16 July 2004. Researchers have realized over the last decade or so that stroke and Alzheimer’s disease (AD) have some things in common—kinases that phosphorylate the neurofibrillary tangle protein tau, for example, also mediate stroke damage (see ARF related news story). For this reason, anything that aids stroke recovery may also offer clues to help study AD. Recovery from ischemic stroke depends to some degree on developing new neural connections. So what about proteins like Nogo, which inhibit development of new axons—how do they affect stroke? Not surprisingly, they hinder it, according to a report in the July 7 Journal of Neuroscience.
Stephen Strittmatter and colleagues from Yale University, New Haven, Connecticut, measured recovery of motor function in mice lacking either Nogo or the Nogo receptor. These are key players in Nogo signal transduction, a pathway that mediates the classical inhibition of axonal growth by myelin proteins. When first author Jung-Kil Lee and colleagues measured stroke recovery in mice lacking Nogo receptor (NgR) or Nogo-AB, they found that it was better than in wild-type animals. In a food retrieval test, for example, NgR-negative animals could harvest about 4.5 pellets of food using their affected forepaw, while wild-type animals could only manage about three pellets. Nogo-AB-negative animals did even better, reaping about six pellets. Similar improvements were recorded on the rotarod. These behavioral advantages were accompanied by improvements in axonal plasticity. When Lee used biotin dextran amine to trace axons, he found that axon sprouting in NgR-negative animals was double that in controls.
From a therapeutic perspective these results are encouraging, suggesting that an inhibitor of the Nogo pathway could be developed to help stroke victims. In support of this, Lee and colleagues found that perfusing rat brain with an antibody against NgR helped the animals recover from stroke. Rats receiving the antibody performed about 50 percent better in the food retrieval and rotarod tests. An antibody to Nogo has also been shown previously to aid recovery from spinal cord injury (see ARF related news story), but whether interruption of this signal pathway may have any benefit in AD remains to be seen.—Tom Fagan.
Lee J-K, Kim J-E, Sivula M, Strittmatter SM. Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J. Neurosci. 2004 July 7;24:6209-6217. Abstract