Pathophysiological activity in rat dorsal horn neurones in segments rostral to a chronic spinal cord injury

Hoheisel, Ulrich; Scheifer, Caroline; Trudrung, P.; Unger, Thomas; Mense, Siegfried

doi:10.1016/s0006-8993(03)02571-x

Cited by 32 publications

(12 citation statements)

References 35 publications

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“…The functional outcomes observed in our study – improved gait, hindlimb weight support and decreased pain – would be consistent with previous research demonstrating improved function and/or sparing of propriospinal tracts (limb coordination) [65], reticulospinal tracts (locomotion and weight-bearing stepping) [66], and spinothalamic tracts (neuropathic pain) [67], [68] following SCI. In our study, we did not investigated the sparing of specific spinal tracts via electrophyisiology or dye-tracing experiments; however, an overall increase in residual grey matter likely contributes to improved pain processing pathways (interneurons) and a decrease in aberrant pain [17], [69], [70]. Varying studies report that 26-96% of human patients experience neuropathic pain following SCI [30].…”

Section: Discussionmentioning

confidence: 99%

Delayed Administration of a Bio-Engineered Zinc-Finger VEGF-A Gene Therapy Is Neuroprotective and Attenuates Allodynia Following Traumatic Spinal Cord Injury

et al. 2014

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Following spinal cord injury (SCI) there are drastic changes that occur in the spinal microvasculature, including ischemia, hemorrhage, endothelial cell death and blood-spinal cord barrier disruption. Vascular endothelial growth factor-A (VEGF-A) is a pleiotropic factor recognized for its pro-angiogenic properties; however, VEGF has recently been shown to provide neuroprotection. We hypothesized that delivery of AdV-ZFP-VEGF – an adenovirally delivered bio-engineered zinc-finger transcription factor that promotes endogenous VEGF-A expression – would result in angiogenesis, neuroprotection and functional recovery following SCI. This novel VEGF gene therapy induces the endogenous production of multiple VEGF-A isoforms; a critical factor for proper vascular development and repair. Briefly, female Wistar rats – under cyclosporin immunosuppression – received a 35 g clip-compression injury and were administered AdV-ZFP-VEGF or AdV-eGFP at 24 hours post-SCI. qRT-PCR and Western Blot analysis of VEGF-A mRNA and protein, showed significant increases in VEGF-A expression in AdV-ZFP-VEGF treated animals (p<0.001 and p<0.05, respectively). Analysis of NF200, TUNEL, and RECA-1 indicated that AdV-ZFP-VEGF increased axonal preservation (p<0.05), reduced cell death (p<0.01), and increased blood vessels (p<0.01), respectively. Moreover, AdV-ZFP-VEGF resulted in a 10% increase in blood vessel proliferation (p<0.001). Catwalk™ analysis showed AdV-ZFP-VEGF treatment dramatically improves hindlimb weight support (p<0.05) and increases hindlimb swing speed (p<0.02) when compared to control animals. Finally, AdV-ZFP-VEGF administration provided a significant reduction in allodynia (p<0.01). Overall, the results of this study indicate that AdV-ZFP-VEGF administration can be delivered in a clinically relevant time-window following SCI (24 hours) and provide significant molecular and functional benefits.

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Section: Discussionmentioning

confidence: 99%

Delayed Administration of a Bio-Engineered Zinc-Finger VEGF-A Gene Therapy Is Neuroprotective and Attenuates Allodynia Following Traumatic Spinal Cord Injury

et al. 2014

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“…Mechanisms involved in the establishment of SCI pain are still not fully understood due to difficulties in dissociating traumatic cascade of events occurring in the spinal cord to those arising from the dorsal root ganglia, sympathetic ganglia, and peripheral nerves (O’Brien et al, 1994; Bethea et al, 1998; Miranda et al, 1999; Springer et al, 1999; Yaksh et al, 1999; Saito et al, 2000; Bruce et al, 2002; Hains et al, 2003b; Hoheisel et al, 2003). Furthermore, biochemical events leading to abnormal firing of spinal neurons (Mills et al, 2001; Yezierski et al, 2004), up-regulation of voltage-gated ion channels (Nashmi and Fehlings, 2001; Edwards et al, 2002; Hains et al, 2003a), recruitment of reactive glia (Carlton et al, 2009), and excessive release of excitatory amino acids (excitotoxicity) in the spinal gray and white matters add to the complexity of neuropathic pain in SCI patients (Mills et al, 2001; Zeilig et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Predifferentiated GABAergic Neural Precursor Transplants for Alleviation of Dysesthetic Central Pain Following Excitotoxic Spinal Cord Injury

