Glial reactions in a rodent cauda equina injury and repair model

Ohlsson, Marcus; Hoang, Thao X.; Wu, Jun; Havton, Leif A.

doi:10.1007/s00221-005-0188-6

Cited by 20 publications

(20 citation statements)

References 66 publications

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“…The finding that Pre084 treatment significantly prevented MN death prompted us to analyze its possible effects on glial cell reactivity that is associated with MN loss following root avulsion Ohlsson et al, 2006;Penas et al, 2009). Despite that it has been shown that activation of Sig-1R and Sig-2R by agonists with the same affinity for both receptors suppresses microglial activation in vitro (Hall et al, 2009), we did not observe changes in microglia immunoreactivity by Pre084 treatment at 0.25 mg/kg in vivo.…”

mentioning

confidence: 63%

Sigma Receptor Agonist 2-(4-Morpholinethyl)1 Phenylcyclohexanecarboxylate (Pre084) Increases GDNF and BiP Expression and Promotes Neuroprotection after Root Avulsion Injury

Penas

Pascual‐Font

Mancuso

et al. 2011

Journal of Neurotrauma

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Spinal root avulsion leads to a progressive loss of axotomized motoneurons (MNs). Nowadays, there is no effective treatment to prolong MN survival that could permit recovery as a result of delayed surgical repair. Administration of Sigma-1 receptor (Sig-1R) ligands has been reported to promote beneficial effects after several types of neural injury. In order to shed light of whether Sig-1R ligands could promote MN survival after root avulsion, L4-L5 spinal roots were unilaterally avulsed in adult rats and the Sig-1R agonist Pre084 was administered at different doses. The ventral spinal cords of the animals were studied from 3 to 21 days post-operation (DPO) by using histological, immunohistochemical, and Western blot techniques. Daily treatment with 0.25 mg/kg Pre084 significantly promoted MN survival (68% vs 43% in untreated rats) at 21 DPO, an effect that was antagonized by coadministration of BD1063, an antagonist of Sig-1R. There was a reduction in astroglial- associated immunoreactivity in rats treated with Pre084. Moreover, Pre084 produced an increase in the Sig-1R co-chaperone BiP within MNs, and an increase of GDNF expression by astrocytes in the ventral horn early after injury. Although the mechanisms promoting MN survival by Pre084 remain unclear, we hypothesize that it is mediated at least in part through the increase in these cytoprotective factors. Therefore, early application of Sig-1R agonist appears to be a promising therapy to improve MN survival after root avulsion.

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mentioning

confidence: 63%

Sigma Receptor Agonist 2-(4-Morpholinethyl)1 Phenylcyclohexanecarboxylate (Pre084) Increases GDNF and BiP Expression and Promotes Neuroprotection after Root Avulsion Injury

Penas

Pascual‐Font

Mancuso

et al. 2011

Journal of Neurotrauma

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“…In all of the studies just mentioned, however, sensory afferent damage was inherent to the models being examined. We previously showed that reactive astrocytes, microglia, and macrophages are prominent in the ventral horn at the level of injury after VRA and VRA+Imp, and speculated that their presence was a direct result of neuronal injury (Ohlsson et al, 2006). We now show for the first time that an L6-S1 VRA injury results in significant activation of astrocytes, microglia, and macrophages in the ipsilateral deep dorsal horn gray matter and in the dorsal funiculus of the spinal cord segment immediately rostral to the level of injury, relative to Lam control levels, in spite of the absence of a direct injury to the primary afferents.…”

Section: A Motor Lesion Can Induce Sensory Plasticity Beyond the Levementioning

confidence: 99%

“…Although we have extensively examined autonomic and motoneuron cell death (Hoang et al, 2003), as well as inflammation (Ohlsson et al, 2006) in the ventral horn at the level of injury in this model, it is unknown whether VRA alters the processing of sensory information in the dorsal horn at or beyond the injured segment. As neuropathic pain is a consequence of this type of spinal cord injury in the clinical setting, we propose that the VRA injury may contribute to the development of neuropathic pain.…”

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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“…In line with our results, Brännström et al 30 demonstrated that the neuronal size of adult cat motoneurons is decreased by 29% at 12 weeks after permanent axotomy.Thus, although axotomy has no effect on the survival of the corresponding spinal motoneurons, cell atrophy, synaptic shedding, degeneration of dendrites and activation of microglia is induced, which also is the case following VRA. However, in contrast to the survival rate of motoneurons, an acute implantation of an avulsed root does not significantly affect the activation of glial cells in the ventral horn21 .The molecular mechanisms behind injury induced motoneuron degeneration are not understood, although it appears that trophic factor deprivation8,33 and nitric oxide-mediated oxidative stress 9 is of critical value. Spinal motoneurons express nitric oxide synthase (NOS) after VRA, in contrast to after ventral root transection 9 , where the motoneuron loss can be reduced by inhibition of NOS 10 .…”

mentioning

confidence: 99%

A Morphological and Molecular Characterization of the Spinal Cord after Ventral Root Avulsion or Distal Peripheral Nerve Axotomy Injuries in Adult Rats

Wiberg

Kingham

Novikova

2017

Journal of Neurotrauma

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Retrograde cell death in sensory dorsal root ganglion cells following peripheral nerve injury is well established. However, available data regarding the underlying mechanism behind injury induced motoneuron death are conflicting. By comparing morphological and molecular changes in spinal motoneurons after L4-L5 ventral root avulsion (VRA) and distal peripheral nerve axotomy (PNA) 7 and 14 days postoperatively, we aimed to gain more insight about the mechanism behind injury-induced motoneuron degeneration. Morphological changes in spinal cord were assessed by using quantitative immunohistochemistry. Neuronal degeneration was revealed by decreased immunostaining for microtubule-associated protein-2 in dendrites and synaptophysin in presynaptic boutons after both VRA and PNA. Significant motoneuron atrophy was already observed at 7 days post-injury, independently of injury type. Immunostaining for ED1 reactive microglia was significantly elevated in all experimental groups, as well as the astroglial marker glial fibrillary acidic protein (GFAP). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of the ventral horn from L4-L5 spinal cord segments revealed a significant upregulation of genes involved in programmed cell death including caspase-3, caspase-8, and related death receptors TRAIL-R, tumor necrosis factor (TNF)-R, and Fas following VRA. In contrast, following PNA, caspase-3 and the death receptor gene expression levels did not differ from the control, and there was only a modest increased expression of caspase-8. Moreover, the altered gene expression correlated with protein changes. These results show that the spinal motoneurons reacted in a similar fashion with respect to morphological changes after both proximal and distal injury. However, the increased expression of caspase-3, caspase-8, and related death receptors after VRA suggest that injury- induced motoneuron degeneration is mediated through an apoptotic mechanism, which might involve both the intrinsic and the extrinsic pathways.

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Glial reactions in a rodent cauda equina injury and repair model

Cited by 20 publications

References 66 publications

Sigma Receptor Agonist 2-(4-Morpholinethyl)1 Phenylcyclohexanecarboxylate (Pre084) Increases GDNF and BiP Expression and Promotes Neuroprotection after Root Avulsion Injury

Sigma Receptor Agonist 2-(4-Morpholinethyl)1 Phenylcyclohexanecarboxylate (Pre084) Increases GDNF and BiP Expression and Promotes Neuroprotection after Root Avulsion Injury

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

A Morphological and Molecular Characterization of the Spinal Cord after Ventral Root Avulsion or Distal Peripheral Nerve Axotomy Injuries in Adult Rats

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