Elsevier

Injury

Volume 43, Issue 7, July 2012, Pages 1124-1130
Injury

Neuroprotective effects of racemic ketamine and (S)-ketamine on spinal cord injury in rat

https://doi.org/10.1016/j.injury.2012.02.022Get rights and content

Abstract

Background

The aim of this study was to investigate and to compare the potential neuroprotective effects of racemic ketamine, (S)-ketamine and methylprednisolone after an experimental spinal cord injury model in rats.

Methods

Fifty-nine Wistar albino rats were divided into three main groups as acute stage (A), subacute stage (SA) and sham groups and then acute and subacute stage groups were divided into four groups regarding the used drug as control (CONT), racemic ketamine (RK), (S)-ketamine (SK) and methylprednisolone (MP) groups. A dorsal laminectomy was performed; and spinal cord injury was induced by using a temporary aneurysm clip. Four hours later from the clip compression, except those of the sham and control groups, the drugs (60 mg/kg racemic ketamine, 60 mg/kg (S)-ketamine or 30 mg/kg methylprednisolone) were administered intraperitoneally. At 72th h and 7th days of the study, the spinal cords of rats were removed from T8 level to the conus medullaris level. The specimens were and evaluated histopathologically, tissue lipid peroxidation (LPO) and myeloperoxidation (MPO) levels were measured and biochemically.

Results

The histopathological results were similar both in the acute and in the subacute stage groups. There was a statistically significant difference among all groups regarding the tissue LPO levels (p < 0.001). There was a statistically significant difference between the CONT-A group and the MP-A, RK-A and SK-A groups (p = 0.004, p < 0.001 and p = 0.007, respectively) in acute stage and between the CONT-SA group and SK-SA group (p = 0.002) in subacute stage. There was a statistically significant difference among all groups regarding the tissue MPO levels (p = 0.001). The median MPO levels were similar among acute stage groups (p = 0.057), but there was a statistical difference among subacute stage groups (p = 0.046).

Conclusion

(S)-ketamine is more effective than methylprednisolone and racemic ketamine to reduce the LPO levels in subacute stage of spinal cord injury in rats. And, it is as effective as methylprednisolone in preventing secondary spinal cord injury histopathologically.

Introduction

Traumatic spinal cord injury (SCI) is still a major clinical problem with permanent neurological deficits and secondary complications. The initial mechanical damage causing immediate cell death in the spinal cord is known as primary injury and inevitable. After primary injury, lesions greatly enlarge and worsen by secondary injury.1 Secondary injury mechanisms involve excessive release of glutamate and aspartate, intracellular calcium overload, the activation of arachidonic acid cascade, and the induction of free radical induced lipid peroxidation (LPO) which has often been suggested to be an important factor in post-traumatic neuronal degeneration.2 Although the exact mechanism is unknown, altered blood flow and changes in microvascular permeability, as well as sympathetic stimuli including norepinephrine may contribute to the development of secondary injury.3, 4, 5, 6, 7, 8

Methylprednisolone, a potent immunosupressive glucocorticoid, has beneficial effects in improving neurologic recovery when administered within 8 h after the onset of the SCI. It reduces the progression of oedema and has antioxidant and cell membrane stabilising properties.9 Taoka et al. showed that methylprednisolone reduces the severity of SCI by inhibiting activated leucocytes.10 The neuroprotective effect of methylprednisolone can be related to an interaction with the cytokine cascade and decrease in the production TNF-α and IL-6.11 Although the precise mechanism of action of methylprednisolone is not completely understood, it is the most commonly used agent as a standard care for SCI.12, 13 While it is effective in experimental and clinical studies, the use of high-dose corticosteroids has recently been questioned.14, 15 Therefore, an increasing number of studies now focus on potential neuroprotective agents against secondary injury.3, 4, 5, 6, 7, 8

