Article type: Research Article
Authors: Abrahamson, Eric E.a; b | Poloyac, Samuel M.d | Dixon, C. Edwarda; e | Dekosky, Steven T.f | Ikonomovic, Milos D.a; b; c; *
Affiliations:
[a] Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, University of Pittsburgh, Pittsburgh PA, USA
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[b] Department of Neurology, University of Pittsburgh, Pittsburgh PA, USA
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[c] Department of Psychiatry, University of Pittsburgh, Pittsburgh PA, USA
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[d] Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh PA, USA
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[e] Department of Neurosurgery, University of Pittsburgh, Pittsburgh PA, USA
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[f] Department of Neurology and McKnight Brain Institute, University of Florida, Gainesville, FL, USA
Correspondence:
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Corresponding author: Milos Ikonomovic, M.D., Department of Neurology, University of Pittsburgh, Thomas Detre Hall of the WPIC, Room 1421, 3811 O’Hara Street, Pittsburgh, PA 15213. Tel.: +1 412 802 3004; Fax: +1 412 647 2777; E-mail: [email protected].
Abstract: Background:Altered glutamatergic neurotransmission after traumatic brain injury (TBI) contributes to excitotoxic cell damage and death. Prevention or suppression of such changes is a desirable goal for treatment of TBI. Memantine (3,5-dimethyl-1-adamantanamine), an uncompetitive NMDA receptor antagonist with voltage-dependent open channel blocking kinetics, was reported to be neuroprotective in preclinical models of excitotoxicity, brain ischemia, and in TBI when administered prophylactically, immediately, or within minutes after injury. Methods:The current study examined effects of memantine administered by single intraperitoneal injection to adult male rats at a more clinically relevant delay of one hour after moderate-severe controlled cortical impact (CCI) injury or sham surgery. Histopathology was assessed on days 1, 7, 21, and 90, vestibulomotor function (beam balance and beam walk) was assessed on days 1–5 and 71–75, and spatial memory (Morris water maze test, MWM) was assessed on days 14–21 and 83–90 after CCI injury or sham surgery. Results:When administered at 10 mg/kg, but not 2.5 or 5 mg/kg, memantine preserved cortical tissue and reduced neuronal degeneration 1 day after injury, and attenuated loss of synaptophysin immunoreactivity in the hippocampus 7 days after injury. No effects of 10 mg/kg memantine were observed on histopathology at 21 and 90 days after CCI injury or sham surgery, or on vestibulomotor function and spatial memory acquisition assessed during any of the testing periods. However, 10 mg/kg memantine resulted in trends for improved search strategy in the MWM memory retention probe trial. Conclusions:Administration of memantine at a clinically-relevant delay after moderate-severe CCI injury has beneficial effects on acute outcomes, while more significant improvement on subacute and chronic outcomes may require repeated drug administration or its combination with another therapy.
Keywords: Excitotoxicity, glutamate, hippocampus, NMDA, traumatic brain injury
DOI: 10.3233/RNN-190909
Journal: Restorative Neurology and Neuroscience, vol. 37, no. 3, pp. 245-263, 2019
