Newsdesk

820 http://neurology.thelancet.com Vol 5 October 2006

Newborn neurons may help heal brain after strokeIschaemic stroke may trigger neuro-genesis and migration of newborn neurons into ischaemic brain regions, an international team of researchers report. This process could contribute to recovery after a stroke and represent a new target for stroke therapy.

Neurogenesis in damaged regions of the brain has been shown in animal models of stroke, and this study provides the fi rst evidence that it may also occur in human beings.

David Greenberg (Buck Institute for Age Research, Novato, CA, USA) and collaborators looked for markers of neurogenesis in brain biopsies from patients who had had an ischaemic stroke and from control patients with no evidence of neurological disease. Samples were stained with antibodies against markers of cell proliferation and neuronal lineage. Compared with

control samples, which showed no staining, samples from stroke patients expressed markers associated with newborn neurons (Proc Natl Acad Sci USA 2006; 103: 13198–202).

Markers of neurogenesis were localised to cells in the ischaemic penumbra—tissue surrounding the ischaemic core that is hypoperfused but still viable. New neurons had a migratory phenotype and tended to cluster near blood vessels, which are known to produce growth factors that boost proliferation and growth. The researchers suggest that the newborn neurons might migrate from other regions of the brain, using blood vessels as scaff olds or destination markers.

Greenberg suggests that compens-atory neurogenesis induced by stroke could represent a new target for stroke treatment. “We know many

ways to increase neurogenesis under non-stroke conditions, including drugs, growth factors, environmental enrichment, and activity. This suggests it might be possible to improve recovery from stroke by using these approaches to enhance neurogenesis further, beyond what occurs in stroke without such treatments”, he says.

Andreas Arvidsson (Lund University, Sweden) cautions that it is not yet known whether the new neurons produced after a stroke can integrate into neuronal circuitry and thus contribute to functional recovery. “If such integration occurs or could be stimulated, these fi ndings could lead to the development of therapeutic means for stimulation of neuronal replacement in humans”, Arvidsson says.

Helen Frankish

p53—now it is needed for nerve regenerationp53, most famous for its role in suppressing tumours by inducing cells with damaged DNA to undergo apoptosis, seems also to be needed for neurite outgrowth in primary neurons and other nerve cells and in axon regeneration (EMBO J 2006; published online Aug 31. DOI: 10.1038/sj.emboj.7601292). These fi ndings could herald unexpected ways of promoting nerve-cell regeneration in patients with neurodegenerative disorders or trauma-induced nerve damage.

Nerve cell and axon regeneration is known to need remodelling of the cytoskeleton, and it is associated with the timely expression of several genes, including the actin-binding protein Coronin 1b and GTPase Rab13. “These proteins might play a part in the recovery of damaged neurons in experimental spinal-cord injuries and are required for effi cient neurite outgrowth in PC-12 cells and primary neurons”, explains Maria

Laura Avantaggiati (Georgetown University, Washington DC, USA). “The coordination of their expression suggests that the same transcription factor could be regulating both. p53 encourages PC-12 cell survival after administering nerve growth factor, probably by interacting with neuron-specifi c transcription factors, so we wondered if it might be involved in nerve-cell regrowth by modulating Coronin 1b and GTPase Rab13 production.”

The researchers fi rst used computer simulations to see whether p53 and the promoters of the GTPase Rab13 genes could interact, and found both to have multiple p53 transcription binding sites. They then showed that this binding occurred in vivo and that both genes became upregulated upon over-expression of p53.

“We found a correlation between p53 expression and that of Coronin 1b and GTPase Rab13 during neurite outgrowth and neuronal maturation,

and when we inhibited p53 everything stopped”, explained coauthor Simone Giovanni (University of Tuebingen, Germany). “This clearly shows a relation exists between p53 and nerve-cell growth and remodelling.”

Further experiments showed that the acetylation of p53 at lysine 320 threw the switch that started its interaction with the promoters of Coronin 1b and GTPase Rab13—a vital step in encouraging neurite growth.

“This work surprisingly suggests that ‘switching on’ this p53 system could help injured nerve cells regrow”, remarks David Park (Ottawa Health Research Institute, Ottawa, Canada). “However, what causes p53 to become acetylated at lysine 320, and not [at another position] which might cause apoptosis, remains unknown. We need to know more about how p53 might impact regeneration, but it is an exciting area worthy of attention.”

Adrian Burton