Spinal Cord Injury in the Rat: Treatment with Bacterial Lipopolysaccharide and Indomethacin Enhances Cellular Repair and Locomotor Function

Guth, Lloyd; Zhang, Ziyin; DiProspero, Nicholas A.; Joubin, Katherine; Fitch, Michael T.

doi:10.1006/exnr.1994.1043

Cited by 103 publications

(65 citation statements)

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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%

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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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Section: 30mentioning

confidence: 99%

“…This is first time up to our knowledge that somebody has demonstrated influence of indomethacin on FFA level and cell membrane integrity in SCI model. Guth et al 35 have discovered beneficial influence of LPS and indomethacin combination on Tarlov's score in SCI in cats. Indomethacin alone was not tested.…”

Section: 30mentioning

confidence: 99%

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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“…Such injuries trigger a characteristic selfperpetuating progression of degenerative processes that eventually result in tissue destruction and often in permanent paraplegia or quadriplegia (1)(2)(3)(4)(5). Any single therapy is not likely to be effective in attenuating these autodestructive processes because so many factors are involved (6)(7)(8).…”

mentioning

confidence: 99%

“…Combined treatment of rats with spinal cord injury with an antiinflammatory substance, indomethacin (IM), and a stimulator of cytokine secretion, bacterial lipopolysaccharide (LPS), reduced the amount of cavitation and increased cellular in-growth into the lesion to a greater extent than did treatment with either substance alone, but restoration of motor function was marginal (1). In the present study, we examined the effects of two steroids that have pleiotropic effects in neural and nonneural tissues, dehydroepiandrosterone sulfate (DHEAS) (9)(10)(11) and pregnenolone (PREG) (12)(13)(14)(15), with a view to achieving further enhancement of functional recovery after injury.…”

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confidence: 99%

Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury.

Guth

Zhang

Roberts

1994

Proc. Natl. Acad. Sci. U.S.A.

108

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Controlled compressive injury to rat spinal cord was chosen to test therapies that might attenuate the progression of tissue destruction and locomotor deficits that characteristically occur after spinal injury. A highly significant reduction of damage was achieved by immediate postinjury treatment with a combination of the following: an antlinflammatory substance, indomethacin; a stimulator of cytokine secretion, bacterial lipopolysaccharide; and the parent steroid, from which all other steroids arise, pregnenolone. This treatment reduced histopathological changes, spared tissue from secondary injury, and increased restoration of motor function.Remarkably, 11 of 16 of the animals treated with the above combination were able to stand and walk at 21 days after injury, 4 of them almost normally. The results were far superior to those obtained in controls or in animals to which the substances were given separately or in combinations of two. This approach may prove to be applicable to nervous system injury, in general, and to injury in other tissues.Development of a pharmacological therapy to attenuate consequences of traumatic spinal cord injuries has proven to be difficult. Such injuries trigger a characteristic selfperpetuating progression of degenerative processes that eventually result in tissue destruction and often in permanent paraplegia or quadriplegia (1-5). Any single therapy is not likely to be effective in attenuating these autodestructive processes because so many factors are involved (6-8). The key to attenuation of damage and eventual successful regeneration of injured spinal cord may lie in optimization of relations among affected neurons and surrounding nonneural cells by (i) stimulating release ofgrowth-promoting cytokines and lymphokines by nonneural cells while suppressing the effects ofcytotoxic ones, (ii) maintaining sufficient activity in injured neurons to achieve adequate genomic transcription for production of neuron-produced trophic substances, and (iii) facilitating coordinative processes that enable neural, metabolic, and immune systems, separately and together, to cycle freely through their operational modes to achieve structural and functional reconstitution.Combined treatment of rats with spinal cord injury with an antiinflammatory substance, indomethacin (IM), and a stimulator of cytokine secretion, bacterial lipopolysaccharide (LPS), reduced the amount of cavitation and increased cellular in-growth into the lesion to a greater extent than did treatment with either substance alone, but restoration of motor function was marginal (1). In the present study, we examined the effects of two steroids that have pleiotropic effects in neural and nonneural tissues, dehydroepiandrosterone sulfate (DHEAS) (9-11) and pregnenolone (PREG) (12-15), with a view to achieving further enhancement of functional recovery after injury. MATERIALS AND METHODSTest Animals and Surgical Procedures. Sprague-Dawley female rats (170-200 g) were anesthetized with 4% (wt/vol) chloral hydrate (400 mg/kg, intr...

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“…The consensus is that these models have to be reliable, and reproducible, which make it possible to predict outcomes and test possible therapeutic measures. These models include contusion (Allen, D'Angelo et al 1974;Basso, Beattie et al 1996), compression (Guth, Zhang et al 1994), ischemia (Kanellopoulos, Kato et al 1997), and crush (Zhang and Guth 1997;Zhang, Krebs et al 1997) injuries, which generate controlled injuries that mimic some, but not all, clinical aspects of the mechanical damage and posttraumatic ischemia that occur following human SCI. The transection (Noble and Wrathall 1989) hemisection Xu, Chen et al 1997;) model provides a controlled inj ury for unequivocally evaluating axonal regeneration strategies.…”

Section: Experimental Modelsfor Scimentioning

confidence: 99%

Gene therapy and cellular transplantation : towards a combination strategy for spinal cord injury repair.

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Spinal Cord Injury in the Rat: Treatment with Bacterial Lipopolysaccharide and Indomethacin Enhances Cellular Repair and Locomotor Function

Cited by 103 publications

References 0 publications

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

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

Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury.

Gene therapy and cellular transplantation : towards a combination strategy for spinal cord injury repair.

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