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 placebocontrolled
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.
Cognitive enhancer, D-cycloserine, glutamate receptors, stroke.
Institute for Drug Research, The Hebrew University, Jerusalem, 91120, Israel.