Time-Dependent Long-Term Effect of Memantine following Repetitive Mild Traumatic Brain Injury.

Area of Science:

• Neuroscience
• Neurology
• Pharmacology

Background:

• Repetitive mild traumatic brain injury (rmTBI) leads to acute and chronic symptoms, with limited therapeutic options.
• N-methyl-D-aspartate receptor (NMDAR) blockade is a potential strategy to mitigate post-injury excitotoxicity.
• Previous studies suggest immediate memantine treatment improves acute outcomes after rmTBI.

Purpose of the Study:

• To determine if acute memantine treatment offers long-term benefits after rmTBI.
• To investigate the efficacy of delayed memantine treatment following rmTBI.
• To assess the impact of treatment timing on behavioral and neuropathological outcomes.

Main Methods:

• Animals were subjected to rmTBI using a weight drop model with rotational acceleration.
• Animals were randomized to receive memantine treatment immediately, 3 months, or 6 months post-injury.
• Behavioral assessments were conducted at 1, 4, and 7 months; neuropathological outcomes were analyzed at 7 months.

Main Results:

• Chronic behavioral deficits (anxiety, motor coordination, spatial learning) and neuropathology (neuroinflammation, tau phosphorylation) were observed post-rmTBI.
• Memantine treatment, initiated immediately or 6 months post-injury, demonstrated greater rescue of microglial neuroinflammation compared to vehicle or 3-month treatment.
• A small but durable effect of memantine was observed in mild concussive injuries, particularly concerning neuroinflammation.

Conclusions:

• Memantine treatment timing influences its efficacy in mitigating rmTBI-induced neuroinflammation and behavioral changes.
• Immediate or delayed (6-month) memantine administration may offer protective effects against chronic consequences of rmTBI.
• Memantine alone may be insufficient for comprehensive rmTBI treatment, advocating for multi-therapy approaches with consideration for treatment timing.