Neuroprotection, Plasticity Manipulation, and Regenerative Strategies to Improve Cardiovascular Function following Spinal Cord Injury

Squair, Jordan W.; West, Christopher R.; KrassioukovAndrei, V

doi:10.1089/neu.2014.3743

Cited by 18 publications

(7 citation statements)

References 75 publications

(190 reference statements)

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“…In vivo and in vitro studies have shown that, following spinal cord injury (SCI), a substantial number of spinal neurons survive despite severe symptoms of motor and sensory deficit arising from the secondary lesion process that extends, within the first 24 hr, the pathological degeneration to initially spared spinal areas (Ahuja et al., ; Dell'Anno & Strittmatter, ; Filous & Schwab, ; Kuzhandaivel, Nistri, Mazzone, & Mladinic, ; Quraishe, Forbes, & Andrews, ). This observation is corroborated by clinical studies (Hoh, Mercier, Hussey, & Lane, ; Kaelan, Jacobsen, & Kakulas, ; Squair, West, & Krassioukov, ). The question then arises about the nature of the intrinsic protective mechanisms that can avoid a more extensive neuronal damage.…”

Section: Introductionsupporting

confidence: 66%

Pharmacological induction of Heat Shock Protein 70 by celastrol protects motoneurons from excitotoxicity in rat spinal cord in vitro

Petrović

Kaur

Tomljanović

et al. 2018

Eur J of Neuroscience

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The secondary phase of spinal cord injury arising after the primary lesion largely extends the damage severity with delayed negative consequences for sensory‐motor pathways. It is, therefore, important to find out if enhancing intrinsic mechanisms of neuroprotection can spare motoneurons that are very vulnerable cells. This issue was investigated with an in vitro model of rat spinal cord excitotoxicity monitored for up to 24 hr after the primary injury evoked by kainate. This study sought to pharmacologically boost the expression of heat shock proteins (HSP) to protect spinal motoneurons using celastrol to investigate if the rat spinal cord can upregulate HSP as neuroprotective mechanism. Despite its narrow range of drug safety in vitro, celastrol was not toxic to the rat spinal cord at 0.75 μM concentration and enhanced the expression of HSP70 by motoneurons. When celastrol was applied either before or after kainate, the number of dead motoneurons was significantly decreased and the nuclear localization of the cell death biomarker AIF strongly inhibited. Nevertheless, electrophysiological recording showed that protection of lumbar motor networks by celastrol was rather limited as reflex activity was impaired and fictive locomotion largely depressed, suggesting that functional deficit persisted, though the networks could express slow rhythmic oscillations. While our data do not exclude further recovery at later times beyond the experimental observations, the present results indicate that the upregulated expression of HSP in the aftermath of acute injury may be an interesting avenue for early protection of spinal motoneurons.

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Section: Introductionsupporting

confidence: 66%

Pharmacological induction of Heat Shock Protein 70 by celastrol protects motoneurons from excitotoxicity in rat spinal cord in vitro

Petrović

Kaur

Tomljanović

et al. 2018

Eur J of Neuroscience

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“…The prevailing explanation for the characteristic decline in LV dimensions is reduced venous return resulting from the loss of descending sympatho‐excitatory control from the rostral ventrolateral medulla (Krassioukov & Fehlings, ; Squair et al . ) as well as reduced muscle pump activity (Raymond et al . ; Faghri & Yount, ) and impaired venous compliance (Wecht et al .…”

Section: Discussionmentioning

confidence: 99%

Spinal cord injury‐induced cardiomyocyte atrophy and impaired cardiac function are severity dependent

