Severity-dependent expression of pro-inflammatory cytokines in traumatic spinal cord injury in the rat

Yang, Liqun; Jones, Nigel R.; Blumbergs, Peter; Heuvel, Corinna van den; Moore, Emma J.; Manavis, Jim; Sarvestani, Ghafar T.; Ghabriel, M. N.

doi:10.1016/j.jocn.2004.06.011

Cited by 127 publications

(99 citation statements)

References 55 publications

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“…Particularly in MBP-T cell and NSC combined groups, mRNA expression of these neurotrophins were significantly higher compared with those of other groups. Moreover, consistent with previous reports [72][73][74][75], proinflammatory cytokines, such as IFN-γ, IL-1β, and TNF-α, were also highly expressed in the injured spinal cord. However, no differences were detected among groups.…”

Section: Discussionsupporting

confidence: 92%

“…Anti-inflammatory cytokines, such as IL-10, IL-4, and IL-13, have been shown to be neuroprotective [39,[79][80][81][82]. Pro-inflammatory cytokines, such as IFN-γ, IL-1β and TNF-α, have been shown to be detrimental in CNS injury [72][73][74][75]. Therefore, we showed that MBP-Tcell passive immunization improves the local microenvironment by changing the balance between beneficial and detrimental cytokines.…”

Section: Discussionmentioning

confidence: 83%

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Effects of Olig2-Overexpressing Neural Stem Cells and Myelin Basic Protein-Activated T Cells on Recovery from Spinal Cord Injury

Shen

Wang

et al. 2012

Neurotherapeutics

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Neural stem cell (NSC) transplantation is a major focus of current research for treatment of spinal cord injury (SCI). However, it is very important to promote the survival and differentiation of NSCs into myelinating oligodendrocytes (OLs). In this study, myelin basic protein-activated T (MBP-T) cells were passively immunized to improve the SCI microenvironment. Olig2-overexpressing NSCs were infected with a lentivirus carrying the enhanced green fluorescent protein (GFP) reporter gene to generate Olig2-GFP-NSCs that were transplanted into the injured site to differentiate into OLs. Transferred MBP-T cells infiltrated the injured spinal cord, produced neurotrophic factors, and induced the differentiation of resident microglia and/or infiltrating blood monocytes into an "alternatively activated" anti-inflammatory macrophage phenotype by producing interleukin-13. As a result, the survival of transplanted NSCs increased fivefold in MBP-T cell-transferred rats compared with that of the vehicle-treated control. In addition, the differentiation of MBP-positive OLs increased 12-fold in Olig2-GFP-NSC-transplanted rats compared with that of GFP-NSC-transplanted controls. In the MBP-T cell and Olig2-GFP-NSC combined group, the number of OL-remyelinated axons significantly increased compared with those of all other groups. However, a significant decrease in spinal cord lesion volume and an increase in spared myelin and behavioral recovery were observed in Olig2-NSC-and NSC-transplanted MBP-T cell groups. Collectively, these results suggest that MBP-T cell adoptive immunotherapy combined with NSC transplantation has a synergistic effect on histological and behavioral improvement after traumatic SCI. Although Olig2 overexpression enhances OL differentiation and myelination, the effect on functional recovery may be surpassed by MBP-T cells.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 83%

Effects of Olig2-Overexpressing Neural Stem Cells and Myelin Basic Protein-Activated T Cells on Recovery from Spinal Cord Injury

Shen

Wang

et al. 2012

Neurotherapeutics

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“…In our experiments, the TNF-␣ and IL-6 in untreated animals peaked by day 2 and thereafter declined, even without treatment. The observed peaks are delayed compared with the reports in other studies of a range of 1-6 h of neurons and microglia, respectively (36,37). Furthermore, Pan et al (38) have shown rapid induction (minutes) of proinflammatory cytokine mRNAs in SCI arising from the spinal cord itself.…”

