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No protective effect of the NMDA antagonist memantine in experimental spinal cord injuries
M von Euler1, M Li-Li, S Whittemore
1Department of Clinical Neuroscience and Family Medicine, Karolinska Institutet, Huddinge University Hospital, Sweden.
Abstract:
We have investigated the effect of memantine, a clinically used NMDA receptor antagonist, in two experimental animals models of spinal cord injury. The lesions were laser-induced photothrombosis to induce focal spinal cord ischemia and clip compression to mimic traumatic spinal cord injury. Pre- or posttreatment of rats with a dose of memantine (20 mg/kg ip) previously shown to be neuroprotective in cerebral ischemia, failed to affect both the neurological and morphological outcome of ischemic spinal cord injury. Likewise, memantine had no effects on neurological and morphological outcome after experimental traumatic injury. In view of the regional heterogeneity of NMDA receptors, the affinity of memantine for spinal cord NMDA receptors was also determined by studying displacement of [3H] (+)-5-methyl-10,11-dihydro-5-H-dibenzo[a,d]cyclohepten-5-10-imine (MK-801) to rat and human spinal cord homogenates. We found that memantine had an affinity for NMDA receptors in the spinal cord (Ki = 0.58 microM) that was significantly lower compared to that of the cerebral cortex (Ki = 0.23 microM) and that the affinity for NMDA receptors in human spinal cord was even lower. We conclude that in view of available data, memantine should not be chosen for clinical studies on neuroprotection in spinal cord injuries and that the lack of protective effect is most likely due to insufficient affinity of memantine for spinal cord NMDA receptors.
Insights
Memantine, an NMDA receptor antagonist, did not improve outcomes in rat models of spinal cord injury. Its lower affinity for spinal cord NMDA receptors likely explains this lack of neuroprotection.
Area of Science:
- Neuroscience
- Pharmacology
- Neurosurgery
Background:
- Spinal cord injury (SCI) presents significant neurological challenges.
- NMDA receptor antagonists are explored for neuroprotection.
- Memantine is a clinically used NMDA receptor antagonist.
Purpose of the Study:
- To evaluate memantine's efficacy in experimental spinal cord injury models.
- To determine memantine's affinity for spinal cord NMDA receptors.
Main Methods:
- Two rat SCI models were used: laser-induced photothrombosis and clip compression.
- Memantine was administered pre- or post-injury.
- NMDA receptor binding affinity was assessed using [3H] MK-801 displacement assays.
Main Results:
- Memantine failed to improve neurological or morphological outcomes in both SCI models.
- Memantine exhibited lower affinity for spinal cord NMDA receptors compared to cerebral cortex.
- Affinity for human spinal cord NMDA receptors was even lower.
Conclusions:
- Memantine is unlikely to be effective for neuroprotection in spinal cord injuries.
- Insufficient binding affinity to spinal cord NMDA receptors is the probable reason for memantine's lack of efficacy.