Squair

Liu

Tetzlaff

et al. 2018

Experimental Physiology

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What is the central question of this study? How does the severity of spinal cord injury affect left ventricular mechanics, function and the underlying cardiomyocyte morphology? What is the main finding and its importance? Here, we show that severe, but not moderate, spinal cord injury causes cardiomyocyte atrophy, altered left ventricular mechanics and impaired cardiac function. The principal aim of the present study was to assess how the severity of spinal cord injury (SCI) affects left ventricular (LV) mechanics, function and underlying cardiomyocyte morphology. Here, we used different severities of T3 spinal cord contusions (MODERATE, 200 kdyn contusion; SEVERE, 400 kdyn contusion; SHAM) and combined standard echocardiography with speckle tracking analyses to investigate in vivo cardiac function and deformation (contractility) after experimental SCI in the Wistar rat. In addition, we investigated changes in the intrinsic structure of cardiac myocytes ex vivo. We demonstrate that SEVERE SCI induces a characteristic decline in LV chamber size and a reduction in in vivo LV deformation (i.e. radial strain) throughout the entire systolic portion of the cardiac cycle [25.6 ± 3.0 versus 44.5 ± 8.1% (Pre-injury); P = 0.0029]. SEVERE SCI also caused structural changes in cardiomyocytes, including decreased length [115.6 ± 7.63 versus 125.8 ± 6.75 μm (SHAM); P = 0.0458], decreased width [7.78 ± 0.71 versus 10.78 ± 1.08 μm (SHAM); P = 0.0015] and an increase in the length/width ratio [14.88 ± 0.66 versus 11.74 ± 0.89 (SHAM); P = 0.0018], which was significantly correlated with LV flow-generating capacity after SCI (i.e. stroke volume, R = 0.659; P = 0.0013). Rats with MODERATE SCI exhibited no changes in any metric versus SHAM. This is the first study to demonstrate that the severity of SCI determines the course of changes in the intrinsic structure of cardiomyocytes, which are directly related to contractile function of the LV.

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“…Patients with spinal cord damage often suffer from cardiovascular disease, a leading cause of death for these individuals [ 65 ]. Following SCI, autonomic nervous system impairment results in blood pressure and heart rate dysregulation [ 66 ].…”

Section: Role Of Inflammation and Immunity In Post-sci Complicationsmentioning

confidence: 99%

Multiple organ dysfunction and systemic inflammation after spinal cord injury: a complex relationship

Sun

Jones

Chen

et al. 2016

J Neuroinflammation

160

122

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Spinal cord injury (SCI) is a devastating event that results in significant physical disabilities for affected individuals. Apart from local injury within the spinal cord, SCI patients develop a variety of complications characterized by multiple organ dysfunction or failure. These disorders, such as neurogenic pain, depression, lung injury, cardiovascular disease, liver damage, kidney dysfunction, urinary tract infection, and increased susceptibility to pathogen infection, are common in injured patients, hinder functional recovery, and can even be life threatening. Multiple lines of evidence point to pathological connections emanating from the injured spinal cord, post-injury systemic inflammation, and immune suppression as important multifactorial mechanisms underlying post-SCI complications. SCI triggers systemic inflammatory responses marked by increased circulation of immune cells and pro-inflammatory mediators, which result in the infiltration of inflammatory cells into secondary organs and persistence of an inflammatory microenvironment that contributes to organ dysfunction. SCI also induces immune deficiency through immune organ dysfunction, resulting in impaired responsiveness to pathogen infection. In this review, we summarize current evidence demonstrating the relevance of inflammatory conditions and immune suppression in several complications frequently seen following SCI. In addition, we highlight the potential pathways by which inflammatory and immune cues contribute to multiple organ failure and dysfunction and discuss current anti-inflammatory approaches used to alleviate post-SCI complications. A comprehensive review of this literature may provide new insights into therapeutic strategies against complications after SCI by targeting systemic inflammation.

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Neuroprotection, Plasticity Manipulation, and Regenerative Strategies to Improve Cardiovascular Function following Spinal Cord Injury

Cited by 18 publications

References 75 publications

Pharmacological induction of Heat Shock Protein 70 by celastrol protects motoneurons from excitotoxicity in rat spinal cord in vitro

Pharmacological induction of Heat Shock Protein 70 by celastrol protects motoneurons from excitotoxicity in rat spinal cord in vitro

Spinal cord injury‐induced cardiomyocyte atrophy and impaired cardiac function are severity dependent

Multiple organ dysfunction and systemic inflammation after spinal cord injury: a complex relationship

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