Pharmacological Therapy for Acute Spinal Cord Injury

Hurlbert, R. John; Hadley, Mark N.; Walters, Beverly C.; Aarabi, Bizhan; Dhall, Sanjay S.; Gelb, Daniel E.; Rozzelle, Curtis J.; Ryken, Timothy C.; Theodore, Nicholas

doi:10.1227/neu.0b013e31827765c6

Cited by 335 publications

(166 citation statements)

References 31 publications

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“…In spite of the proposed beneficial outcome of attenuating neuroinflammatory processes elicited by SCI, high doses of MP bear severe side effects that include a persistent state of immunosuppression that leads to infections and metabolic complications as well as pulmonary and adrenal insufficiency and gastrointestinal ulcers and bleeding [2, 3, 25] and even an increased risk of pneumonia and sepsis [26]. MP has been proven to reduce inflammation by blocking cytokine cascades and inhibiting T cell activation and extravasation, which are important mechanisms of neurodegeneration under chronic inflammatory conditions such as multiple sclerosis [27], and for many decades now, it has been thought that MP contributes to reducing neuroinflammation and to some extent relieving the complications of SCI associated with mechanisms of secondary damage such as BSCB alterations and edema formation.…”

Section: Discussionmentioning

confidence: 99%

“…There is a limited understanding of the cellular and molecular events that are involved in this pathology and of the processes that contribute to tissue damage and failure of neuroregenerative mechanisms; therefore, therapeutic strategies to treat SCI are scant. To date, there is no pharmacological treatment available for SCI with proven efficacy; the only available protocol currently employed is high doses of methylprednisolone (MP), but its use is highly controversial because the beneficial effects have not been reproducible and are outweighed by severe side effects [2, 3]. More than 30 years ago, MP was considered to reduce lipid peroxidation triggered as secondary damage following SCI [4] and its use is largely justified on the National Acute Spinal Cord Injury Studies trial II (NASCIS II) [5, 6], in which the major finding was that a subgroup of patients treated with 30 mg/kg bolus at hospital admission followed by 5.4 mg/kg/h for the next 23 h starting before 8 h of contusion showed a slight improvement in light touch and pinprick sensation and a very subtle motor improvement.…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, the studies that had the potential to validate the NASCIS II trial lack methodological soundness, which limits the ability to draw any conclusions; thus, the positive findings of NASCIS II have never been confirmed with well-designed randomized control trials [7]. Nonetheless, administration of MP following SCI continues to be a common practice [8–11] notwithstanding that it is no longer recommended in the guidelines for the management of acute SCI of the American Association of Neurological surgeons [2]. …”

Section: Introductionmentioning

confidence: 99%

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Methylprednisolone Administration Following Spinal Cord Injury Reduces Aquaporin 4 Expression and Exacerbates Edema

Cabrera-Aldana¹,

Ruelas

Aranda

et al. 2017

Mediators of Inflammation

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Spinal cord injury (SCI) is an incapacitating condition that affects motor, sensory, and autonomic functions. Since 1990, the only treatment administered in the acute phase of SCI has been methylprednisolone (MP), a synthetic corticosteroid that has anti-inflammatory effects; however, its efficacy remains controversial. Although MP has been thought to help in the resolution of edema, there are no scientific grounds to support this assertion. Aquaporin 4 (AQP4), the most abundant component of water channels in the CNS, participates in the formation and elimination of edema, but it is not clear whether the modulation of AQP4 expression by MP plays any role in the physiopathology of SCI. We studied the functional expression of AQP4 modulated by MP following SCI in an experimental model in rats along with the associated changes in the permeability of the blood-spinal cord barrier. We analyzed these effects in male and female rats and found that SCI increased AQP4 expression in the spinal cord white matter and that MP diminished such increase to baseline levels. Moreover, MP increased the extravasation of plasma components after SCI and enhanced tissue swelling and edema. Our results lend scientific support to the increasing motion to avoid MP treatment after SCI.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Methylprednisolone Administration Following Spinal Cord Injury Reduces Aquaporin 4 Expression and Exacerbates Edema

Cabrera-Aldana¹,

Ruelas

Aranda

et al. 2017

Mediators of Inflammation

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“…Three phases occur after SCI: acute (hours to days), sub-acute (days to weeks), and chronic (months to years). Many repair strategies have been proposed and tested in models of acute and sub-acute SCI such as tissue protection using corticosteroids and gangliosides (Hurlbert et al, 2013), anti-inflammatory reagents (Hawthorne and Popovich, 2011; Ren and Young, 2013), factors to promote axonal regeneration such as neurotrophic factors, blockage/removal of inhibitory factors, and tissue/cell transplantation (Cafferty et al, 2007; Hollis and Tuszynski, 2011; Tetzlaff et al, 2011; McCall et al, 2012; Cregg et al, 2014). Indeed, cell transplantation has been shown to be one of the most promising strategies to promote functional recovery in acute and subacute SCI.…”

