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Experimental neoplastic spinal cord compression: effect of ketamine and MK-801 on edema and prostaglandins
T Siegal1, T Siegal, E Shohami
1Department of Neurology, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Abstract:
Excitotoxin-induced neural tissue damage is mediated through specific receptors. We studied the in vivo effect of two selective N-methyl-D-aspartate receptor antagonists on the compressed spinal cord segments of rats harboring a thoracolumbar epidural tumor. The effect of a single intramuscular treatment with either MK-801 (3 mg/kg) or ketamine (110 mg/kg) given at the onset of paraplegia was evaluated 30 hours later. In saline-treated control animals, significant increases in water content, prostaglandin E2, and 6-keto-prostaglandin F1 alpha were evident. Treatment with either agent resulted in a normal water content in the compressed segments but had no effect on prostaglandin synthesis. Evaluation of the effect of treatment on the course of the disease required dose reduction by 45% for ketamine and by 30% for MK-801, to avoid the excessive sedative effect. Treatment was started at the first appearance of neurological dysfunction (Grade 1) and continued to paraplegia (Grade 5). The mean time interval between Grades 1 and 5 was 2.1 +/- 0.3 days in saline-treated control animals, and it was not significantly altered by either ketamine or MK-801. Our study indicates that in the end stage of epidural compression, when ischemia is present, excitotoxins probably participate in the evolution of a cytotoxic edema. It is suggested that treatment initiated at the onset of paraplegia may still reduce the cytotoxic edema, but its potential clinical value requires further investigations.
Insights
Selective N-methyl-D-aspartate receptor antagonists reduced cytotoxic edema in rats with spinal cord compression. However, these treatments did not alter disease progression or prostaglandin synthesis.
Area of Science:
- Neuroscience
- Pharmacology
- Spinal Cord Injury Research
Background:
- Excitotoxicity contributes to neural tissue damage via specific receptors.
- Spinal cord compression from tumors can lead to significant neurological deficits.
- N-methyl-D-aspartate (NMDA) receptors play a role in excitotoxic injury.
Purpose of the Study:
- To investigate the in vivo effects of NMDA receptor antagonists on spinal cord segments compressed by epidural tumors in rats.
- To evaluate the impact of MK-801 and ketamine on cytotoxic edema and prostaglandin synthesis following spinal cord compression.
- To assess the potential of these antagonists in mitigating neurological damage and disease progression.
Main Methods:
- Rats with thoracolumbar epidural tumors underwent spinal cord compression.
- Single intramuscular treatments of MK-801 or ketamine were administered at the onset of paraplegia.
- Evaluations included water content, prostaglandin E2, and 6-keto-prostaglandin F1 alpha levels 30 hours post-treatment.
- Neurological function was graded, and time to paraplegia was recorded.
Main Results:
- Saline-treated controls showed increased water content and prostaglandin levels in compressed segments.
- MK-801 and ketamine normalized water content but did not affect prostaglandin synthesis.
- Dose reductions were necessary for ketamine (45%) and MK-801 (30%) due to sedation.
- Neither antagonist significantly altered the time course from initial dysfunction to paraplegia.
Conclusions:
- Excitotoxins likely contribute to cytotoxic edema in the late stages of spinal cord compression with ischemia.
- Treatment initiated at the onset of paraplegia may reduce cytotoxic edema.
- Further research is needed to determine the clinical utility of NMDA receptor antagonists for spinal cord injury.