Is Indomethacin Harmful in Spinal Cord Injury Treatment?

Güven, Mehmet; Çırak, Bayram; Yüceer, Nurullah; Ozveren, Faik

doi:10.1159/000028860

Cited by 12 publications

(7 citation statements)

References 61 publications

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“…1a). Interestingly, indomethacin, an NSAID that has been tested in several SCI studies with minimal benefit (Guven et al, 1999;Pantovic et al, 2005;Schwab et al, 2004), does not block Rho signaling in our in vitro studies.…”

Section: Ibuprofen Blocks Rho-mediated Signalingmentioning

confidence: 76%

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Wang

Budel

Baughman

et al. 2009

Journal of Neurotrauma

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The GTP-binding protein RhoA regulates microfilament dynamics in many cell types and mediates the inhibition of axonal regeneration by myelin and chondroitin sulfate proteoglycans. Unlike most other nonsteroidal anti-inflammatory drugs, ibuprofen suppresses basal RhoA activity (Zhou et al., 2003). A recent report suggested that ibuprofen promotes corticospinal axon regeneration after spinal cord injury (Fu et al., 2007). Here, we confirm that ibuprofen reduces ligand-induced Rho signaling and myelin-induced inhibition of neurite outgrowth in vitro. Following 4 weeks of subcutaneous administration of ibuprofen, beginning 3 days after spinal cord contusion, animals recovered walking function to a greater degree, with twice as many rats achieving a hind limb weight-bearing status. We examined the relative role of tissue sparing, axonal sprouting, and axonal regeneration in the action of ibuprofen. Histologically, ibuprofen-treated animals display an increase in spared tissue without an alteration in astrocytic or microglial reaction. Ibuprofen increases axonal sprouting from serotonergic raphespinal axons, and from rostral corticospinal fibers in the injured spinal cord, but does not permit caudal corticospinal regeneration after spinal contusion. Treatment of mice with complete spinal cord transection demonstrates long-distance raphespinal axon regeneration in the presence of ibuprofen. Thus, administration of ibuprofen improves the recovery of rats from a clinically relevant spinal cord trauma by protecting tissue, stimulating axonal sprouting, and allowing a minor degree of raphespinal regeneration.

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Section: Ibuprofen Blocks Rho-mediated Signalingmentioning

confidence: 76%

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Wang

Budel

Baughman

et al. 2009

Journal of Neurotrauma

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“…Being an inhibitor of COX, it inhibits formation of prostaglandins and thromboxanes. 34 Several reports have been published on indomethacin as a PLA 2 inhibitor in human neutrophils, 34,35 but the expected decrease in AA release has never been observed in humans. 34 Recent reports have shown that indomethacin inhibits proteinases, in particular cathepsin B and calpain, and attenuates degradation of basic myelin and neurofilament proteins in the spinal cord.…”

Section: 30mentioning

confidence: 99%

“…34 Several reports have been published on indomethacin as a PLA 2 inhibitor in human neutrophils, 34,35 but the expected decrease in AA release has never been observed in humans. 34 Recent reports have shown that indomethacin inhibits proteinases, in particular cathepsin B and calpain, and attenuates degradation of basic myelin and neurofilament proteins in the spinal cord. 36 Additionally, indomethacin reduces cerebral blood flow by preventing the formation of cerebral vasodilating prostaglandins, inducing hyperventilation and vasoconstriction of cerebral vessels.…”

Section: 30mentioning

confidence: 99%

“…According to Guven et al, 34 the administration of 3.0 mg/kg indomethacin immediately after spinal injury induced significant lipid peroxidation and led Guven et al 34 to suggest the possibility that early post-traumatic indomethacin treatment may be harmful in spinal cord injury. However, when they examined the early postinjury period, the detected changes were rather small.…”

Section: 30mentioning

confidence: 99%

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Effect of indomethacin on motor activity and spinal cord free fatty acid content after experimental spinal cord injury in rabbits

et al. 2005

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Study design: Determination of functional and biochemical parameters as well as the effect of specific therapies on these parameters, in the experimental model of neurotrauma in rabbits. Objective: To assess the effect of indomethacin (0.1-3.0 mg/kg for 9 days), a potent inhibitor of endogenous prostaglandin synthesis, on the motor activity and on the spinal cord tissue concentration of free palmitic, stearic, oleic, arachidonic and docosahexaenoic acids in an experimental model of a spinal cord injury in rabbits. Setting: Faculty of Medicine, University of Rijeka, Croatia. Methods: The animals were randomly divided into nine experimental groups, four sham and/ or vehicle-treated and five indomethacin-treated (including one sham-operated and four injured groups). Laminectomy was followed by contusion of the spinal cord, using a modification of the technique of Albin. Motor activity was controlled daily during the course of the next nine postoperation days and scored using Tarlov's system. Spinal cord samples from the impact injury site were taken and frozen in liquid nitrogen. Total lipids were isolated and purified by a modification of the method of Folch. Free fatty acids (FFAs) were separated from the total lipid extract by preparative thin-layer chromatography, converted to the corresponding methyl esters and identified using gas chromatography, using nonadecanoic acid as the internal standard. Results: The concentrations of all analysed free fatty acids were increased in the spinal cord after neurotrauma, in comparison to control tissues. Treatment of injured rabbits with indomethacin resulted in a significant decrease in spinal cord FFAs and exerted a positive effect on neurotrauma-induced motor impairment. Conclusion: These results indicate a mechanism whereby indomethacin protects rabbits from the sequellae of neuronal damage caused by trauma, and suggests that it may be beneficial in the therapy of neurotrauma.

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“…These findings are in contrast to the observations of Guth et al [85], who found that indomethacin did not affect cavity formation. Moreover, indomethacin was thought to be harmful in SCI treatment by inducing lipid peroxidation to a significant degree [87]. Since SCI results in concomitant tissue necrosis and wound healing, a goal of neuroprotective therapy is to regulate the dynamic balance between these destructive and reparative processes.…”

Section: Anti-inflammatory Interventionsmentioning

confidence: 99%

Actual Aspects of Treatment Strategies in Spinal Cord Injury

Mautes

Steudel

2002

European Journal of Trauma

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Treatment in the Acute Phase: Processes of secondary injury significantly enlarge tissue damage after spinal cord injury (SCI). Ischemic and inflammatory processes play a major role. Animal models have shown that in the acute stage, there are numerous possibilities of preventing secondary tissue damage after SCI including barbiturate coma, hypothermia, tissue oxygenation, administration of antioxidants and neuropeptides, as well as maintenance of the ionic homeostasis and balance between anti-and pro-inflammatory strategies. Only methylprednisolone (MP) has given consistent enough results in clinical trials to justify its wide use today, although the effects are small and the mechanism of action (radical scavenger, anti-inflammatory, anti-edema) is not understood. The role of inflammation is also far from being clear; damaging as well as positive, tissue-protecting effects are described and probably occur simultaneously. Treatment in the Chronic Phase: In the chronic stage, strategies to promote axonal regeneration and compensatory sprouting of fibers include support of neuronal survival, promotion of axonal growth by the use of antibodies to block white matter inhibitors or influencing the surrounding through application of neurotrophins or substances that minimize scar formation or bridge the damaged tissue through transplantation. Although several of these procedures have yielded exciting results in animal models, none of them has reached the level of clinical trials yet.

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Is Indomethacin Harmful in Spinal Cord Injury Treatment?

Cited by 12 publications

References 61 publications

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Effect of indomethacin on motor activity and spinal cord free fatty acid content after experimental spinal cord injury in rabbits

Actual Aspects of Treatment Strategies in Spinal Cord Injury

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