Intranasal delivery of the NMDA receptor antagonist MK-801 attenuates ultra-acute excitotoxic neurochemical responses after concussion in rats: comparative pharmacological evaluation against ketamine

TL;DR

Intranasal MK-801 reduces harmful brain chemical surges after concussion in rats, unlike ketamine, suggesting it could be a better treatment option.

Contribution

Demonstrates that intranasal MK-801 effectively targets ultra-acute excitotoxic responses after concussion, which ketamine does not under similar conditions.

Findings

Intranasal MK-801 reduced early amino acid surges and excitotoxic index after concussion.

MK-801 improved recovery time compared to vehicle-treated animals.

Ketamine did not significantly alter neurochemical responses or recovery time.

Abstract

Concussion triggers rapid and transient surges in extracellular amino acids, largely driven by pathological activation of N-methyl-D-aspartate (NMDA) receptors. Targeting this ultra-acute excitotoxic window remains challenging, in part because many NMDA receptor antagonists exhibit slow delivery kinetics or limited brain penetrance when administered systemically. Intranasal drug delivery may help overcome these limitations by enabling faster central nervous system access. Here, we compared the capacity of intranasally administered MK-801, a high-affinity non-competitive NMDA receptor antagonist, and intranasal ketamine, a clinically used antagonist with distinct pharmacokinetic and receptor-binding properties, to modulate early neurochemical responses following experimental concussion.

Adult rats underwent a validated weight-drop concussion model followed by continuous hippocampal microdialysis. Extracellular glutamate, taurine, glycine, gamma-aminobutyric acid, glutamine, and serine were quantified every 10 min for 60 min before and after injury using high-performance liquid chromatography. Animals received intranasal MK-801 (10 mg/kg), ketamine (10 mg/kg), or vehicle immediately after concussion or sham procedures. Righting time was recorded as an early post-treatment behavioral outcome. MK-801 concentrations in plasma and brain were quantified by liquid chromatography-tandem mass spectrometry to assess central exposure. A composite excitotoxic index was calculated to summarize excitatory-inhibitory neurochemical imbalance.

Vehicle-treated concussed animals exhibited marked elevations in glutamate, taurine, and glycine within the first 10 min post-injury, accompanied by prolonged righting times. Intranasal MK-801 attenuated these ultra-acute neurochemical surges, reduced the composite excitotoxic index, and was associated with shorter righting times comparable to those observed in sham animals. In contrast, intranasal ketamine did not significantly alter amino acid dynamics or righting time under the conditions tested. MK-801 achieved measurable brain exposure following intranasal administration, with comparable brain-to-plasma ratios in sham and concussed animals.

Intranasal delivery of MK-801 modulates ultra-acute excitotoxic neurochemical disturbances following concussion in a rodent model. The lack of comparable effects with ketamine under the tested conditions highlights the importance of pharmacokinetic properties and receptor-binding kinetics when targeting the brief post-injury excitotoxic window. These findings provide proof-of-concept evidence supporting further investigation of rapid intranasal NMDA receptor antagonism as a strategy to influence early glutamatergic dysregulation after concussion.

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