Memantine improves outcomes after repetitive traumatic brain injury
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 4 days) 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.
Traumatic Brain Injury Concussion Repetitive Concussion NMDAR
Zhengrong Mei Jianhua Qiu Sasha Alcon Jumana Hashim Alexander Rotenberg Yan Sun William P.Meehan Ⅲ Rebekah Mannix
Department of Pharmacy, The Third Affiliated Hospital, Guangzhou Medical University Division of Emergency Medicine,Boston Children”s Hospital;Harvard Medical School Division of Emergency Medicine,Boston Children”s Hospital Harvard Medical School;Department of Neurology, Boston Children”s Hospital Department of Neurology, Boston Children”s Hospital Division of Emergency Medicine,Boston Children”s Hospital;Harvard Medical School;The Micheli Center
国内会议
广州
英文
86-96
2017-12-16（万方平台首次上网日期，不代表论文的发表时间）