Aktuelle Neurologie 2009; 36 - V241
DOI: 10.1055/s-0029-1238431

Role of Nogo-A in neuronal survival in the reperfused ischaemic brain

A El Ali 1, E Kilic 1, Ü Kilic 1, Z Guo 1, CL Bassetti 1, ME Schwab 1, DM Hermann 1
  • 1Essen; Zürich, CH

Nogo-A is an oligodendroglial neurite outgrowth inhibitor, the deactivation of which enhances brain plasticity and functional recovery in animal models of ischemic stroke and spinal cord trauma. A clinical trial with Nogo-A antibodies in spinal cord trauma is currently in progress. A clinical study in stroke is planned.

All previous studies were carried out in permanent stroke models; we recently aimed to characterize the plasticity-promoting effects of Nogo-A-/- after transient focal cerebral ischemia. Strikingly, Nogo-A-/- mice submitted to 30min middle cerebral artery (MCA) occlusion revealed an increased mortality, associated with exacerbated neurological deficits, when compared with wildtype animals. Based on these findings, we evaluated the effect of an acute Nogo-A deactivation in the reperfused brain using a systematic approach assessing effects of (a) Nogo-A-/- and (b) neutralizing Nogo-A antibodies (11C7) that we delivered both immediately after, and 24 hours prior to a stroke.

Protein expression and interaction studies, demonstrate that Nogo-A regulates the activity of two proteins involved in neurite sprouting inhibition, RhoA and Rac1, maintaining stress kinases p38/MAPK, SAPK/JNK1/2 and phosphatase-and-tensin homolog (PTEN) activities low, thus enhancing neuronal survival. Whereas, Nogo-A blockade leads; to Rac1 overactivation which activates p38/MAPK and SAPK/JNK1/2, and to RhoA deactivation which stimulates PTEN activity, inhibiting Akt, ERK1/2 survival pathways, and initiating p53 and RhoB dependent cell death.

In view of this novel role of Nogo-A in promoting neuronal survival by controlling Rac1/RhoA balance, clinical trials should be aware of potential injurious effects of axonal growth-promoting therapies. Thus, Nogo-A antibodies should not be used in the very acute stroke phase. Moreover, we believe that our data may exemplify a bystander action of plasticity-related strategies on neuronal survival, which has not been recognized in the past.