Section: Discussionmentioning

confidence: 59%

Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury

Gorio

Madaschi

Stefano

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

114

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Inflammation plays a major pathological role in spinal cord injury (SCI). Although antiinflammatory treatment using the glucocorticoid methyprednisolone sodium succinate (MPSS) improved outcomes in several multicenter clinical trials, additional clinical experience suggests that MPSS is only modestly beneficial in SCI and poses a risk for serious complications. Recent work has shown that erythropoietin (EPO) moderates CNS tissue injury, in part by reducing inflammation, limiting neuronal apoptosis, and restoring vascular autoregulation. We determined whether EPO and MPSS act synergistically in SCI. Using a rat model of contusive SCI, we compared the effects of EPO [500 -5,000 units͞kg of body weight (kg-bw)] with MPSS (30 mg͞kg-bw) for proinflammatory cytokine production, histological damage, and motor function at 1 month after a compression injury. Although high-dose EPO and MPSS suppressed proinflammatory cytokines within the injured spinal cord, only EPO was associated with reduced microglial infiltration, attenuated scar formation, and sustained neurological improvement. Unexpectedly, coadministration of MPSS antagonized the protective effects of EPO, even though the EPO receptor was up-regulated normally after injury. These data illustrate that the suppression of proinflammatory cytokines alone does not necessarily prevent secondary injury and suggest that glucocorticoids should not be coadministered in clinical trials evaluating the use of EPO for treatment of SCI.cytokines ͉ glucocorticoids ͉ inflammation ͉ neuroprotection ͉ trauma

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“…Inflammatory processes characteristic of the acute stage of injury are likely to alter the actions of morphine. Pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), are significantly upregulated 1, 3, and 6 hrs after a contusion injury, returning to background levels 1-2 days after injury [35,36]. Morphine appears to further increase pro-inflammatory cytokine levels by activating μ-receptors on spinal glial cells [37,38,39,40].…”

Section: Discussionmentioning

confidence: 99%

“…Second, pro-inflammatory cytokines have been linked to cytotoxic effects in the nervous system [43,44,45]. Yang et al [36] suggest that there is a critical balance between beneficial and toxic effects that depends on cytokine concentrations.…”

Section: Discussionmentioning

confidence: 99%

The impact of morphine after a spinal cord injury

Hook

Liu

Washburn

et al. 2007

Behavioural Brain Research

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Nociceptive stimulation, at an intensity that elicits pain-related behavior, attenuates recovery of locomotor and bladder functions, and increases tissue loss after a contusion injury. These data imply that nociceptive input (e.g., from tissue damage) can enhance the loss of function after injury, and that potential clinical treatments, such pretreatment with an analgesic, may protect the damaged system from further secondary injury. The current study examined this hypothesis and showed that a potential treatment (morphine) did not have a protective effect. In fact, morphine appeared to exacerbate the effects of nociceptive stimulation. Experiment 1 showed that after spinal cord injury 20 mg/kg of systemic morphine was necessary to induce strong antinociception and block behavioral reactivity to shock treatment, a dose that was much higher than that needed for sham controls. In Experiment 2, contused rats were given one of three doses of morphine (Vehicle, 10, 20 mg/kg) prior to exposure to uncontrollable electrical stimulation or restraint alone. Despite decreasing nociceptive reactivity, morphine did not attenuate the long-term consequences of shock. Rats treated with morphine and shock had higher mortality rates, and displayed allodynic responses to innocuous sensory stimuli three weeks later. Independent of shock, morphine per se undermined recovery of sensory function. Rats treated with morphine alone also had significantly larger lesions than those treated with saline. These results suggest that nociceptive stimulation affects recovery despite a blockade of pain-elicited behavior. The results are clinically important because they suggest that opiate treatment may adversely affect the recovery of function after injury.

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Severity-dependent expression of pro-inflammatory cytokines in traumatic spinal cord injury in the rat

Cited by 127 publications

References 55 publications

Effects of Olig2-Overexpressing Neural Stem Cells and Myelin Basic Protein-Activated T Cells on Recovery from Spinal Cord Injury

Effects of Olig2-Overexpressing Neural Stem Cells and Myelin Basic Protein-Activated T Cells on Recovery from Spinal Cord Injury

Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury

The impact of morphine after a spinal cord injury

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