Section: Introductionmentioning

confidence: 99%

Transplantation of neural progenitor cells in chronic spinal cord injury

et al. 2016

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Previous studies demonstrated that neural progenitor cells (NPCs) transplanted into a subacute contusion injury improve motor, sensory, and bladder function. In this study we tested whether transplanted NPCs can also improve functional recovery after chronic spinal cord injury (SCI) alone or in combination with the reduction of glial scar and neurotrophic support. Adult rats received a T10 moderate contusion. Thirteen weeks after the injury they were divided into four groups and received either: 1. Medium (control), 2. NPC transplants, 3. NPC + lentivirus vector expressing chondroitinase, or 4. NPC + lentivirus vectors expressing chondroitinase and neurotrophic factors. During the 8 weeks post-transplantation the animals were tested for functional recovery and eventually analyzed by anatomical and immunohistochemical assays. The behavioral tests for motor and sensory function were performed before and after injury, and weekly after transplantation, with some animals also tested for bladder function at the end of the experiment. Transplant survival in the chronic injury model was variable and showed NPCs at the injury site in 60% of the animals in all transplantation groups. The NPC transplants comprised less than 40% of the injury site, without significant anatomical or histological differences among the groups. All groups also showed similar patterns of functional deficits and recovery in the 12 weeks after injury and in the 8 weeks after transplantation using the Basso, Beattie, and Bresnahan rating score, the grid test, and the Von Frey test for mechanical allodynia. A notable exception was group 4 (NPC together with chondroitinase and neurotrophins), which showed a significant improvement in bladder function. This study underscores the therapeutic challenges facing transplantation strategies in a chronic SCI in which even the inclusion of treatments designed to reduce scarring and increase neurotrophic support produce only modest functional improvements. Further studies will have to identify the combination of acute and chronic interventions that will augment the survival and efficacy of neural cell transplants.

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“…While preclinical studies have identified a number of potential neuroprotective agents [3], [4], none of these have shown marked therapeutic efficacy in human SCI trials [5], [6]. One likely explanation is that multiple pathophysiological mechanisms are being activated simultaneously and current single drug therapies only affect a subset of these.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of GADD34, the Stress-Inducible Regulatory Subunit of the Endoplasmic Reticulum Stress Response, Does Not Enhance Functional Recovery after Spinal Cord Injury

et al. 2014

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Activation of the endoplasmic reticulum stress response (ERSR) is a hallmark of various pathological diseases and/or traumatic injuries. Restoration of ER homeostasis can contribute to improvement in the functional outcome of these diseases. Using genetic and pharmacological inhibition of the PERK-CHOP arm of the ERSR, we recently demonstrated improvements in hindlimb locomotion after spinal cord injury (SCI) and implicated oligodendrocyte survival as a potential mechanism. Here, we investigated the contribution of stress-inducible PPP1R15A/GADD34, an ERSR signaling effector downstream of CHOP that dephosphorylates eIF2α, in the pathogenesis of SCI. We show that although genetic ablation of GADD34 protects oligodendrocyte precursor cells (OPCs) against ER stress-mediated cell death in vitro and results in differential ERSR attenuation in vivo after SCI, there is no improvement in hindlimb locomotor function. Guanabenz, a FDA approved antihypertensive drug, was recently shown to reduce the burden of misfolded proteins in the ER by directly targeting GADD34. Guanabenz protected OPCs from ER stress-mediated cell death in vitro and attenuated the ERSR in vivo after SCI. However, guanabenz administration failed to rescue the locomotor deficits after SCI. These data suggest that deletion of GADD34 alone is not sufficient to improve functional recovery after SCI.

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Pharmacological Therapy for Acute Spinal Cord Injury

Cited by 335 publications

References 31 publications

Methylprednisolone Administration Following Spinal Cord Injury Reduces Aquaporin 4 Expression and Exacerbates Edema

Methylprednisolone Administration Following Spinal Cord Injury Reduces Aquaporin 4 Expression and Exacerbates Edema

Transplantation of neural progenitor cells in chronic spinal cord injury

Inhibition of GADD34, the Stress-Inducible Regulatory Subunit of the Endoplasmic Reticulum Stress Response, Does Not Enhance Functional Recovery after Spinal Cord Injury

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