PMID- 24168367
OWN - NLM
STAT- MEDLINE
DCOM- 20150223
LR  - 20191027
IS  - 1996-3181 (Electronic)
IS  - 1871-5273 (Linking)
VI  - 13
IP  - 4
DP  - 2014
TI  - Novel approach to the role of NMDA receptors in traumatic brain injury.
PG  - 567-73
AB  - For more than two decades the intensive research effort on the role of NMDA 
      receptors (NMDAR) in traumatic brain injury (TBI) and cerebral ischemia (stroke) 
      was led by the observations that extracellular concentrations of glutamate and 
      aspartate are elevated after the insult and play a major role in brain 
      pathologies. Indeed, NMDAR antagonists were shown to improve post-injury recovery 
      in animal models and subsequently, large scale placebo-controlled clinical trials 
      in TBI and stroke were performed with NMDAR antagonists. However, all these 
      trials have demonstrated either no benefit or even deleterious effects. The 
      discrepancy between the animal and human studies prompted us to investigate the 
      temporal changes of the NMDAR after brain insult in TBI and stroke mouse models. 
      We found that the early hyperactivation of the NMDAR is followed by loss of 
      functional NMDAR which persists for weeks. Such dynamic changes could well 
      explain the discrepancies between the preclinical and clinical experience as well 
      as suggest alternative modes of treatment, namely, activation, rather than 
      blockade of the NMDAR in the sub-acute period after TBI and stroke. Stimulation 
      of the glycine modulatory site of the glycine/NMDAR by the partial agonist 
      Dcycloserine (DCS) when given at least 24 hrs after TBI or stroke was shown to 
      improve recovery of neurobehavioral and cognitive functions. It was also shown to 
      restore impaired hippocampal Long-Term potentiation (LTP) and induce expression 
      of Brain Derived-Neurotrophic Factor (BDNF) in a TBI model and to improve 
      somatosensory and cognitive function in a stroke model. Experiments to optimize 
      the DCS treatment paradigm showed that similar benefits were demonstrated in TBI 
      mice whether the drug was given as a single injection at 24 or 72 hrs post 
      injury, or as double (24 and 48 hrs) or triple (24, 48 and 72 hrs) doses. 
      Interestingly, beneficial effects of DCS were reported in a range of animal 
      models of human diseases as well as in several clinical indications thought to 
      involve disruptions in NMDAR function, such as drug addiction, post-traumatic 
      stress disorder, Parkinson's disease, aging and psychiatric disorders. As DCS has 
      a good safety profile, and is already in use in humans in several different 
      indications, and based on studies with DCS in the mouse TBI model, a multi-center 
      prospective randomized controlled clinical trial, aiming to assess the effect of 
      a single dose of DCS on cognitive outcome in patients with moderate TBI has 
      recently begun.
FAU - Shohami, Esther
AU  - Shohami E
FAU - Biegon, Anat
AU  - Biegon A
AD  - Institute for Drug Research, The Hebrew University, Jerusalem, 91120, Israel. 
      esty@cc.huji.ac.il.
LA  - eng
GR  - 1R01NS050285/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United Arab Emirates
TA  - CNS Neurol Disord Drug Targets
JT  - CNS & neurological disorders drug targets
JID - 101269155
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 95IK5KI84Z (Cycloserine)
SB  - IM
MH  - Animals
MH  - Brain/drug effects/physiopathology
MH  - Brain Injuries/*drug therapy/*physiopathology
MH  - Brain Ischemia/drug therapy/physiopathology
MH  - Cycloserine/pharmacology
MH  - Humans
MH  - Mental Disorders/drug therapy/physiopathology
MH  - Neuroprotective Agents/pharmacology
MH  - Randomized Controlled Trials as Topic
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
EDAT- 2013/10/31 06:00
MHDA- 2015/02/24 06:00
CRDT- 2013/10/31 06:00
PHST- 2012/11/10 00:00 [received]
PHST- 2013/01/07 00:00 [revised]
PHST- 2013/01/11 00:00 [accepted]
PHST- 2013/10/31 06:00 [entrez]
PHST- 2013/10/31 06:00 [pubmed]
PHST- 2015/02/24 06:00 [medline]
AID - CNSNDDT-EPUB-57030 [pii]
AID - 10.2174/18715273113126660196 [doi]
PST - ppublish
SO  - CNS Neurol Disord Drug Targets. 2014;13(4):567-73. doi: 
      10.2174/18715273113126660196.