SAN DIEGO—Schwann cells play a pivotal role in axonal health and in regeneration after injury. Therefore, understanding Schwann cell biology under normal conditions and in disease states can create new therapeutic opportunities for neuroprotection and/or axonal protection, said Ahmet Höke, MD, PhD, at the 130th Annual Meeting of the American Neurological Association.

Dr. Höke, Associate Professor of Neurology and Neuroscience, and Director, Neuromuscular Division, Johns Hopkins University in Baltimore, discussed two themes related to neuroprotection in the peripheral nervous system—the concept of changes in Schwann cells associated with chronic denervation and how they can be used to screen for therapeutic opportunities, and how the endogenous neuroprotective pathway that exists between the axon and the Schwann cell can be studied for novel therapeutic options for peripheral nerve diseases.

SCHWANN CELLS AND CHRONIC DENERVATION

"Some of the earliest and best-characterized studies on the importance of chronic denervations came after World War II," Dr. Höke said. This includes Lyons and Woodhall’s 1949 publication regarding a series of approximately 2,000 patients with nerve injuries. The authors demonstrated that when no repair was attempted, no recovery was seen in transected nerves; however, an immediate repair to an injured nerve at day 2 resulted in "successful regeneration into the distal nerves and functional recovery." Delaying the repair of a laceration in a nerve for up to 10 months resulted in "minimal regeneration into the distal nerve segment and no functional recovery." In 1995, Fu and Gordon linked this to chronic denervation in Schwann cells in the distal parts of an injured nerve.

To identify genes that might be up-regulated in denervated Schwann cells, Dr. Höke transected sciatic nerves in adult rats and harvested distal sciatic nerves at different time points. "With the harvested tissue, we performed focused microarrays that screen for a variety of neurotrophic factors," said Dr. Höke. "As expected, there was up-regulation of certain known neurotrophic factors such as nerve growth factor, glial cell line–derived neurotrophic factor, and brain-derived neurotrophic factor. But, to our surprise, we saw a significant increase in another growth factor, called pleiotrophin, as early as two days after transection. We confirmed the microarray observations with real-time reverse transcription–polymerase chain reaction and saw an expression pattern that mimicked glial cell line–derived neurotrophic factor. There was up-regulation of pleiotrophin early on, but this was not sustained with chronic denervation."

A NEUROTROPHIC ROLE FOR PLEIOTROPHIN?

Dr. Höke described experimental studies in his laboratory that investigated a potential neurotrophic role for pleiotrophin. Using an in vitro culture system, Dr. Höke’s group added recombinant human pleiotrophin in Gelfoam^® away from the spinal cord explants to determine whether a point source of pleiotrophin "could provide trophic and tropic support to regenerate motor axons," he said. "Under a controlled condition, motor axons in these spinal cord explants grow within the gray matter but rarely cross the white matter tracts and leave the explant. In contrast, when pleiotrophin was provided from a point source and released from the Gelfoam slowly, the motor axons crossed the white matter tracts and grew toward the pleiotrophin source. In a sense, they formed mini–ventral rootlets. Subsequently, pleiotrophin was found to promote regeneration of transection peripheral axons in rats."

Pleiotrophin was also shown to protect motor neurons against chronic glutamate toxicity in spinal cord explant cultures and to rescue facial motor neurons in rats, as has been seen previously with glial cell line–derived neurotrophic factor. Future directions include dissecting out the tropic and trophic signaling in motor neurons, developing small molecule mimics of pleiotrophin that have similar tropic and trophic activity in motor neurons, testing of adeno-associated virus-pleiotrophin in the superoxide dismutase 1 mutant model of amyotrophic lateral sclerosis (ALS), and using pleiotrophin in biodegradable nanofiber nerve guides for nerve regeneration.

ON THE NEUROPROTECTIVE PATHWAY

Dr. Höke also discussed data from his laboratory that "point to crosstalk that exists between the sensory neurons and their Schwann cells and the relevance of this crosstalk to neuroprotection or axonal protection." Models of diabetic, HIV, and chemotherapy-induced peripheral neuropathies suggest that endogenous neuroprotective pathways can be augmented by recombinant human erythropoietin; however, the potential barriers to its use in chronic conditions include increases in hematocrit and thromboembolic events. Future directions in erythropoietin-mediated neuroprotection in the peripheral nervous system include clinical trials of HIV and docetaxel neuropathy, regulation of erythropoietin signaling in Schwann cells, and seeking to understand mechanisms underlying neuroprotective signaling in neurons.

"To date, most ‘neuroprotective’ strategies have focused on rescuing the neuronal cell body or preventing cell death, but in many diseases affecting the peripheral nervous system, there is often no cell death," Dr. Höke pointed out. "Even a minimal distal degeneration of axons, mediated by local events, can lead to a functional loss of the neuron. There is a growing body of literature suggesting that mechanisms underlying cell death in neurons and axonal degeneration are different and that we need to pay attention to local events in the axon.

"Another issue that brings up the relevance of Schwann cells in neurodegenerative disorders is the realization that disorders such as ALS are likely to be noncell autonomous; ie, nonneuronal cells play an important role in disease pathogenesis," Dr. Höke continued. "Yet, most of the recent research has focused attention to CNS glia or the target tissues and ignored the Schwann cells, which have a much higher cell-to-neuron ratio. We need to consider dysfunction in Schwann cells as a potential target for investigating pathogenesis in neurodegenerative disorders affecting the peripheral nervous system."

A PROMISING FUTURE

According to Dr. Höke, the most promising treatment from this line of work "will be generation of small molecule or oligopeptide derivatives of pleiotrophin for peripheral nervous system diseases. So far, there have been many clinical trials of large molecule growth factors in diabetic neuropathy, HIV neuropathy, Parkinson’s disease, and ALS, and none of them has worked, partly because of blood-brain barrier issues and partly because dosing is difficult with large molecules. The first use of actual pleiotrophin may be in a nerve repair paradigm, where you can incorporate the whole molecule into a biodegradable nerve conduit, which will also serve as a slow-release substrate, and see its effects on nerve regeneration."

Dr. Höke anticipates that preclinical development will be completed within the next two years, after which medical device companies will be approached to conduct clinical trials.

NR

—Debra Hughes

Suggested Reading
Fu SY, Gordon T. Contributing factors to poor functional recovery after delayed nerve repair: prolonged denervation. J Neurosci. 1995;15(5 pt 2):3886-3895.
Höke A, Cornblath DR. Peripheral neuropathies in human immunodeficiency virus infection. Suppl Clin Neurophysiol. 2004;57:195-210.
Höke A, Keswani SC. Neuroprotection in the PNS: erythropoietin and immunophilin ligands. Ann N Y Acad Sci. 2005;1053:491-501.
Lyons WR, Woodhall B. Atlas of Peripheral Nerve Injuries. Philadelphia: WB Saunders; 1949.