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Vascular disruption and the role of angiogenic proteins after spinal cord injury.

ABSTRACT: Spinal cord injuries (SCI) can result in devastating paralysis, for which there is currently no robustly efficacious neuroprotective/neuroregenerative treatment. When the spinal cord is subjected to a traumatic injury, the local vasculature is disrupted and the blood-spinal cord barrier is compromised. Subsequent inflammation and ischemia may then contribute to further secondary damage, exacerbating neurological deficits. Therefore, understanding the vascular response to SCI and the molecular elements that regulate angiogenesis has considerable relevance from a therapeutic standpoint. In this paper, we review the nature of vascular damage after traumatic SCI and what is known about the role that angiogenic proteins-angiopoietin 1 (Ang1), angiopoietin 2 (Ang2) and angiogenin-may play in the subsequent response. To this, we add recent work that we have conducted in measuring these proteins in the cerebrospinal fluid (CSF) and serum after acute SCI in human patients. Intrathecal catheters were installed in 15 acute SCI patients within 48 h of injury. CSF and serum samples were collected over the following 3-5 days and analysed for Ang1, Ang2 and angiogenin protein levels using a standard ELISA technique. This represents the first description of the endogenous expression of these proteins in an acute human SCI setting.

SUBMITTER: Ng MT

PROVIDER: S-EPMC3296011 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Vascular disruption and the role of angiogenic proteins after spinal cord injury.

Ng Michelle T L MT Stammers Anthea T AT Kwon Brian K BK

Translational stroke research 20111013 4

Spinal cord injuries (SCI) can result in devastating paralysis, for which there is currently no robustly efficacious neuroprotective/neuroregenerative treatment. When the spinal cord is subjected to a traumatic injury, the local vasculature is disrupted and the blood-spinal cord barrier is compromised. Subsequent inflammation and ischemia may then contribute to further secondary damage, exacerbating neurological deficits. Therefore, understanding the vascular response to SCI and the molecular el ...[more]

PMID: 22448202

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Project description:Acute spinal cord injury (SCI) induces secondary hemorrhage and initial blood-spinal cord barrier (BSCB) disruption. The transient receptor potential melastatin 4 (Trpm4) together with sulfonylurea receptor 1 (Sur1) forms the Sur1-Trpm4 channel complex. The up-regulation of Sur1-Trpm4 after injury plays a crucial role in secondary hemorrhage, which is the most destructive mechanism in secondary injuries of the central nervous system (CNS). The matrix metalloprotease (MMP)-mediated disruption of the BSCB leads to an inflammatory response, neurotoxin production and neuronal cell apoptosis. Thus, preventing secondary hemorrhage and BSCB disruption should be an important goal of therapeutic interventions in SCI. Methods: Using a moderate contusion injury model at T10 of the spinal cord, flufenamic acid (FFA) was injected intraperitoneally 1 h after SCI and then continuously once per day for one week. Results: Trpm4 expression is highly up-regulated in capillaries 1 d after SCI. Treatment with flufenamic acid (FFA) inhibited Trpm4 expression, secondary hemorrhage, and capillary fragmentation and promoted angiogenesis. In addition, FFA significantly inhibited the expression of MMP-2 and MMP-9 at 1 d after SCI and significantly attenuated BSCB disruption at 1 d and 3 d after injury. Furthermore, we found that FFA decreased the hemorrhage- and BSCB disruption-induced activation of microglia/macrophages and was associated with smaller lesions, decreased cavity formation, better myelin preservation and less reactive gliosis. Finally, FFA protected motor neurons and improved locomotor functions after SCI. Conclusion: This study indicates that FFA improves functional recovery, in part, due to the following reasons: (1) it inhibits the expression of Trpm4 to reduce the secondary hemorrhage; and (2) it inhibits the expression of MMP-2 and MMP-9 to block BSCB disruption. Thus, the results of our study suggest that FFA may represent a potential therapeutic agent for promoting functional recovery.

Dataset Information

Vascular disruption and the role of angiogenic proteins after spinal cord injury.

Publications

Vascular disruption and the role of angiogenic proteins after spinal cord injury.

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