Intranasal ketamine attenuates neuronal damage and behavioral deficits following mild fluid percussion injury.

Abstract

Mild traumatic brain injury (mTBI) induces neuronal swelling, dendritic distortion, and microvascular damage. Following the initial insult, neurons undergo depolarization, triggering cortical spreading depolarization (SD) that contributes to secondary damage. Evidence indicates that N-methyl-d-aspartate (NMDA) receptor antagonists may counteract calcium imbalance and attenuate SD, thereby offering neuroprotection. In this study, we hypothesized that intranasal ketamine (INK), an NMDA receptor antagonist, could provide therapeutic benefit in mTBI. C57BL/6 mice were subjected to mild lateral fluid percussion injury (FPI) and treated intranasally with ketamine for seven days. INK-treated mice showed faster neurological recovery, reflected by improved neurological severity scores (NSS). Behavioral analyses revealed significant anxiolytic, antidepressant, and cognitive benefits, along with enhanced neuromuscular coordination and strength. Golgi-Cox staining demonstrated improved neuronal morphology, with greater dendritic length, arborization, and spine density in INK-treated mice. Histological analysis revealed fewer dead neurons in cortical and hypothalamic regions (P < 0.01). Additionally, INK significantly reduced neuroinflammatory changes in cortical and hippocampal (CA1 and CA3) regions (P < 0.05). Taken together, our results indicate that one week of low-dose INK following mTBI mitigates secondary neurodegeneration and promotes functional recovery. These findings highlight INK as a promising neuroprotective adjuvant for improving outcomes after mTBI.

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