Targeting Glutamate Excitotoxicity With Memantine Modulates Glial Response and Protects Motoneurons After Spinal Root Lesion

Spinal root injuries trigger longitudinal spinal cord damage, leading to motoneuron degeneration, gliosis, and synaptic loss. Glutamate excitotoxicity through NMDA and AMPA receptor overstimulation is a key driver of this pathology, highlighting NMDA receptor antagonists as potential neuroprotective agents. Here, we evaluated the effects of memantine after unilateral L4-L6 ventral root crush (VRC) in adult C57BL/6JUnib mice. Animals received daily oral gavage of vehicle or memantine (30, 45, or 60 mg/kg) for 14 days. At 28 days post-injury, histological analysis showed that memantine reduced astrogliosis and microglial activation, while enhancing motoneuron survival (most pronounced at 45 mg/kg, p < 0.001) and preserving synaptic coverage (p < 0.01), without significant changes in VGLUT-1 or GAD65 expression. Consistently, RT-qPCR analysis revealed early upregulation of inflammatory markers (Ccr2, Itgam) in vehicle-treated mice, which was attenuated by memantine at 3-7 days post-injury (p < 0.05). These findings indicate that memantine confers neuroprotection in VRC by modulating inflammatory gene expression, mitigating gliosis, and promoting motoneuron survival, supporting its therapeutic potential in spinal cord injuries.