Neuroprotective effects of racemic ketamine and (S)-ketamine on spinal cord injury in rat
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.
References (37)
- et al.
Dose-dependent neuroprotective effects of melatonin on experimental spinal cord injury in rats
Surg Neurol
(2005) - et al.
Neuroprotective effects of novel NMDA antagonist Gacylidine, after experimental contusive spinal cord injury in adult rats
Brain Res
(2000) - et al.
The neuroprotective effect of dexmedetomidine in hippocampus of rabbits after subarachnoid hemorrhage
Surg Neurol
(2009) - et al.
Methylprednisolone treatment in acute spinal cord injury: the myth challenged through a structured analysis of published literature
Spine J
(2006) - et al.
Neuroprotection of S(−) ketamine isomer in global forebrain ischemia
Brain Res
(2001) - et al.
The effects of NMDA receptor antagonists over intestinal ischemia/reperfusion injury in rats
Eur J Pharmacol
(2009) - et al.
Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction
Anal Biochem
(1979) - et al.
Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms
J Neurosurg
(1991) - et al.
The effect of duration of compression on lipid peroxidation after experimental spinal cord injury
Neurosurg Rev
(1998) - et al.
Does dexmedetomidine reduce secondary damage after spinal cord injury? An experimental study
Eur Spine J
(2009)
Comparison of the effects of melatonin and methylprednisolone in experimental spinal cord injury
J Neurosurg
Dexmedetomidine improves neurologic outcome from incomplete ischemia in rat
Anesthesiology
Histologic characterization of acute spinal cord injury treated with intravenous methylprednisolone
Orthop Trauma
Methylprednisolone reduces spinal cord injury in rats without affecting tumor necrosis factor-alpha production
J Neurotrauma
Methylprednisolone inhibits production of interleukin-1beta and interleukin-6 in the spinal cord following compression injury in rats
J Neurosurg Anesthesiol
Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-year follow-up data. Results of the Second National Acute Spinal Cord Injury Study
J Neurosurg
Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow-up data. Results of the Third National Acute Spinal Cord Injury randomized controlled trial
J Neurosurg
Steroids and spinal cord injury: revisiting the NASCIS 2 and NASCIS 3 trials
J Trauma
Cited by (20)
Protecting the injured central nervous system: Do anesthesia or hypothermia ameliorate secondary injury?
2023, Experimental NeurologySubanesthetic dose of S-ketamine improved cognitive dysfunction via the inhibition of hippocampal astrocytosis in a mouse model of post-stroke chronic stress
2023, Journal of Psychiatric ResearchCitation Excerpt :Interestingly, our results also highlight that the LTP was impaired after MCAO + CRS exposure, which is consistent with previously published studies (Zhong et al., 2020; Kwon et al., 2021). S-ketamine has been reported to not only significantly reduce depression-like symptoms in treatment-resistant depression (Ruberto et al., 2020) but also exhibit excellent neuroprotective effects against ischemia/reperfusion injury (Kose et al., 2012). Previous studies have reported that ketamine administration significantly ameliorated surgical treatment-associated cognitive dysfunction in clinical practice and animal models (Li et al., 2022; Hudetz et al., 2009).
Effects of thoracic paravertebral block combined with s-ketamine on postoperative pain and cognitive function after thoracoscopic surgery
2022, HeliyonCitation Excerpt :As a dextroform of the traditional analgesic-sedative ketamine, s-ketamine has a more substantial analgesic effect and fewer adverse effects. Subanaesthetic doses of s-ketamine can reduce acute opioid tolerance, inhibit nociceptive hypersensitivity, and relieve acute postoperative pain [6, 7]. The combined application of the two techniques is consistent with the Enhanced recovery after surgery (ERAS) multimodal analgesia concept; however, few studies have explored the combined application of these techniques and predominantly focused on changes in cognitive function following surgery.
Ketamine; history and role in anesthetic pharmacology
2022, NeuropharmacologyCitation Excerpt :Ket has been reported to produce neuroprotective actions against spinal cord ischemia (Yu et al., 2008) and compression (Kose et al., 2012) or contusion-induced (Tang et al., 2015) injury in rats or rabbits. Kose and colleagues (Kose et al., 2012) compared the neuroprotective effects of racemic Ket, S(+)Ket and methylprednisolone in spinal compression injury in rats. Spinal injury was evaluated biochemically using tissue lipid peroxidation (LPO) and myeloperoxidase (MPO) levels.
Evaluation of the analgesic effect of fentanyl–ketamine and fentanyl–lidocaine constant rate infusions in isoflurane-anesthetized dogs undergoing thoracolumbar hemilaminectomy
2021, Veterinary Anaesthesia and AnalgesiaCitation Excerpt :In humans undergoing spinal surgery, administration of perioperative ketamine resulted in decreased postoperative opioid requirements and pain scores (Pendi et al. 2018) and, in another study, reduced neuropathic pain from acute spinal cord injury (Kim et al. 2013). Ketamine was beneficial in models of spinal cord injury in rats by reducing lipid peroxidation and preventing neuronal degeneration (Kose et al. 2012). In the present study, dogs administered perioperative ketamine had similar requirements for rescue analgesia compared with dogs administered lidocaine.