{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T20:43:47Z","timestamp":1777927427066,"version":"3.51.4"},"reference-count":126,"publisher":"SAGE Publications","issue":"13-14","license":[{"start":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T00:00:00Z","timestamp":1719792000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurotrauma"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:p>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 pre-clinical 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 5 days) and randomized to memantine treatment immediately, 3 months, or 6 months post-injury, with a treatment duration of one month. Behavioral outcomes were assessed at 1, 4, and 7 months post-injury. Neuropathological outcomes were characterized at 7 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 6 months post-injury, appears to confer greater rescue of neuroinflammatory changes (microglia) than vehicle or treatment at the 3-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, although 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.<\/jats:p>","DOI":"10.1089\/neu.2023.0423","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T08:30:34Z","timestamp":1714120234000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Time-Dependent Long-Term Effect of Memantine following Repetitive Mild Traumatic Brain Injury"],"prefix":"10.1177","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5972-4316","authenticated-orcid":false,"given":"Masen L.","family":"Boucher","sequence":"first","affiliation":[{"name":"Division of Emergency Medicine, Boston Children\u2019s Hospital, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace","family":"Conley","sequence":"additional","affiliation":[{"name":"Invicro, Needham, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3248-7082","authenticated-orcid":false,"given":"Nicholas J.","family":"Morriss","sequence":"additional","affiliation":[{"name":"University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Ospina-Mora","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Qiu","sequence":"additional","affiliation":[{"name":"Division of Emergency Medicine, Boston Children\u2019s Hospital, Boston, Massachusetts, USA."},{"name":"Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebekah","family":"Mannix","sequence":"additional","affiliation":[{"name":"Division of Emergency Medicine, Boston Children\u2019s Hospital, Boston, Massachusetts, USA."},{"name":"Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William P.","family":"Meehan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Division of Sports Medicine, Boston Children\u2019s Hospital, Boston, Massachusetts, USA."},{"name":"The Micheli Center for Sports Injury Prevention, Waltham, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2024,7,17]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1017\/s0033291700049588"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1928.02700150029009"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001893"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1981.55.5.0708"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1990.73.6.0889"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(02)00164-3"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1080\/02699052.2022.2109749"},{"key":"e_1_3_5_9_2","volume-title":"Neuroscience","author":"Purves D","year":"2001","unstructured":"Purves D, , Augustine GJ, , Fitzpatrick D, et al. (eds). Neuroscience. 2nd edition. Sunderland, Sinauer Associates: MA; 2001.","edition":"2"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.109.002451"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2004.06.034"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2006.23.950"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23150"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2013.01.075"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.10181"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0305741101"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/cn500303k"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2015.3912"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.3233\/RNN-190909"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2018.01.140"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2017.04.018"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2015.05.017"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s007010050286"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(01)02617-8"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1089\/089771502320914679"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.980"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.csm.2010.08.003"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1097\/00042752-200107000-00011"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.290.19.2549"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1249\/mss.0b013e3180383da5"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1097\/htr.0b013e318257fbc6"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-170672"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.CON.0000429180.60095.d0"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0028-3908(99)00019-2"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14658"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23858"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.3171\/2014.7.JNS14272"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhaa157"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2017.04.017"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2019.10.016"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2016.4528"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22744-6"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1227\/NEU.0b013e318265a439"},{"key":"e_1_3_5_44_2","unstructured":"Thompson E. Mouse Brain Above; 2020; Zenodo. Available from: https:\/\/zenodo.org\/records\/3925971 [Last accessed: March18 2024]."