Amantadine improves cognitive outcome and increases neuronal survival after fluid percussion traumatic brain injury in rats

Tao Wang, Xian Jian Huang, Ken C. Van, Gregory T. Went, Jack T. Nguyen, Bruce G Lyeth

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

This study evaluated the effects of clinically relevant concentrations of amantadine (AMT) on cognitive outcome and hippocampal cell survival in adult rats after lateral fluid percussion traumatic brain injury (TBI). AMT is an antagonist of the N-methyl-D-aspartate-type glutamate receptor, increases dopamine release, blocks dopamine reuptake, and has an inhibitory effect on microglial activation and neuroinflammation. Currently, AMT is clinically used as an antiparkinsonian drug. Amantadine or saline control was administered intraperitoneally, starting at 1 h after TBI followed by dosing three times daily for 16 consecutive days at 15, 45, and 135 mg/kg/day. Terminal blood draws were obtained from TBI rats at the time of euthanasia at varying time points after the last amantadine dose. Pharmacokinetics analysis confirmed that the doses of AMT achieved serum concentrations similar to those observed in humans receiving therapeutic doses (100-400 mg/day). Acquisition of spatial learning and memory retention was assessed using the Morris water maze (MWM) on days 12-16 after TBI. Brain tissues were collected and stained with Cresyl-violet for long-term cell survival analysis. Treatment with 135mg/kg/day of AMT improved acquisition of learning and terminal cognitive performance on MWM. The 135-mg/kg/day dosing of AMT increased the numbers of surviving CA2-CA3 pyramidal neurons at day 16 post-TBI. Overall, the data showed that clinically relevant dosing schedules of AMT affords neuroprotection and significantly improves cognitive outcome after experimental TBI, suggesting that it has the potential to be developed as a novel treatment of human TBI.

Original languageEnglish (US)
Pages (from-to)370-377
Number of pages8
JournalJournal of Neurotrauma
Volume31
Issue number4
DOIs
StatePublished - Feb 15 2014

Fingerprint

Percussion
Amantadine
Dopamine
Cell Survival
Antiparkinson Agents
Traumatic Brain Injury
Euthanasia
Water
Pyramidal Cells
Glutamate Receptors
Survival Analysis
N-Methyl-D-Aspartate Receptors
Appointments and Schedules
Therapeutics
Pharmacokinetics
Learning

Keywords

  • dopamine
  • hippocampus
  • Morris water maze
  • pharmacokinetics
  • traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Amantadine improves cognitive outcome and increases neuronal survival after fluid percussion traumatic brain injury in rats. / Wang, Tao; Huang, Xian Jian; Van, Ken C.; Went, Gregory T.; Nguyen, Jack T.; Lyeth, Bruce G.

In: Journal of Neurotrauma, Vol. 31, No. 4, 15.02.2014, p. 370-377.

Research output: Contribution to journalArticle

Wang, Tao ; Huang, Xian Jian ; Van, Ken C. ; Went, Gregory T. ; Nguyen, Jack T. ; Lyeth, Bruce G. / Amantadine improves cognitive outcome and increases neuronal survival after fluid percussion traumatic brain injury in rats. In: Journal of Neurotrauma. 2014 ; Vol. 31, No. 4. pp. 370-377.
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