Antithrombin reduces the ischemia/reperfusion-induced spinal cord injury in rats by attenuating inflammatory responses

Hirose, K; Okajima, Kenji; Taoka, Yuji; Uchiba, Mitsuhiro; Nakano, Kan Yu; Utoh, Junichi; Kitamura, Nobuo

doi:10.1160/th03-06-0385

Cited by 29 publications

(17 citation statements)

References 42 publications

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“…It is especially surprising that MPSSmediated suppression of IL-6 was not associated with an improved motor score, because changes of this cytokine have been associated with a parallel modulation of injury in experimental SCI (40,41). It should be noted that, in contrast to MPSS, other experimental treatments attenuating the acute inflammatory response, e.g., the hydroxymethylglutaryl CoA reductase inhibitor atorvastatin (42) or antithrombin (43), among others, show significant benefits in preclinical models.…”

Section: Discussionmentioning

confidence: 99%

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.

115

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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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Section: Discussionmentioning

confidence: 99%

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.

115

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“…30 Restoring capillary flow either directly or by reducing inflammation in these flow restricted microregions might prove beneficial during reperfusion. 31,32 There is evidence for a heterogeneous distribution of brain injury during ischemia and reperfusion. 11 This heterogeneous pattern of cerebral O 2 supply/consumption balance during reperfusion might be related to the initial ischemic damage or to reperfusion injury.…”

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confidence: 99%

Cerebral Ischemia and Reperfusion Increases the Heterogeneity of Local Oxygen Supply/Consumption Balance

Weiss

Grayson

Liu

et al. 2013

Stroke

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Background and Purpose-After cerebral vessel blockage, local blood flow and O 2 consumption becomes lower and oxygen extraction increases. With reperfusion, blood flow is partially restored. We examined the effects of ischemia-reperfusion on the heterogeneity of local venous oxygen saturation in rats in order to determine the pattern of microregional O 2 supply/consumption balance in reperfusion. Methods-The middle cerebral artery was blocked for 1 hour using the internal carotid approach in 1 group (n=9) and was then reperfused for 2 hours in another group (n=9) of isoflurane-anesthetized rats. Regional cerebral blood flow was determined using a C 14 -iodoantipyrine autoradiographic technique. Regional small vessel arterial and venous oxygen saturations were determined microspectrophotometrically. Results-After 1 hour of ischemia, local cerebral blood flow (92±10 versus 50±10 mL/min per 100 g) and O 2 consumption (4.5±0.6 versus 2.7±0.5 mL O 2 /min per 100 g) decreased compared with the contralateral cortex. Oxygen extraction increased (4.7±0.2 versus 5.4±0.3 mL O 2 /100 mL) and the variation in small vein (20-60 μm) O 2 saturation as determined by its coefficient of variation (=100×SD/mean) increased (5.5 versus 10.5). With 2 hours of reperfusion, the blood flow decrement was reduced and O 2 consumption returned to the value in the contralateral cortex. Oxygen extraction remained elevated in the ischemic-reperfused area and the coefficient of variation of small vein O 2 saturation increased further (17.3). Conclusions-These

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“…After the wound was closed, animals were returned to the cages and allowed to recover. This technique creates spinal cord injury in the lumbosacral segment, which causes paraplegia in a reproducible manner (Hirose et al, 2000(Hirose et al, , 2004.…”

Section: Methodsmentioning

confidence: 99%

“…Animals that never recovered completely from the surgery and then died within 24 h after reperfusion were excluded from the analyses. The motor function of rats was assessed in a masked manner using the Tarlov's scale and the inclined-plane test as described previously (Hirose et al, 2000(Hirose et al, , 2004. The Tarlov's motor scale is as follows: 0, no voluntary movement (complete paraplegia); 1, perceptible movement at the joint; 2, good joint mobility but inability to stand; 3, ability to stand and walk; and 4, complete recovery.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, it has been shown that neutrophils play a central role in development of the pathologic condition of ischemia/reperfusion (I/ R)-induced tissue injury (Bednar et al, 1997). We previously demonstrated that physiologic anticoagulants, such as activated protein C (Hirose et al, 2000) and antithrombin (Hirose et al, 2004), reduce I/R-induced SCI in rats by inhibiting neutrophil activation.…”

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confidence: 99%

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Atrial Natriuretic Peptide Reduces Ischemia/Reperfusion-Induced Spinal Cord Injury in Rats by Enhancing Sensory Neuron Activation

Nakayama

Harada²,

Asano³

et al. 2007

The Journal of Pharmacology and Experimental Therapeutics

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We recently demonstrated that calcitonin gene-related peptide (CGRP) released from sensory neurons reduces spinal cord injury (SCI) by inhibiting neutrophil activation through an increase in the endothelial production of prostacyclin (PGI 2 ). Carperitide, a synthetic ␣-human atrial natriuretic peptide (ANP), reduces ischemia/reperfusion (I/R)-induced tissue injury. However, its precise therapeutic mechanism(s) remains to be elucidated. In the present study, we examined whether ANP reduces I/R-induced spinal cord injury by enhancing sensory neuron activation using rats. ANP increased CGRP release and cellular cAMP levels in dorsal root ganglion neurons isolated from rats in vitro. The increase in CGRP release induced by ANP was reversed by pretreatment with capsazepine, an inhibitor of vanilloid receptor-1 activation, or with (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3Ј,2Ј,1Ј-kl]pyrrolo[3,4-i][1,6]-benzodiazocine-10-carboxylic acid hexyl ester (KT5720), an inhibitor of protein kinase A (PKA), suggesting that ANP might increase CGRP release from sensory neurons by activating PKA through an increase in the cellular cAMP level. Spinal cord ischemia was induced in rats using a balloon catheter placed in the aorta. ANP reduced mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. ANP significantly enhanced I/R-induced increases in spinal cord tissue levels of CGRP and 6-keto-prostaglandin F 1␣ . a stable metabolite of PGI 2 . ANP inhibited I/R-induced increases in spinal cord tissue levels of tumor necrosis factor and myeloperoxidase. Pretreatment with 4Ј-chloro-3-methoxycinnamanilide (SB366791), a specific vanilloid receptor-1 antagonist, and indomethacin reversed the effects of ANP. These results strongly suggest that ANP might reduce I/R-induced SCI in rats by inhibiting neutrophil activation through enhancement of sensory neuron activation.

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Antithrombin reduces the ischemia/reperfusion-induced spinal cord injury in rats by attenuating inflammatory responses

Cited by 29 publications

References 42 publications

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

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

Cerebral Ischemia and Reperfusion Increases the Heterogeneity of Local Oxygen Supply/Consumption Balance

Atrial Natriuretic Peptide Reduces Ischemia/Reperfusion-Induced Spinal Cord Injury in Rats by Enhancing Sensory Neuron Activation

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