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NBQX treatment improves mitochondrial function and reduces oxidative events after spinal cord injury
Xiaojun Mu1, Robert D Azbill, Joe E Springer
1Department of Anatomy, Center for Spinal Cord and Brain Injury Research, University of Kentucky Medical Center, Lexington, Kentucky 40536-0084, USA.
Abstract:
The purpose of this study was to examine the effects of inhibiting ionotropic glutamate receptor subtypes on measures of oxidative stress events at acute times following traumatic spinal cord injury (SCI). Rats received a moderate contusion injury and 15 min later were treated with one of two doses of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzol[f]quinoxaline-7-sulfonamide disodium (NBQX), MK-801, or the appropriate vehicle. At 4 h following injury, spinal cords were removed and a crude synaptosomal preparation obtained to examine mitochondrial function using the MTT assay, as well as measures of reactive oxygen species (ROS), lipid peroxidation, and glutamate and glucose uptake. We report here that intraspinal treatment with either 15 or 30 nmol of NBQX improves mitochondrial function and reduces the levels of ROS and lipid peroxidation products. In contrast, MK-801, given intravenously at doses of 1.0 or 5.0 mg/kg, was without effect on these same measures. Neither drug treatment had an effect on glutamate or glucose uptake, both of which are reduced at acute times following SCI. Previous studies have documented that drugs acting on non-N-methyl-D-aspartate (NMDA) receptors exhibit greater efficacy compared to NMDA receptor antagonists on recovery of function and tissue sparing following traumatic spinal cord injury. The results of this study provide a potential mechanism by which blockade of the non-NMDA ionotropic receptors exhibit positive effects following traumatic SCI.
Insights
Inhibiting non-NMDA receptors with NBQX reduced oxidative stress after spinal cord injury (SCI) in rats. MK-801 targeting NMDA receptors showed no effect, suggesting NBQX
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Traumatic spinal cord injury (SCI) triggers oxidative stress, impacting neuronal function.
- Ionotropic glutamate receptors play a critical role in SCI pathophysiology.
- Targeting specific receptor subtypes may offer therapeutic benefits.
Purpose of the Study:
- To investigate the effects of inhibiting non-N-methyl-D-aspartate (non-NMDA) and N-methyl-D-aspartate (NMDA) receptors on oxidative stress markers post-SCI.
- To explore the potential mechanisms underlying neuroprotection in acute SCI.
Main Methods:
- Rats with moderate contusion SCI were treated with NBQX (non-NMDA antagonist) or MK-801 (NMDA antagonist) or vehicle.
- Mitochondrial function, reactive oxygen species (ROS), lipid peroxidation, and neurotransmitter uptake were assessed at 4 hours post-injury.
- MTT assay was used to evaluate mitochondrial activity.
Main Results:
- NBQX treatment significantly improved mitochondrial function and reduced ROS and lipid peroxidation.
- MK-801 treatment had no significant effect on oxidative stress markers or mitochondrial function.
- Neither drug affected glutamate or glucose uptake, which were reduced post-SCI.
Conclusions:
- Blockade of non-NMDA ionotropic receptors with NBQX demonstrates neuroprotective effects in acute SCI by mitigating oxidative stress.
- These findings suggest a mechanistic basis for the superior efficacy of non-NMDA receptor antagonists in SCI recovery.
- Targeting non-NMDA receptors represents a promising therapeutic strategy for managing acute traumatic spinal cord injury.