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

Repetitive mild traumatic brain injury (rmTBI, e.g. sports concussions) may be associated with both acute and chronic symptoms and neurological changes. Despite the common occurrence of these injuries, therapeutic strategies are limited. One potentially promising approach is N-methyl-d-aspartate receptor (NMDAR) blockade to alleviate the effects of post-injury glutamatergic excitotoxicity. Initial preclinical work using the NMDAR antagonist, memantine, suggests that immediate treatment following rmTBI improves a variety of acute outcomes. It remains unclear 1) whether acute memantine treatment has long-term benefits and 2) whether delayed treatment following rmTBI is beneficial, which are both clinically relevant concerns. To test this, animals were subjected to rmTBI via a weight drop model with rotational acceleration (five hits in five days) and randomized to memantine treatment either immediately, three-months, or six-months post-injury, with a treatment duration of one month. Behavioral outcomes were assessed at one-, four-, and seven-months post-injury. Neuropathological outcomes were characterized at seven-months post-injury. We observed chronic changes in behavior (anxiety-like behavior, motor coordination, spatial learning and memory), as well as neuroinflammation (microglia, astrocytes) and tau phosphorylation (T231). Memantine treatment, either immediately or six-months post-injury, appears to confer greater rescue of neuroinflammatory changes (microglia) than vehicle or treatment at the three-month time point. Although memantine is already being prescribed chronically to address persistent symptoms associated with rmTBI, this study represents the first evidence of which we are aware to suggest a small, but durable effect of memantine treatment in mild, concussive injuries. This effect suggests that memantine, while potentially beneficial, is insufficient to treat all aspects of rmTBI alone, and should be combined with other therapeutic agents in a multi-therapy approach, with attention given to the timing of treatment.