Chatter between neurons can help protect them from the ravages of free radical damage, according to a report published today (Mar 23) in Nature.

Free radical, or oxidative, damage besets neurons as they age normally or degenerate due to chronic disorders, such as Alzheimer's or Parkinson's, or in acute events, such as strokes. University of Edinburgh neuroscientist Giles Hardingham and colleagues found that N-methyl-D-aspartate (NMDA) receptors, whose activation is critical to synaptic transmission, modulate a web of antioxidant pathways, preventing or reversing the effects of oxidative damage on nerve cells. "This was the first time that it was seen that synaptic activity can regulate the vulnerability of neurons to oxidative stress," Hardingham told The Scientist.

Hardingham and his team suppressed normal NMDA receptor activity in rat and mouse neurons and tracked cell survival and the downstream transcription of genes involved in oxidation-reduction pathways. They found that NMDA receptor activity enhances the activity of two antioxidant proteins, thioredoxin and peroxiredoxin, while promoting resistance to oxidative stress by downregulating Txnip, a thioredoxin inhibitor.

"It seems that the synaptic activity tells [nerve] cells how to protect one another," Burnham Institute for Medical Research neuroscientist Stuart Lipton told The Scientist.

Lipton, also a neurologist, said that Hardingham's study gave unprecedented insight into how synaptic activity influences the intricate network of antioxidant pathways in neurons. "Nobody had any idea that these post-transcriptional modifications were occurring," said Lipton, who was not involved with the study.

Hardingham and his team also showed in vivo that these protective pathways were compromised in instances of acute neuronal damage, such as stroke. Because oxidative damage is known to be a feature of other neurological disorders, the same enzymatic systems may be important in the progression of Alzheimer's disease and other similar diseases. "Obviously it's a possibility," Hardingham said, "but it remains to be seen if life-long patterns of synaptic activity might influence [a neuron's] accumulation of oxidative damage in vivo over a number of years."

Hardingham says that his group is now trying to identify small molecules that can modulate antioxidant pathways in neurons to prevent or reverse oxidative stress. This research could lead to drugs that reverse the symptoms of stroke or protect people from long-term neurological damage. "It's really very early days in this study, but it's promising for sure," Hardingham said.

Lipton has already developed a drug - memantine - that allows synaptic NMDA receptor activity but blocks extra-synaptic NMDA receptor activity, which is known to contribute to the progression of Alzheimer's disease. Lipton said that Hardingham's study provides further support for the mechanism at play behind memantine's effectiveness. "Now we understand better why [the drug] works," Lipton said. Memantine, under the trade name Namenda, gained FDA approval in 2003 for treating Alzheimer's disease.