Image courtesy of J. Fenwick.

Stroke is one of the most common causes of brain damage and disability, and many avenues are being explored in the search for therapeutic advances. One approach is to block the ability of NMDA (N-methyl-d-aspartate) receptors to mediate ischaemic damage, but blocking the receptors themselves is not a feasible strategy. Aarts and colleagues have come up with another option: using small peptides to block the interaction of NMDA receptors with the protein PSD95 (postsynaptic density 95), which couples the receptors to the rest of the postsynaptic machinery and to excitotoxicity.

We know that NMDA receptors mediate excitotoxicity through their interaction with PSD95, and that mutations in PSD95 that block downstream signalling initiated by NMDA receptors can also prevent ischaemic damage. But knocking out or mutating PSD95 is not a useful approach to treating stroke, and blocking NMDA receptors is harmful. However, Aarts et al. reasoned that it might be possible to block the interaction between NMDA receptors and PSD95. They developed a small peptide consisting of the carboxy-terminal nine residues of the NR2B subunit of the NMDA receptor (the domain that binds to PSD95), fused to the cell-membrane transduction domain of the HIV Tat protein (to allow the peptide to enter cells).

In cultures, the fusion peptide entered neurons and reduced the binding of the NR2B subunit to PSD95 without interfering with NMDA receptor currents or calcium influx. It also reduced neuronal death induced by NMDA treatment — even if the peptide was given one hour after the NMDA.

But will this strategy work in vivo? After showing that the peptide could enter the brain when injected intraperitoneally in rats, the authors tested whether it could reduce the harmful effects of transient middle cerebral artery occlusion (MCAO) — a commonly used model of stroke. Injection of the peptide either before or one hour after the onset of MCAO not only reduced the volume of the resulting infarct, but also significantly reduced the severity of neurological symptoms (postural reflex and forelimb placing deficits) caused by the occlusion.

This work presents exciting possibilities for developing new treatments for stroke. Although much work will be needed to ensure that suppressing signalling downstream of the NMDA receptor has no harmful side effects, there is cause for optimism.