},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.071027"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.02.014"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1037\/0033-2909.83.3.482"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0166-4328(01)00452-1"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(84)90007-4"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1162\/089976698300017908"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.857654"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/b978-0-12-802395-2.00025-0"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006247"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2013.29"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2013.36"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.11.021"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-017-0013-6"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2008.11.023"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39328-1"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-023-00601-y"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.4679"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V75.1.40.40"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1641"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2017.13"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00672"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2013.00018"},{"key":"e_1_3_5_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17204-5"},{"key":"e_1_3_5_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2020.01.006"},{"key":"e_1_3_5_69_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9658-2_2"},{"key":"e_1_3_5_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05453"},{"key":"e_1_3_5_71_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2021.0165"},{"key":"e_1_3_5_72_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlac018"},{"key":"e_1_3_5_73_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2013.00030"},{"key":"e_1_3_5_74_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0053376"},{"key":"e_1_3_5_75_2","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2016.199"},{"key":"e_1_3_5_76_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20275"},{"key":"e_1_3_5_77_2","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.20-01-00251.2000"},{"key":"e_1_3_5_78_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(19960408)367:3<361::AID-CNE4>3.0.CO;2-3s"},{"key":"e_1_3_5_79_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.1082"},{"key":"e_1_3_5_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-2236(96)10047-3"},{"key":"e_1_3_5_81_2","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.4456-04.2005"},{"key":"e_1_3_5_82_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10519"},{"key":"e_1_3_5_83_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23626"},{"key":"e_1_3_5_84_2","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2009.64"},{"key":"e_1_3_5_85_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2006.08.017"},{"key":"e_1_3_5_86_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13125"},{"key":"e_1_3_5_87_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1326"},{"key":"e_1_3_5_88_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws322"},{"key":"e_1_3_5_89_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9020456"},{"key":"e_1_3_5_90_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-022-00533-z"},{"key":"e_1_3_5_91_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5395.1914"},{"key":"e_1_3_5_92_2","doi-asserted-by":"publisher","DOI":"10.1038\/31508"},{"key":"e_1_3_5_93_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-142844"},{"key":"e_1_3_5_94_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2014.01.024"},{"key":"e_1_3_5_95_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.01.010"},{"key":"e_1_3_5_96_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.08.023"},{"key":"e_1_3_5_97_2","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.4361-12.2013"},{"key":"e_1_3_5_98_2","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.2868-05.2005"},{"key":"e_1_3_5_99_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100620"},{"key":"e_1_3_5_100_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511065103"},{"key":"e_1_3_5_101_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-016-2546-5"},{"key":"e_1_3_5_102_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2008.06498.x"},{"key":"e_1_3_5_103_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090452"},{"key":"e_1_3_5_104_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2018.6046"},{"key":"e_1_3_5_105_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2019.6602"},{"key":"e_1_3_5_106_2","doi-asserted-by":"publisher","DOI":"10.1097\/nen.0000000000000059"},{"key":"e_1_3_5_107_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0153608"},{"issue":"3","key":"e_1_3_5_108_2","first-page":"228","article-title":"The neurometabolic cascade of concussion","volume":"36","author":"Giza CC","year":"2001","unstructured":"Giza CC, , Hovda DA. The neurometabolic cascade of concussion. J Athl Train, 2001; 36(3):228\u2013235.","journal-title":"J Athl Train"},{"key":"e_1_3_5_109_2","doi-asserted-by":"publisher","DOI":"10.1227\/neu.0000000000000505"},{"key":"e_1_3_5_110_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.csm.2020.08.001"},{"key":"e_1_3_5_111_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2016.4823"},{"key":"e_1_3_5_112_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1527-3458.2003.tb00254.x"},{"key":"e_1_3_5_113_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2022.110609"},{"key":"e_1_3_5_114_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0081004"},{"key":"e_1_3_5_115_2","doi-asserted-by":"publisher","DOI":"10.1177\/104012371502700308"},{"key":"e_1_3_5_116_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04993-7"},{"key":"e_1_3_5_117_2","doi-asserted-by":"publisher","DOI":"10.1177\/0269881114538543"},{"key":"e_1_3_5_118_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910280107"},{"key":"e_1_3_5_119_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007092"},{"key":"e_1_3_5_120_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2015.00073"},{"key":"e_1_3_5_121_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2017.5170"},{"key":"e_1_3_5_122_2","doi-asserted-by":"publisher","DOI":"10.1097\/htr.0000000000000280"},{"key":"e_1_3_5_123_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2007.0313"},{"key":"e_1_3_5_124_2","doi-asserted-by":"publisher","DOI":"10.3945\/an.113.005280"},{"key":"e_1_3_5_125_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-021-01546-6"},{"key":"e_1_3_5_126_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb2639"},{"key":"e_1_3_5_127_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-73227-5"}],"container-title":["Journal of Neurotrauma"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/neu.2023.0423","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/neu.2023.0423","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/neu.2023.0423","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T22:44:20Z","timestamp":1777675460000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/neu.2023.0423"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7]]},"references-count":126,"journal-issue":{"issue":"13-14","published-print":{"date-parts":[[2024,7]]}},"alternative-id":["10.1089\/neu.2023.0423"],"URL":"https:\/\/doi.org\/10.1089\/neu.2023.0423","relation":{},"ISSN":["0897-7151","1557-9042"],"issn-type":[{"value":"0897-7151","type":"print"},{"value":"1557-9042","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7]]}}}