Novel Approach to the Role of NMDA Receptors in Traumatic Brain Injury

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 D-cycloserine (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.