Memantine improves outcomes after repetitive traumatic brain injury

Abstract

Repetitive mild traumatic brain injury (rmTBI; e.g., sports concussions) is common and results in significant cognitive impairment. Targeted therapies for rmTBI are lacking, though evidence from other injury models indicates that targeting N-methyl-d-aspartate (NMDA) receptor (NMDAR)-mediated glutamatergic toxicity might mitigate rmTBI-induced neurologic deficits. However, there is a paucity of preclinical or clinical data regarding NMDAR antagonist efficacy in the rmTBI setting. To test whether NMDAR antagonist therapy improves outcomes after rmTBI, mice were subjected to rmTBI injury (4 injuries in 4days) and randomized to treatment with the NMDA antagonist memantine or with vehicle. Functional outcomes were assessed by motor, anxiety/impulsivity and mnemonic behavioral tests. At the synaptic level, NMDAR-dependent long-term potentiation (LTP) was assessed in isolated neocortical slices. At the molecular level, the magnitude of gliosis and tau hyper-phosphorylation was tested by Western blot and immunostaining, and NMDAR subunit expression was evaluated by Western blot and polymerase chain reaction (PCR). Compared to vehicle-treated mice, memantine-treated mice had reduced tau phosphorylation at acute time points after injury, and less glial activation and LTP deficit 1 month after injury. Treatment with memantine also corresponded to normal NMDAR expression after rmTBI. No corresponding protection in behavior outcomes was observed. Here we found NMDAR antagonist therapy may improve histopathological and functional outcomes after rmTBI, though without consistent corresponding improvement in behavioral outcomes. These data raise prospects for therapeutic post-concussive NMDAR antagonism, particularly in athletes and warriors, who suffer functional impairment and neurodegenerative sequelae after multiple concussions.

Modeling sports‐related mild traumatic brain injury in animals—A systematic review

“…Factors that influenced p‐tau development in the assessed studies were the total number of impacts and length of time between impacts. Where a greater number of impacts were administered, p‐tau was demonstrated in the acute phase (Mei et al, ), and at times also remained at high levels even at delayed follow‐up (Briggs et al, ; Kane et al, ). Following single impacts, p‐tau expression was less likely to be seen (Namjoshi et al, ).…”

Novel therapies for combating chronic neuropathological sequelae of TBI

“…For example, tau transgenic mice (uninjured) treated with epothilone D showed attenuated tau pathology and improved cognition compared to wild type mice (Brunden et al, 2010;Zhang et al, 2012a). Interestingly, memantine administered after rmTBI in adult C57Bl6 mice reduced markers of tau phosphorylated at Thr231 (Mei et al, 2018). Other studies report p-tau-reducing effects of antioxidants (Du et al, 2016), PP2A activation (Shultz et al, 2015;Tan et al, 2016), DHA treatment (Begum et al, 2014), endocannabinoids (Zhang et al, 2015), and JNK inhibition (Tran et al, 2012).…”

Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here?

“…This mechanism of NMDA-mediated damage has been shown to occur in several CNS injury models, including TBI and stroke ( 81 ). In animal models of TBI, memantine treatment decreased the accumulation of phosphorylated tau proteins in the cortical tissue at early, although not chronic time points (up to 30 days post-injury), and suppressed microglial activation ( 82 ). A similar study showed that memantine decreased cerebral infarct area, increased neuronal survival in the perilesional hemisphere, and decreased levels of microgliosis and astrogliosis ( 83 ).…”