Neurological disorders: Stimulating findings
Two teams show that the loss of NMDA—receptor function may underlie cognitive and neurological decline after head injury, rather than the hyperactivation of NMDA receptors, as previously thought.
Traumatic brain injury is a principal cause of fatalities and neurological or cognitive impairments in young people in Western society. It has long been thought that hyperactivation of N-methyl-D-aspartate (NMDA) receptors — excitatory receptors that are crucial for the formation of memories — underlies cognitive and neurological decline after head injury. Now, however, the teams of Biegon and Shohami challenge this assumption and show that loss of NMDA-receptor function might underlie these impairments.
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Traumatic and ischaemic brain injuries trigger an increased release of excitatory neurotransmitters for  30 min after head injury in animals, and for 6 h to several days in humans. Delayed neuronal death and decline in function follow. Moreover, compounds that block NMDA receptors reduce cell death and improve outcome in animal models: this is most effective if the blockers are given less than 30–60 min after injury. But, surprisingly, clinical trials in humans that involved blocking NMDA receptors for several days after head injury have failed, and were actually associated with an increase in adverse effects.
So, might the duration of this NMDA-receptor hyperactivation in humans have been overestimated? This is the hypothesis that Biegon and Shohami tested.
They started by using autoradiography of a radiolabelled compound that blocks activated NMDA receptors (MK801) in a mouse model of closed head injury: it turned out that NMDA hyperactivation was indeed short-lived (< 1 h) as shown by an increase in the density of MK801 binding. This might explain the short therapeutic window in animal models of traumatic brain injury. Intriguingly, a marked loss of function of NMDA receptors, which was longer lasting ( 7 days), followed this excessive stimulation.
The next step was to use NMDA to stimulate NMDA receptors at 24 and 48 h after traumatic brain injury. This significantly attenuated the neurological and cognitive deficits 2 weeks later. In support of this, NMDA blockers cancelled the beneficial effects of NMDA and led to a worsening of cognitive and neurological deficits.
This extended loss of NMDA-receptor function might therefore provide a therapeutic window for the treatment of cognitive and neurological deficits after head injury. The duration of this therapeutic window, however, needs to be determined in humans before clinical trials can take place. Once established, stimulation of NMDA receptors in the subacute post-injury phase might benefit brain-injured patients.
Alison Rowan
References
- Biegon, A. et al. Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: implications for treatment of neurological and cognitive deficits. Proc. Natl Acad. Sci. USA 101, 5117–5122 (2004) | Article | PubMed |
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