is induced by lumbosacral ventral root avulsion injury and ameliorated by root reimplantation into the spinal cord

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

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