Larry Benowitz, PhD
Professor of Neurosurgery and Opthamology, Harvard Medical School
Director, Laboratories for Neuroscience Research in Neurosurgery, Boston Children’s Hospital
Spinal cord damage, stroke, and other types of CNS injury can lead to permanent losses in movement, sensation, thinking, and/or other functions. Failure to recover from CNS injury is due in large part to the inability of nerve cells (neurons) to regenerate their connections and/or the limited capacity of undamaged neurons to form compensatory connections. Our lab has discovered some of the key molecules that control axon growth and has developed methods to promote the rewiring of brain connections after injury. Using the optic nerve as a classic model of a CNS pathway that normally fails to regenerate after injury, we discovered that if we induce an inflammatory reaction in the eye, cells of myeloid lineage (neutrophils and macrophages) enter the eye and secrete oncomodulin, an atypical and previously unknown growth factor. Oncomodulin binds to a high-affinity receptor on neurons and, together with co-factors, causes retinal ganglion cells to revert to an active growth state and begin regenerating axons into the optic nerve. If this treatment is combined with treatments that promote regeneration through other mechanisms (e.g., counteracting cell-extrinsic inhibitors of axon growth or deleting the gene for the PTEN phosphatase), retinal ganglion cells are able to regenerate their axons all the way from the eye to the brain, restore normal connections, and regain some simple visual responses. More recently, we have discovered that one of the earliest events to occur in retinal neurons following optic nerve injury is a rapid increase in free (ionic) zinc in the synapses that inhibitory retinal interneurons (amacrine cells) make onto the dendrites of retinal ganglion cells; over a period of 2-3 days, high levels of ionic zinc accumulate in the latter cells themselves. Chelating zinc leads to extensive axon regeneration and the persistent survival of many retinal ganglion cells. In other research from our lab, we discovered that inosine, a small, naturally occurring molecule derived from adenosine, stimulates nerve cells to extend axons in cell culture. We went on to show that inosine activates Mst3b, which serves as a key part of the signal transduction pathway through which trophic factors control axon growth. The administration of inosine in an animal model of stroke promotes the rewiring of brain connections and functional recovery. This effect is further enhanced when inosine is combined with environmental enrichment or with an agent that counteracts inhibitory signals associated with myelin. Finally, we have also shown that inosine strongly enhances anatomical reorganization and functional outcome after spinal cord injury. Our long-term goal is to move these discoveries into the clinic to improve outcome after CNS damage.