et al. 2012

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Intraspinal quisqualic acid (QUIS) injury induce (i) mechanical and thermal hyperalgesia, (ii) progressive self-injurious overgrooming of the affected dermatome. The latter is thought to resemble painful dysesthesia observed in spinal cord injury (SCI) patients. We have reported previously loss of endogenous GABA immunoreactive (IR) cells in the superficial dorsal horn of QUIS rats 2 weeks post injury. Further histological evaluation showed that GABA-, glycine-, and synaptic vesicular transporter VIAAT-IR persisted but were substantially decreased in the injured spinal cord. In this study, partially differentiated GABA-IR embryonic neural precursor cells (NPCs) were transplanted into the spinal cord of QUIS rats to reverse overgrooming by replenishing lost inhibitory circuitry. Rat E14 NPCs were predifferentiated in 0.1 ng/ml FGF-2 for 4 h prior to transplantation. In vitro immunocytochemistry of transplant cohort showed large population of GABA-IR NPCs that double labeled with nestin but few colocalized with NeuN, indicating partial maturation. Two weeks following QUIS lesion at T12-L1, and following the onset of overgrooming, NPCs were transplanted into the QUIS lesion sites; bovine adrenal fibroblast cells were used as control. Overgrooming was reduced in >55.5% of NPC grafted animals, with inverse relationship between the number of surviving GABA-IR cells and the size of overgrooming. Fibroblast-control animals showed a progressive worsening of overgrooming. At 3 weeks post-transplantation, numerous GABA-, nestin-, and GFAP-IR cells were present in the lesion site. Surviving grafted GABA-IR NPCs were NeuN+ and GFAP−. These results indicate that partially differentiated NPCs survive and differentiate in vivo into neuronal cells following transplantation into an injured spinal cord. GABA-IR NPC transplants can restore lost dorsal horn inhibitory signaling and are useful in alleviating central pain following SCI.

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“…At-level pain-like behavioral responses post-SCI may be associated with hyperactivity of remaining intact spinothalamic dorsal horn neurons [7]. After chronic SCI, these dorsal horn neurons exhibit higher background activities, altered discharge patterns, increases in responsiveness to brush and pinch, and longer after-discharges [10, 18]. A significant (62%) increase in metabotropic glutamate receptor subtype 1 immunoreactivity has been demonstrated for spinothalamic tract neurons located immediately rostral to the epicenter of a T9 contusion [36], implicating the thalamus as an important supraspinal site contributing to chronic SCI pain.…”

mentioning

confidence: 99%

Sex and hormonal variations in the development of at-level allodynia in a rat chronic spinal cord injury model

Hubscher

Fell

Gupta

2010

Neuroscience Letters

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The development of central neuropathic pain varies among patients with spinal cord injury (SCI). The factors contributing to the development and perpetuation of segmental pain (at-level allodynia) has been the focus of ongoing experiments in our laboratory. One such factor is hormonal status. We have shown previously, using a male rat model of SCI, that a severe contusion injury is necessary for the development of allodynia in trunk regions at and just above the level of a T8 injury. In this study, we examined at-level sensitivity for SCI ovariectomized (ovx) and cycling female rats as well as for SCI males implanted with either a placebo pellet or one that slowly releases 17β-estradiol. The proportion of ovx SCI female rats and placebo-treated SCI males displaying pain-like behaviors to touch/pressure of at-level dermatomes up to six weeks post-injury (67% and 75%, respectively) was similar to our previous studies on SCI males (69%). In contrast, significantly fewer cycling SCI female rats and 17β-estradiol treated SCI male rats showed sensitivity to touch at-level (26% and 30%, respectively). These results implicate 17β-estradiol as a potential target that can readily be modulated to prevent segmental pain following SCI.

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Pathophysiological activity in rat dorsal horn neurones in segments rostral to a chronic spinal cord injury

Cited by 32 publications

References 35 publications

Delayed Administration of a Bio-Engineered Zinc-Finger VEGF-A Gene Therapy Is Neuroprotective and Attenuates Allodynia Following Traumatic Spinal Cord Injury

Delayed Administration of a Bio-Engineered Zinc-Finger VEGF-A Gene Therapy Is Neuroprotective and Attenuates Allodynia Following Traumatic Spinal Cord Injury

Predifferentiated GABAergic Neural Precursor Transplants for Alleviation of Dysesthetic Central Pain Following Excitotoxic Spinal Cord Injury

Sex and hormonal variations in the development of at-level allodynia in a rat chronic spinal cord injury model

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