Ketamine is an anaesthetic agent, which inhibits N-methyl-d-aspartate (NMDA) receptors. Ketamine has two enantiomers because of its molecular structure: S(+) ketamine and R(−) ketamine.16 Several experimental studies suggest that ketamine may be capable of producing neuroprotective effects.17, 18, 19, 20, 21 Racemic ketamine inhibits nitric oxide synthesis and nitric oxide-dependent cyclic guanosine monophosphate production stimulated by glutamate and glutamate analogues in primary culturs of cortical neurons and glia.19 This ketamine-induced inhibition of glutamate receptors may contribute to cellular protection against ischemic injury. The data obtained from experimental studies emphasize that the salutary actions of ketamine in models of neuronal injury appear to be stereoselective.17, 18, 21, 22 While racemic and (S)- but not (R)-ketamine attenuate injury after glutamate exposure or axonal transection in rat hippocampal neurons in vitro, neuroregenerative effects appear only with (S)-ketamine.17 Ketamine may also decrease the severity of neuronal damage by interfering with the inflammatory response to ischemia. Ketamine suppresses lipopolysaccharide-induced TNF-α, IL-6, and IL-8 production and inhibits neutrophil adhesion to the endothelium in vitro.23 Ketamine also enhances neurologic outcome concomitant with reduction in plasma catecholamine concentrations in a rat model of incomplete cerebral ischemia.24 Additionally, it has been shown that, ketamine protects various tissues from ischemia/reperfusion (I/R) injury, such as myocardium, skeletal muscle, intestinal tissue, kidney and reduces malondialdehyde levels, a specific marker of LPO, in these tissues.25, 26, 27, 28

To the best of our knowledge, there has been no research on the neuroprotective effects of ketamine-enantiomers after SCI. This study was designed to investigate and to compare the possible neuroprotective effects of racemic ketamine, (S)-ketamine and methylprednisolone after an experimental SCI model in rats.

Section snippets

Materials

The investigation was conducted in accordance with the Guide for Care and Use of Laboratory Animals published by US National Institutes of Health (NIH Publication no. 85-23, revised 1996) and approval has been received from the Animal Ethics Committee of The Ministry of Health Ankara Research and Training Hospital.

Racemic ketamine (Ketalar®, Pfizer Inc., USA), (S)-ketamine (Ketanest® S, Pfizer Inc., USA), and methylprednisolone (Depo-medrol®, Pharmacia & Upjohn Company, Kalamazoo, USA) were

Histopathological analysis

Spinal cord sections from the sham group in 72 h after operation had normal histological structure (Fig. 2). There was a statistically significant difference among all groups regarding histopathological grades (X2 = 73.493, p < 0.001), and this significance was result from the SHAM group. There was a statistically significant difference neither among acute stage groups nor among the subacute stage groups regarding the histopathological grades (X2 = 6.396, p = 0.380; and X2 = 2.250, p = 0.522, respectively).

Histopathological evaluation

In this study, there was mild to severe degree of neuronal destruction with demyelination and cavity formation in all acute stage groups except the SHAM group (Fig. 2). Grade III degeneration was lowest with a 14.3% frequency in SK-A group (Table 1). Because, there was not a statistical significance among acute stage groups regarding the histopathological grades, it can be said that racemic ketamine and (S)-ketamine are as effective as methyprednisolone to reduce the severity of neuronal damage

Conclusions

We have three major observations in this experimental study:

  • (1)

    Both racemic ketamine and (S)-ketamine reduce LPO levels in the acute stage of SCI in rat. But only the effect of (S)-ketamine prolongs to the subacute stage.

  • (2)

    Only racemic ketamine reduces MPO levels originating from the lysosomes of inflammatory cells in the acute stage of SCI in rat. But this protective effect does not prolong to the subacute stage.

  • (3)

    Because, there was not a statistically significant difference among the study groups,

Conflict of interest statement

The authors declare that they have no conflict of interest.

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