Nature Medicine | Spoonful of Medicine

The wrong target

There’s a remarkable number of drugs that people use for which the mechanism of action is unknown, and two papers in the Journal of Neuroscience illustrate this point from two different perspectives.

Methylprednisolone is an anti-inflammatory drug that is often used — with modest success — in multiple sclerosis and (off label) after spinal cord injury. People think that its effect depends on its ability to dampen inflammation but, as Jin-Moo Lee and colleagues show, the drug seems to act in vitro and in vivo (at least in rats) by preventing oligodendrocyte apoptosis through the indirect activation of glucocorticoid receptors. By contrast, the drug has no such protective effect on neurons, which may start to account for its limited therapeutic effect.

The second paper has to do with a drug that people use with recreational, as opposed to therapeutic, purposes — ecstasy. Carla Busceti and her colleagues report that giving ecstasy to mice results in a transient increase in the phosphorylation of tau — the same molecule that is phosphorylated in Alzheimer disease and in a series of conditions known as tauopathies. They further show that the increased phosphorylation, which is primarily seen in the hippocampus, depends on both GSK3β and cdk5, a pair of kinases known to phosphorylate tau. So, ecstasy induces the expression of Dickkopf-1, which inhibits Wnt signalling, thereby increasing GSK3β activity, and it also induces the expression of p25, a known activator of cdk5. It’s very hard to know if there is any relationship between these biochemical changes and neurological diseases, but it would be very interesting to see if there is an increased incidence of any tauopathy in frequent users of ecstasy. I guess we’ll have to wait for epidemiological studies to know the answer.

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