d-Cycloserine improves functional outcome after traumatic brain injury with wide therapeutic window

Amos Adeleye, Esther Shohami*, Dean Nachman, Alexander Alexandrovich, Victoria Trembovler, Rami Yaka, Yigal Shoshan, Jasbeer Dhawan, Anat Biegon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

It has been long thought that hyperactivation of N-methyl-d-aspartate (NMDA) receptors underlies neurological decline after traumatic brain injury. However, all clinical trials with NMDA receptor antagonists failed. Since NMDA receptors are down-regulated from 4 h to 2 weeks after brain injury, activation at 24 h, rather than inhibition, of these receptors, was previously shown to be beneficial in mice. Here, we tested the therapeutic window, dose regimen and mechanism of action of the NMDA receptor partial agonist d-cycloserine (DCS) in traumatic brain injury. Male mice were subjected to trauma using a weight-drop model, and administered 10 mg/kg (i.p.) DCS or vehicle once (8, 16, 24, or 72 h) twice (24 and 48 h) or three times (24, 48 and 72 h). Functional recovery was assessed for up to 60 days, using a Neurological Severity Score that measures neurobehavioral parameters. In all groups in which treatment was begun at 24 or 72 h neurobehavioral function was significantly better than in the vehicle-treated groups. Additional doses, on days 2 and 3 did not further improve recovery. Mice treated at 8 h or 16 h post injury did not differ from the vehicle-treated controls. Co-administration of the NMDA receptor antagonist MK-801 completely blocked the protective effect of DCS given at 24 h. Infarct volume measured by 2,3,5-triphenyltetrazolium chloride staining at 48 h or by cresyl violet at 28 days was not affected by DCS treatment. Since DCS is used clinically for other indications, the present study offers a novel approach for treating human traumatic brain injury with a therapeutic window of at least 24 h.

Original languageAmerican English
Pages (from-to)25-30
Number of pages6
JournalEuropean Journal of Pharmacology
Volume629
Issue number1-3
DOIs
StatePublished - 10 Mar 2010

Bibliographical note

Funding Information:
This study was supported by NIH grant 1R01NS050285 (A. Biegon) and, in part, by a grant from the IDF and the Israel Ministry of Defense (E. Shohami). E. Shohami is the incumbent of the Dr. Leon and Dr. Mina Deutsch Chair in Psychopharmacology at The Hebrew University, and a member of the Brettler Center for Research in Molecular Pharmacology and Therapeutics, The Hebrew University.

Keywords

  • Glutamate
  • Head injury
  • N-methyl-d-aspartate (NMDA) receptor
  • Neuroprotection

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